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A Safety and Pharmacokinetics (PK) Study of Venetoclax in Participants With Non-Hodgkin's Lymphoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02055820
Recruitment Status : Completed
First Posted : February 5, 2014
Results First Posted : December 20, 2018
Last Update Posted : November 5, 2019
Sponsor:
Collaborator:
AbbVie
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Lymphoma, Non-Hodgkin
Interventions Drug: Venetoclax
Drug: Cyclophosphamide
Drug: Obinutuzumab
Drug: Rituximab
Drug: Doxorubicin
Drug: Vincristine
Drug: Prednisone
Enrollment 267
Recruitment Details

Phase I: Patients must have histologically confirmed B‑cell NHL (never received R‑CHOP treatment), except MCL or SLL.

Any relapsed/refractory patients should have received only a single previous treatment regimen

Phase II: Patients must have previously untreated CD20‑positive DLBCL and IPI score must be 2-5.

Pre-assignment Details The data reported for participant flow is based on safety population, which includes all participants who received at least one dose of study medication.
Arm/Group Title Venetoclax+R-CHOP 200 mg Venetoclax+R-CHOP 400 mg Venetoclax+R-CHOP 600 mg Venetoclax+R-CHOP 800 mg Venetoclax+R-CHOP 800 mg Phase II Venetoclax+G-CHOP 200 mg Venetoclax+G-CHOP 400 mg Venetoclax+G-CHOP 600 mg Venetoclax+G-CHOP 800 mg A Venetoclax+G-CHOP 800 mg B
Hide Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-10; Cycles 2-8 Days 1-10, Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Period Title: Phase I: Dose-Finding
Started 7 3 8 6 0 7 7 6 6 6
Completed 0 [1] 0 [1] 0 [1] 0 [1] 0 0 [1] 0 [1] 0 [1] 0 [1] 0 [1]
Not Completed 7 3 8 6 0 7 7 6 6 6
Reason Not Completed
Withdrawal by Subject             0             0             0             0             0             1             0             0             0             0
Death             1             0             1             2             0             0             0             0             0             0
Participants still in study             6             3             7             4             0             6             7             6             6             6
[1]
Study is still ongoing
Period Title: Phase II: Expansion
Started 0 0 0 0 208 0 0 0 0 0
Completed 0 0 0 0 0 [1] 0 0 0 0 0
Not Completed 0 0 0 0 208 0 0 0 0 0
Reason Not Completed
Unspecified Reason             0             0             0             0             3             0             0             0             0             0
Participants still in study             0             0             0             0             177             0             0             0             0             0
Lost to Follow-up             0             0             0             0             3             0             0             0             0             0
Withdrawal by Subject             0             0             0             0             10             0             0             0             0             0
Death             0             0             0             0             15             0             0             0             0             0
[1]
Study is still on-going
Arm/Group Title Venetoclax+R-CHOP 200 mg Venetoclax+R-CHOP 400 mg Venetoclax+R-CHOP 600 mg Venetoclax+R-CHOP 800 mg Venetoclax+R-CHOP 800 mg Phase II Venetoclax+G-CHOP 200 mg Venetoclax+G-CHOP 400 mg Venetoclax+G-CHOP 600 mg Venetoclax+G-CHOP 800 mg A Venetoclax+G-CHOP 800 mg B Total
Hide Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-10; Cycles 2-8 Days 1-10, Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Total of all reporting groups
Overall Number of Baseline Participants 7 3 8 6 211 7 7 6 6 6 267
Hide Baseline Analysis Population Description
Intent to Treat (ITT) population included all enrolled participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants 3 participants 8 participants 6 participants 211 participants 7 participants 7 participants 6 participants 6 participants 6 participants 267 participants
67.0  (9.2) 61.0  (13.1) 57.0  (9.5) 56.3  (11.9) 61.4  (12.8) 52.1  (16.2) 60.9  (6.3) 66.7  (4.2) 60.5  (13.7) 66.8  (6.7) 61.2  (12.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 3 participants 8 participants 6 participants 211 participants 7 participants 7 participants 6 participants 6 participants 6 participants 267 participants
Female
3
  42.9%
2
  66.7%
2
  25.0%
2
  33.3%
95
  45.0%
2
  28.6%
5
  71.4%
4
  66.7%
4
  66.7%
2
  33.3%
121
  45.3%
Male
4
  57.1%
1
  33.3%
6
  75.0%
4
  66.7%
116
  55.0%
5
  71.4%
2
  28.6%
2
  33.3%
2
  33.3%
4
  66.7%
146
  54.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 3 participants 8 participants 6 participants 211 participants 7 participants 7 participants 6 participants 6 participants 6 participants 267 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
4
   1.9%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
4
   1.5%
Not Hispanic or Latino
6
  85.7%
1
  33.3%
2
  25.0%
3
  50.0%
154
  73.0%
6
  85.7%
3
  42.9%
4
  66.7%
5
  83.3%
6
 100.0%
190
  71.2%
Unknown or Not Reported
1
  14.3%
2
  66.7%
6
  75.0%
3
  50.0%
53
  25.1%
1
  14.3%
4
  57.1%
2
  33.3%
1
  16.7%
0
   0.0%
73
  27.3%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 3 participants 8 participants 6 participants 211 participants 7 participants 7 participants 6 participants 6 participants 6 participants 267 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
5
   2.4%
0
   0.0%
1
  14.3%
0
   0.0%
0
   0.0%
0
   0.0%
6
   2.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
   1.4%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
   1.1%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
4
   1.9%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
4
   1.5%
White
6
  85.7%
1
  33.3%
2
  25.0%
2
  33.3%
157
  74.4%
7
 100.0%
2
  28.6%
4
  66.7%
5
  83.3%
4
  66.7%
190
  71.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
  14.3%
2
  66.7%
6
  75.0%
4
  66.7%
42
  19.9%
0
   0.0%
4
  57.1%
2
  33.3%
1
  16.7%
2
  33.3%
64
  24.0%
1.Primary Outcome
Title Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)
Hide Description DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade >/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not 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 occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was 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 were considered DLTs.
Time Frame Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population: All participants who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses. Here, participants in the Dose Finding phase were analyzed.
Arm/Group Title Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800mg Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800 mg A Venetoclax + G-CHOP 800 mg B
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Venetoclax + G-CHOP 800 mg A Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm venetoclax was delivered in Cycle 1 on Days 4-10 and Cycles 2-8 on Days 1-10. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm ventoclax was delivered in Cycle 1 on Days 4-8 and Cycles 2-8 on Days 1-5. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 7 3 8 6 7 7 6 6 6
Measure Type: Number
Unit of Measure: Participants
1 0 1 0 2 1 1 0 0
2.Primary Outcome
Title Percentage of Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC)
Hide Description CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy
Time Frame Baseline up to end of treatment (up to approximately 36 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
Hide Arm/Group Description:
Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 211
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
68.2
(61.50 to 74.47)
3.Primary Outcome
Title Percentage of Participants With CR Defined by PET/CT Scan in Dual Expressor Diffuse Large B-Cell Lymphoma (DE-DLBCL) Participants Assessed by IRC
Hide Description CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
Time Frame Baseline up to end of treatment (up to approximately 36 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
Hide Arm/Group Description:
Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 81
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
66.7
(55.32 to 76.76)
4.Secondary Outcome
Title Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)
Hide Description

AUC was calculated based on measurement of venetoclax concentration in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.

Data are reported as hour*micrograms per milliliter (hr*mcg/mL)

Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
Arm/Group Title Venetoclax + R-CHOP 800mg Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800 mg Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800mg
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I and II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 1 6 4 8 124 7 7 6 10
Mean (Standard Deviation)
Unit of Measure: hr*mcg/mL
.66 [1]   (NA) 2.51  (.97) 3.87  (2.41) 3.70  (1.59) 4.51  (2.32) 2.55  (1.13) 4.33  (1.31) 5.13  (2.41) 6.20  (1.71)
[1]
N/A as there is only one participant in this cohort
5.Secondary Outcome
Title Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)
Hide Description Tmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
Arm/Group Title Venetoclax + R-CHOP 100 mg Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800mg Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800 mg
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 1 6 4 8 124 7 7 6 10
Mean (Standard Deviation)
Unit of Measure: Hour
4.0 [1]   (NA) 4.59  (1.08) 6.50  (1.91) 5.52  (2.07) 5.53  (1.55) 5.72  (1.42) 6.56  (1.51) 5.30  (2.38) 5.79  (1.47)
[1]
N/A as there is only one participant in this cohort
6.Secondary Outcome
Title Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)
Hide Description

Cmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.

Data are reported as micrograms per milliliter

Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
Arm/Group Title Venetoclax + R-CHOP 100 mg Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800mg Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800 mg
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 1 6 4 8 124 7 7 6 10
Mean (Standard Deviation)
Unit of Measure: Ug/ML
.09 [1]   (NA) .58  (.32) .92  (.64) .85  (.33) 1.15  (.48) .52  (.21) 1.26  (.30) 1.00  (.58) 1.54  (.37)
[1]
N/A as there is only one participant in this cohort
7.Secondary Outcome
Title Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval
Hide Description Cmin was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts.
Time Frame Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Reporting according to study drug received. One participant mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.
Arm/Group Title Venetoclax + R-CHOP 100 mg Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800mg Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800 mg
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 1 3 2 4 126 7 5 5 6
Mean (Standard Deviation)
Unit of Measure: mcg/mL
0.0714  (0.00) 0.522  (0.441) 0.253  (0.247) 0.387  (0.141) 0.640  (0.451) 0.134  (0.107) 0.395  (0.381) 0.612  (0.535) 0.628  (0.395)
8.Secondary Outcome
Title Prednisone Plasma PK: AUC
Hide Description AUC was determined based on measurement of Predisone concentrations in plasma over time.
Time Frame Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All participants who received study drug and provided at least one post-treatment PK sample. A similar dose strength of prednisone (100 mg) was administered across the treatment arms/venetoclax dose groups. Hence, the data are presented as an overall summary in Cycles 1 and 2.
Arm/Group Title Venetoclax
Hide Arm/Group Description:

All participants in the study.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 54
Mean (Standard Deviation)
Unit of Measure: hr*mcg/mL
Cycle 1, Day 1 Number Analyzed 52 participants
195  (72.8)
Cycle 2, Day 1 Number Analyzed 54 participants
184  (81.2)
9.Secondary Outcome
Title Prednisone Plasma PK: Tmax
Hide Description Tmax was determined based on measurement of Predisone concentrations in plasma over time.
Time Frame Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. A similar dose strength of prednisone (100 mg) was administered across the treatment arms/venetoclax dose groups. Hence, the data are presented as an overall summary in Cycles 1 and 2.
Arm/Group Title Venetoclax
Hide Arm/Group Description:

All participants in the study.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 54
Mean (Standard Deviation)
Unit of Measure: Hour
Cycle 1, Day 1 Number Analyzed 52 participants
2.19  (1.61)
Cycle 2, Day 1 Number Analyzed 54 participants
3.80  (2.52)
10.Secondary Outcome
Title Prednisone Plasma PK: Cmax
Hide Description Cmax was determined based on measurement of Predisone concentrations in plasma over time.
Time Frame Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. A similar dose strength of prednisone (100 mg) was administered across the treatment arms/venetoclax dose groups. Hence, the data are presented as an overall summary in Cycles 1 and 2.
Arm/Group Title Venetoclax
Hide Arm/Group Description:

All participants in the study.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 54
Mean (Standard Deviation)
Unit of Measure: Ng/ML
Cycle 1, Day 1 Number Analyzed 52 participants
49.9  (28.7)
Cycle 2, Day 1 Number Analyzed 54 participants
43.2  (17.6)
11.Secondary Outcome
Title Rituximab PK: Cmax
Hide Description Cmax was determined using the post-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.
Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. The Cmax of rituximab is presented at the 800 mg Venetoclax dose group. Hence, the data is not presented by the treatment arms/Venetoclax dose groups.
Arm/Group Title Venetoclax 800 mg
Hide Arm/Group Description:

All participants in the study, who received 800 mg venetoclax.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: mcg/mL
173  (39.4)
12.Secondary Outcome
Title Rituximab PK: Cmin Within the Dosing Interval
Hide Description Cmin was determined using the pre-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose on Day 1 of Cycle 2.
Time Frame Pre-dose on Cycle 2 Day 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. The Cmin of rituximab is presented at the 800 mg Venetoclax dose group. Hence, the data is not presented by the treatment arms/Venetoclax dose groups.
Arm/Group Title Venetoclax 800 mg
Hide Arm/Group Description:

All participants in the study, who received 800 mg venetoclax.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 8
Mean (Standard Deviation)
Unit of Measure: mcg/mL
26.1  (13)
13.Secondary Outcome
Title Obinutuzumab PK: Cmax
Hide Description Cmax was determined using the post-dose obinutuzumab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1.
Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. The Cmax of obinutuzumab is presented at the 800 mg Venetoclax dose group. Hence, the data is not presented by the treatment arms/Venetoclax dose groups.
Arm/Group Title Venetoclax 800 mg
Hide Arm/Group Description:

All participants in the study, who received 800 mg venetoclax.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 10
Mean (Standard Deviation)
Unit of Measure: mcg/mL
326  (76)
14.Secondary Outcome
Title Cyclophosphamide PK: Cmax
Hide Description Cmax was determined using the post-dose Cyclophosphamide plasma concentrations on Cycle 1 Day 1.
Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Given a single dose strength of Cyclophosphamide was administered across the different Venetoclax dose groups and treatment arms, hence the data are presented as an overall summary.
Arm/Group Title Venetoclax
Hide Arm/Group Description:

All participants in the study.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 36
Mean (Standard Deviation)
Unit of Measure: mcg/mL
32.1  (7.51)
15.Secondary Outcome
Title Doxorubicin PK: Cmax
Hide Description Cmax was determined using the post-dose Doxorubicin plasma concentrations.
Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Given a single dose strength of Doxorubicin was administered across the different Venetoclax dose groups and treatment arms, hence the data are presented as an overall summary.
Arm/Group Title Venetoclax
Hide Arm/Group Description:

All participants in the study.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 24
Mean (Standard Deviation)
Unit of Measure: mcg/mL
1260  (911)
16.Secondary Outcome
Title Vincristine PK: Cmax
Hide Description Cmax was determined using the post-dose Vincristine plasma concentrations.
Time Frame End of Infusion on Cycle 1 Day 1 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample for whom data were available. Given a single dose strength of Vincristine was administered across the different Venetoclax dose groups and treatment arms, hence the data are presented as an overall summary.
Arm/Group Title Venetoclax
Hide Arm/Group Description:

All participants in the study.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Overall Number of Participants Analyzed 28
Mean (Standard Deviation)
Unit of Measure: mcg/mL
54.0  (44.6)
17.Secondary Outcome
Title Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Using the Modified Lugano Classification Assessed by IRC
Hide Description

Objective Response defined as PR (partial response) or CR (complete response) at end of treatment.

CR: Lymph nodes and extra-lymphatic sites with score 1, 2 or 3 on a 5-point scale (with a higher score being a worse outcome). No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.

PR: Lymph nodes and extralymphatic sites with score of 4 or 5 on the 5-point scale with reduced uptake compared with baseline and residual mass(es) of any size. CT-based response criteria for PR must also be met. No new lesions. In bone marrow residual uptake could be higher than in normal marrow but must be reduced compared with baseline; persistent focal changes in the marrow to be considered for further evaluation with magnetic resonance imaging (MRI) or biopsy or an interval scan. OR=PR+CR

Time Frame Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 36 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
Hide Arm/Group Description:
Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 211
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
81.5
(75.61 to 86.51)
18.Secondary Outcome
Title Percentage of Participants Who Are Alive and Without Disease Progression at Month 12
Hide Description Progressive disease (PD) was determined using the modified Lugano classification criteria. For PET-CT-based PD: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) with an increase in intensity of uptake from baseline in target nodes and nodal lesions, new FDG-uptake foci of extranodal lesions consistent with lymphoma at interim or end-of-treatment assessment, no non-measured lesions, new FDG-uptake foci consistent with lymphoma, new or recurrent FDG-uptake foci in bone marrow. For CT-based PD: >/= 50% decrease in SPD of up to 6 target measureable nodes and extranodal sites; non-measured lesion should be absent/normal, have regressed, but not increased; no new lesions.
Time Frame Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
Arm/Group Title Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800mg Venetoclax + R-CHOP 800 mg Phase II Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800 mg A Venetoclax + G-CHOP 800 mg B
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Venetoclax + G-CHOP 800 mg A Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm venetoclax was delivered in Cycle 1 on Days 4-10 and Cycles 2-8 on Days 1-10. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm ventoclax was delivered in Cycle 1 on Days 4-8 and Cycles 2-8 on Days 1-5. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 7 3 8 6 211 7 7 6 6 6
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
85.71
(59.79 to 100.00)
100.00
(100.00 to 100.00)
87.50
(64.58 to 100.00)
66.67
(28.95 to 100.00)
83.62
(76.97 to 90.27)
100.00
(100.00 to 100.00)
75.00
(32.57 to 100.00)
100.00
(100.00 to 100.00)
100.00
(100.00 to 100.00)
100.00
(100.00 to 100.00)
19.Secondary Outcome
Title Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification
Hide Description CR was defined as follows according to modified Lugano classification for CT-based response: Target nodes/nodal masses must have regressed to </= 1.5 cm in longest transverse diameter of a lesion (LDi), no extra-lymphatic sites of disease, absence of non-measured lesions, organ enlargement must have regressed to normal, no new lesions, and if the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy.
Time Frame Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 36 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population: All participants who enrolled in the study were included in the ITT population. Data reported for all participants for whom data were available.
Arm/Group Title Venetoclax + R-CHOP 800 mg Phase II
Hide Arm/Group Description:
Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 211
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
37.4
(30.89 to 44.35)
20.Secondary Outcome
Title Safety: Percentage of Participants With Adverse Events
Hide Description An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time Frame Baseline up to approximately 36 months
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population: All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses
Arm/Group Title Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800mg Venetoclax + R-CHOP 800 mg Phase II Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800 mg A Venetoclax + G-CHOP 800 mg B
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Venetoclax + G-CHOP 800 mg A Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm venetoclax was delivered in Cycle 1 on Days 4-10 and Cycles 2-8 on Days 1-10. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. In this arm ventoclax was delivered in Cycle 1 on Days 4-8 and Cycles 2-8 on Days 1-5. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 7 3 8 6 208 7 7 6 6 6
Measure Type: Number
Unit of Measure: Percentage of Participants
100.00 100.00 100.00 100.00 98.6 100.00 100.00 100.00 100.00 100.00
21.Secondary Outcome
Title Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy
Hide Description Maintenance of relative dose intensity was defined as a dose intensity of >/= 90%.
Time Frame Baseline up to Cycle 6 (cycle length = 21 days)
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Hide Analysis Population Description
Safety population: All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses. Overall R-CHOP and G-CHOP arms were analyzed for this outcome measure.
Arm/Group Title Venetoclax + R-CHOP Arm Venetoclax + G-CHOP 200mg
Hide Arm/Group Description:

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days.

Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days.

Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Overall Number of Participants Analyzed 232 32
Measure Type: Number
Unit of Measure: Percentage of participants
Cyclophosphamide Number Analyzed 229 participants 31 participants
89.5 77.4
Doxorubicin Number Analyzed 229 participants 31 participants
88.6 77.4
Vincristine Number Analyzed 232 participants 32 participants
86.6 78.1
Prednisone Number Analyzed 231 participants 32 participants
87.4 81.3
22.Secondary Outcome
Title Relative Dose Intensity of Venetoclax
Hide Description Dose intensity was categorized as < 80%, 80% to < 85%, 85% to < 90%, or >/= 90%.
Time Frame Baseline up to Cycle 6 (cycle length = 21 days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population: All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population for safety analyses
Arm/Group Title Venetoclax + R-CHOP 200 mg Venetoclax + R-CHOP 400 mg Venetoclax + R-CHOP 600 mg Venetoclax + R-CHOP 800mg Venetoclax + R-CHOP 800 mg Phase II Venetoclax + G-CHOP 200mg Venetoclax + G-CHOP 400mg Venetoclax + G-CHOP 600mg Venetoclax + G-CHOP 800 mg Venetoclax + G-CHOP 800mg B
Hide Arm/Group Description:
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days.
Overall Number of Participants Analyzed 7 3 8 6 208 7 7 6 6 6
Measure Type: Number
Unit of Measure: Percentage of Partcipants
<80% Number Analyzed 7 participants 3 participants 8 participants 6 participants 204 participants 7 participants 7 participants 6 participants 6 participants 6 participants
71.4 0.00 12.5 0.00 26.0 100.00 14.3 50.0 83.3 100.0
80-<85% Number Analyzed 7 participants 3 participants 8 participants 6 participants 204 participants 7 participants 7 participants 6 participants 6 participants 6 participants
0.00 0.00 12.5 0.00 3.4 0.00 14.3 16.7 0.00 0.00
85-<90% Number Analyzed 7 participants 3 participants 8 participants 6 participants 204 participants 7 participants 7 participants 6 participants 6 participants 6 participants
0.00 0.00 12.5 0.00 2.9 0.00 0.00 0.00 16.7 0.00
>=90% Number Analyzed 7 participants 3 participants 8 participants 6 participants 204 participants 7 participants 7 participants 6 participants 6 participants 6 participants
28.6 100.00 62.5 100.00 67.6 0.00 71.4 33.3 0.00 0.00
Time Frame Baseline up to approximately 50 months
Adverse Event Reporting Description Safety population: All participants, who were enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population.
 
Arm/Group Title Venetoclax+R-CHOP 200 mg Venetoclax+R-CHOP 400 mg Venetoclax+R-CHOP 600 mg Venetoclax+R-CHOP 800 mg Venetoclax+R-CHOP 800 mg Phase II Venetoclax+G-CHOP 200 mg Venetoclax+G-CHOP 400 mg Venetoclax+G-CHOP 600 mg Venetoclax+G-CHOP 800 mg A Venetoclax+G-CHOP 800 mg B
Hide Arm/Group Description Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase II: Participants received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-10; Cycles 2-8 Days 1-10, Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. Phase I: Participants received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Participants who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.
All-Cause Mortality
Venetoclax+R-CHOP 200 mg Venetoclax+R-CHOP 400 mg Venetoclax+R-CHOP 600 mg Venetoclax+R-CHOP 800 mg Venetoclax+R-CHOP 800 mg Phase II Venetoclax+G-CHOP 200 mg Venetoclax+G-CHOP 400 mg Venetoclax+G-CHOP 600 mg Venetoclax+G-CHOP 800 mg A Venetoclax+G-CHOP 800 mg B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/7 (14.29%)   0/3 (0.00%)   1/8 (12.50%)   2/6 (33.33%)   15/208 (7.21%)   0/7 (0.00%)   0/7 (0.00%)   0/6 (0.00%)   0/6 (0.00%)   0/6 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Venetoclax+R-CHOP 200 mg Venetoclax+R-CHOP 400 mg Venetoclax+R-CHOP 600 mg Venetoclax+R-CHOP 800 mg Venetoclax+R-CHOP 800 mg Phase II Venetoclax+G-CHOP 200 mg Venetoclax+G-CHOP 400 mg Venetoclax+G-CHOP 600 mg Venetoclax+G-CHOP 800 mg A Venetoclax+G-CHOP 800 mg B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/7 (71.43%)   2/3 (66.67%)   3/8 (37.50%)   3/6 (50.00%)   114/208 (54.81%)   5/7 (71.43%)   4/7 (57.14%)   3/6 (50.00%)   5/6 (83.33%)   5/6 (83.33%) 
Blood and lymphatic system disorders                     
Agranulocytosis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Anaemia  1  0/7 (0.00%)  1/3 (33.33%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Febrile neutropenia  1  3/7 (42.86%)  0/3 (0.00%)  1/8 (12.50%)  2/6 (33.33%)  60/208 (28.85%)  2/7 (28.57%)  2/7 (28.57%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Haemolytic anaemia  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Leukopenia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Neutropenia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  17/208 (8.17%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Thrombocytopenia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  2/6 (33.33%)  0/6 (0.00%) 
Cardiac disorders                     
Acute coronary syndrome  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Atrial fibrillation  1  1/7 (14.29%)  1/3 (33.33%)  0/8 (0.00%)  0/6 (0.00%)  6/208 (2.88%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Atrioventricular block  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Cardiac arrest  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Cardiac failure  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Cardiogenic shock  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Cardiomyopathy  1  0/7 (0.00%)  1/3 (33.33%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Myocardial ischaemia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Sinus tachycardia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Supraventricular tachycardia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Tachycardia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Eye disorders                     
Optic neuropathy  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastrointestinal disorders                     
Diarrhoea  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Diverticular perforation  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Duodenal stenosis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Dysphagia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Enterocolitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastric dilatation  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastric perforation  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastric stenosis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastric ulcer  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastric ulcer perforation  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Gastrointestinal pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Haematemesis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Ileal perforation  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Ileus  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Nausea  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Obstruction gastric  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Oesophageal stenosis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pancreatitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Rectal haemorrhage  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Small intestinal obstruction  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Stomatitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Upper gastrointestinal haemorrhage  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Vomiting  1  0/7 (0.00%)  1/3 (33.33%)  0/8 (0.00%)  0/6 (0.00%)  5/208 (2.40%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
General disorders                     
Asthenia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Fatigue  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Inflammation  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pyrexia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  7/208 (3.37%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Sudden cardiac death  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Hepatobiliary disorders                     
Bile duct stone  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Cholecystitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Cholecystitis acute  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Drug−induced liver injury  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Immune system disorders                     
Hypogammaglobulinaemia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Infections and infestations                     
Acute sinusitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Atypical pneumonia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Cellulitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Clostridium colitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Device related infection  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Diverticulitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Escherichia pyelonephritis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Escherichia urinary tract infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastroenteritis norovirus  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Herpes simplex  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Influenza  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Lower respiratory tract infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Lung infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Meningitis viral  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Nasopharyngitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Neutropenic infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Neutropenic sepsis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Oral candidiasis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Oral herpes  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pneumocystis jirovecii infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pneumocystis jirovecii pneumonia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Pneumonia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  8/208 (3.85%)  1/7 (14.29%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pneumonia respiratory syncytial viral  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pseudomonal sepsis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pseudomonas infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Respiratory tract infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Rhinovirus infection  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Root canal infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Sepsis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  7/208 (3.37%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Sinusitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Skin infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Upper respiratory tract infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Urinary tract infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Urinary tract infection pseudomonal  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Viral infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Injury, poisoning and procedural complications                     
Infusion related reaction  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Ligament rupture  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Post lumbar puncture syndrome  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Spinal fracture  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Toxicity to various agents  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Contusion  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Investigations                     
Biopsy salivary gland  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Blood potassium increased  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
C−reactive protein increased  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Metabolism and nutrition disorders                     
Decreased appetite  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Dehydration  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Diabetes mellitus inadequate control  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Hyperkalaemia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/6 (16.67%) 
Hypokalaemia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Hyponatraemia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Tumour lysis syndrome  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Musculoskeletal and connective tissue disorders                     
Back pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Joint swelling  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pain in extremity  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Spondylolisthesis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                     
Myelodysplastic syndrome  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Nervous system disorders                     
Carotid sinus syndrome  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Epilepsy  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Hypoglossal nerve paresis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Polyneuropathy  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Presyncope  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Syncope  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Transient ischaemic attack  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Psychiatric disorders                     
Confusional state  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Psychotic disorder  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Renal and urinary disorders                     
Acute kidney injury  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders                     
Cough  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Dyspnoea  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Haemoptysis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Hypoxia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Lung disorder  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Organising pneumonia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pleural effusion  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pneumothorax  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Productive cough  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pulmonary embolism  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Skin and subcutaneous tissue disorders                     
Rash maculo−papular  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Vascular disorders                     
Embolism  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Hypotension  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
1
Term from vocabulary, MedDRA version 20.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Venetoclax+R-CHOP 200 mg Venetoclax+R-CHOP 400 mg Venetoclax+R-CHOP 600 mg Venetoclax+R-CHOP 800 mg Venetoclax+R-CHOP 800 mg Phase II Venetoclax+G-CHOP 200 mg Venetoclax+G-CHOP 400 mg Venetoclax+G-CHOP 600 mg Venetoclax+G-CHOP 800 mg A Venetoclax+G-CHOP 800 mg B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   7/7 (100.00%)   3/3 (100.00%)   8/8 (100.00%)   6/6 (100.00%)   205/208 (98.56%)   7/7 (100.00%)   7/7 (100.00%)   6/6 (100.00%)   6/6 (100.00%)   6/6 (100.00%) 
Blood and lymphatic system disorders                     
Anaemia  1  4/7 (57.14%)  0/3 (0.00%)  1/8 (12.50%)  2/6 (33.33%)  72/208 (34.62%)  1/7 (14.29%)  1/7 (14.29%)  1/6 (16.67%)  5/6 (83.33%)  4/6 (66.67%) 
Febrile neutropenia  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  1/6 (16.67%)  13/208 (6.25%)  0/7 (0.00%)  4/7 (57.14%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Haemolytic anaemia  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Leukopenia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  24/208 (11.54%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Neutropenia  1  4/7 (57.14%)  2/3 (66.67%)  5/8 (62.50%)  2/6 (33.33%)  130/208 (62.50%)  2/7 (28.57%)  4/7 (57.14%)  5/6 (83.33%)  6/6 (100.00%)  2/6 (33.33%) 
Pancytopenia  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  1/6 (16.67%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Thrombocytopenia  1  4/7 (57.14%)  1/3 (33.33%)  2/8 (25.00%)  0/6 (0.00%)  54/208 (25.96%)  2/7 (28.57%)  3/7 (42.86%)  2/6 (33.33%)  4/6 (66.67%)  2/6 (33.33%) 
Cardiac disorders                     
Angina pectoris  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Atrial fibrillation  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  7/208 (3.37%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Palpitations  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  8/208 (3.85%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Tachycardia  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  3/208 (1.44%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Cardiac failure  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Congenital, familial and genetic disorders                     
Ichthyosis  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Ear and labyrinth disorders                     
Ear pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Tinnitus  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Eye disorders                     
Dry eye  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Lacrimation increased  1  2/7 (28.57%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  3/208 (1.44%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Vision blurred  1  1/7 (14.29%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  7/208 (3.37%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Photophobia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Vitreous floaters  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Eye pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Gastrointestinal disorders                     
Abdominal distension  1  2/7 (28.57%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  14/208 (6.73%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Abdominal pain  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  1/6 (16.67%)  31/208 (14.90%)  0/7 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  3/6 (50.00%)  1/6 (16.67%) 
Abdominal pain upper  1  0/7 (0.00%)  1/3 (33.33%)  1/8 (12.50%)  0/6 (0.00%)  7/208 (3.37%)  1/7 (14.29%)  1/7 (14.29%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Constipation  1  1/7 (14.29%)  2/3 (66.67%)  3/8 (37.50%)  2/6 (33.33%)  67/208 (32.21%)  6/7 (85.71%)  3/7 (42.86%)  2/6 (33.33%)  2/6 (33.33%)  1/6 (16.67%) 
Diarrhoea  1  3/7 (42.86%)  2/3 (66.67%)  2/8 (25.00%)  3/6 (50.00%)  79/208 (37.98%)  5/7 (71.43%)  3/7 (42.86%)  2/6 (33.33%)  2/6 (33.33%)  1/6 (16.67%) 
Dyspepsia  1  1/7 (14.29%)  1/3 (33.33%)  0/8 (0.00%)  1/6 (16.67%)  22/208 (10.58%)  1/7 (14.29%)  1/7 (14.29%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Dysphagia  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  7/208 (3.37%)  1/7 (14.29%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastrooesophageal reflux disease  1  1/7 (14.29%)  0/3 (0.00%)  1/8 (12.50%)  2/6 (33.33%)  6/208 (2.88%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Gingival pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Haemorrhoids  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  15/208 (7.21%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Mouth ulceration  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  6/208 (2.88%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Nausea  1  3/7 (42.86%)  2/3 (66.67%)  1/8 (12.50%)  5/6 (83.33%)  108/208 (51.92%)  3/7 (42.86%)  4/7 (57.14%)  3/6 (50.00%)  5/6 (83.33%)  4/6 (66.67%) 
Oral pain  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  3/208 (1.44%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Proctalgia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Stomatitis  1  2/7 (28.57%)  1/3 (33.33%)  1/8 (12.50%)  2/6 (33.33%)  23/208 (11.06%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%) 
Toothache  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  3/208 (1.44%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Vomiting  1  0/7 (0.00%)  1/3 (33.33%)  1/8 (12.50%)  2/6 (33.33%)  63/208 (30.29%)  5/7 (71.43%)  4/7 (57.14%)  0/6 (0.00%)  4/6 (66.67%)  1/6 (16.67%) 
Abdominal discomfort  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  3/208 (1.44%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Dental caries  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Dental cyst  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Dry mouth  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  5/208 (2.40%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  0/6 (0.00%) 
Flatulence  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Gastric ulcer  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Gastrointestinal disorder  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
General disorders                     
Asthenia  1  2/7 (28.57%)  1/3 (33.33%)  3/8 (37.50%)  0/6 (0.00%)  33/208 (15.87%)  2/7 (28.57%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Chest pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  11/208 (5.29%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Chills  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  11/208 (5.29%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Fatigue  1  5/7 (71.43%)  0/3 (0.00%)  3/8 (37.50%)  2/6 (33.33%)  80/208 (38.46%)  5/7 (71.43%)  2/7 (28.57%)  2/6 (33.33%)  3/6 (50.00%)  1/6 (16.67%) 
Gait disturbance  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Malaise  1  2/7 (28.57%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  6/208 (2.88%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Mucosal inflammation  1  1/7 (14.29%)  0/3 (0.00%)  2/8 (25.00%)  1/6 (16.67%)  20/208 (9.62%)  1/7 (14.29%)  3/7 (42.86%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Non−cardiac chest pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Oedema  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  3/208 (1.44%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Oedema peripheral  1  2/7 (28.57%)  0/3 (0.00%)  2/8 (25.00%)  0/6 (0.00%)  24/208 (11.54%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  3/6 (50.00%)  1/6 (16.67%) 
Pyrexia  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  2/6 (33.33%)  49/208 (23.56%)  0/7 (0.00%)  5/7 (71.43%)  2/6 (33.33%)  1/6 (16.67%)  2/6 (33.33%) 
Unevaluable event  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Feeling abnormal  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Influenza like illness  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Infusion site extravasation  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  6/208 (2.88%)  1/7 (14.29%)  1/7 (14.29%)  0/6 (0.00%)  1/6 (16.67%)  2/6 (33.33%) 
Hepatobiliary disorders                     
Cholelithiasis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Hyperbilirubinaemia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  3/208 (1.44%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Immune system disorders                     
Hypogammaglobulinaemia  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Hypersensitivity  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Infections and infestations                     
Anorectal infection  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Bronchitis  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  15/208 (7.21%)  0/7 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%) 
Campylobacter gastroenteritis  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Conjunctivitis  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Escherichia bacteraemia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Herpes simplex  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Nasopharyngitis  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  8/208 (3.85%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Oral candidiasis  1  2/7 (28.57%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  9/208 (4.33%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  1/6 (16.67%) 
Pneumocystis jirovecii pneumonia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/208 (0.00%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pneumonia  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  5/208 (2.40%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Pneumonia klebsiella  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Pseudomonal bacteraemia  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Upper respiratory tract infection  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  11/208 (5.29%)  2/7 (28.57%)  0/7 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  1/6 (16.67%) 
Urinary tract infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  17/208 (8.17%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Vulvovaginal candidiasis  1  1/7 (14.29%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Device related infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/6 (16.67%) 
Influenza  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Lung infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  5/208 (2.40%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Oral herpes  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  5/208 (2.40%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Candida infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Cellulitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Cellulitis orbital  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Clostridium difficile colitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Enterovirus infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Erysipelas  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Furuncle  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Oral fungal infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  2/208 (0.96%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%) 
Rhinitis  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  7/208 (3.37%)  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%) 
Sinusitis bacterial  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Skin infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  3/208 (1.44%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Staphylococcal infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Tooth abscess  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Clostridium difficile infection  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Viral upper respiratory tract infection  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Injury, poisoning and procedural complications                     
Hand fracture  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Infusion related reaction  1  1/7 (14.29%)  2/3 (66.67%)  1/8 (12.50%)  2/6 (33.33%)  44/208 (21.15%)  4/7 (57.14%)  1/7 (14.29%)  2/6 (33.33%)  2/6 (33.33%)  3/6 (50.00%) 
Muscle strain  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Thermal burn  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  1/6 (16.67%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Tracheal obstruction  1  0/7 (0.00%)  0/3 (0.00%)  1/8 (12.50%)  0/6 (0.00%)  0/208 (0.00%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%) 
Fall  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  4/208 (1.92%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Procedural pain  1  0/7 (0.00%)  0/3 (0.00%)  0/8 (0.00%)  0/6 (0.00%)  1/208 (0.48%)  0/7 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%) 
Investigations