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Study of Tazemetostat as Single Agent in Solid Tumors or B-cell Lymphomas and in Combination With Prednisolone in DLBCL

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ClinicalTrials.gov Identifier: NCT01897571
Recruitment Status : Completed
First Posted : July 12, 2013
Results First Posted : August 4, 2023
Last Update Posted : March 26, 2024
Sponsor:
Information provided by (Responsible Party):
Ipsen ( Epizyme, Inc. )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions B-cell Lymphomas (Phase 1)
Advanced Solid Tumors (Phase 1)
Diffuse Large B-cell Lymphoma (Phase 2)
Follicular Lymphoma (Phase 2)
Transformed Follicular Lymphoma
Primary Mediastinal Large B-Cell Lymphoma
Interventions Drug: Tazemetostat
Drug: Prednisolone
Enrollment 400
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Phase 1: Tazemetostat 100 mg Phase 1: Tazemetostat 200 mg Phase 1: Tazemetostat 400 mg Phase 1: Tazemetostat 800 mg Phase 1: Tazemetostat 1600 mg Phase 1: Food Effect (All Patients) Phase 1: Tazemetostat 800 mg + Midazolam 2 mg Phase 2 Group 1: Tazemetostat in Relapsed/Refractory (R/R) Follicular Lymphoma (FL) With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R Diffuse Large B-cell Lymphoma (DLBCL) Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy
Hide Arm/Group Description Patients received tazemetostat 100 milligrams (mg) tablets orally twice daily (BID) in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 200 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 400 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 1600 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 200 mg as a single oral dose on Day -8 either after fasting for 8 hours before dosing or immediately after consuming a high-fat breakfast on Day -8. Following a 7-day washout period, patients crossed over to receive the second tazemetostat 200 mg single oral dose on Day -1 in the opposite condition (fed or fasted). Patients received tazemetostat 800 mg orally BID continuously starting on Day 1, with a single oral dose of midazolam 2 mg administered on Day -1 and then on Day 15. Post Day 15, patients continued to receive tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients with R/R FL with mutant enhancer of zeste homolog 2 (EZH2) treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients with R/R DLBCL received 800 mg of tazemetostat monotherapy, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. In addition, these patients also received prednisolone 40 mg/meter square (m^2) on Days 1 to 5 and 15 to 19 from Cycle 1 to Cycle 4 post which tazemetostat monotherapy was continued.
Period Title: Overall Study
Started 6 3 3 14 12 13 13 48 54 163 71
Completed 0 1 0 5 0 0 1 16 19 20 6
Not Completed 6 2 3 9 12 13 12 32 35 143 65
Reason Not Completed
Lost to Follow-up             3             0             0             0             2             0             0             0             1             2             4
Withdrawal by Subject             0             0             0             0             0             0             0             1             4             3             1
Other             1             0             0             3             3             4             7             0             0             0             0
Enrolled in rollover study             0             0             0             0             0             0             0             9             7             9             1
Death             2             2             3             6             7             9             5             22             23             129             59
Arm/Group Title Phase 1: Tazemetostat 100 mg Phase 1: Tazemetostat 200 mg Phase 1: Tazemetostat 400 mg Phase 1: Tazemetostat 800 mg Phase 1: Tazemetostat 1600 mg Phase 1: Food Effect (All Patients) Phase 1: Tazemetostat 800 mg + Midazolam 2 mg Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy Total
Hide Arm/Group Description Patients received tazemetostat 100 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 200 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent Patients received tazemetostat 400 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent Patients received tazemetostat 1600 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 200 mg as a single oral dose on Day -8 either after fasting for 8 hours before dosing or immediately after consuming a high-fat breakfast on Day -8. Following a 7-day washout period, patients crossed over to receive the second tazemetostat 200 mg single oral dose on Day -1 in the opposite condition (fed or fasted). Patients received tazemetostat 800 mg orally BID continuously starting on Day 1, with a single oral dose of midazolam 2 mg administered on Day -1 and then on Day 15. Post Day 15, patients continued to receive tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.

Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.

Tazemetostat: Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.

Tazemetostat: Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.

Patients with R/R DLBCL received 800 mg of tazemetostat monotherapy, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.

Tazemetostat: Patients who received 800 mg of tazemetostat, BID, administered in continuous 28-day cycles.

 Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. In addition, these patients also received prednisolone 40 mg/m^2 on Days 1 to 5 and 15 to 19 from Cycle 1 to Cycle 4 post which tazemetostat monotherapy was continued. Total of all reporting groups
Overall Number of Baseline Participants 6 3 3 14 12 13 13 48 54 163 71 400
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 3 participants 3 participants 14 participants 12 participants 13 participants 13 participants 48 participants 54 participants 163 participants 71 participants 400 participants
51.5  (15.74) 55.0  (30.20) 59.0  (7.00) 56.4  (13.54) 51.6  (21.42) 53.2  (16.39) 55.0  (13.66) 62.0  (8.83) 61.1  (11.38) 63.2  (14.35) 65.4  (11.78) 61.7  (13.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 3 participants 3 participants 14 participants 12 participants 13 participants 13 participants 48 participants 54 participants 163 participants 71 participants 400 participants
Female 1 1 0 4 5 7 8 26 20 72 32 176
Male 5 2 3 10 7 6 5 22 34 91 39 224
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 3 participants 3 participants 14 participants 12 participants 13 participants 13 participants 48 participants 54 participants 163 participants 71 participants 400 participants
Hispanic or Latino 0 0 0 0 0 0 0 0 3 3 1 7
Not Hispanic or Latino 2 1 2 7 6 10 11 38 26 103 62 268
Unknown or Not Reported 4 2 1 7 6 3 2 10 25 57 8 125
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 3 participants 3 participants 14 participants 12 participants 13 participants 13 participants 48 participants 54 participants 163 participants 71 participants 400 participants
American Indian or Alaska Native 0 0 0 0 0 0 0 0 0 0 0 0
Asian 0 0 0 0 0 0 0 0 1 3 1 5
Native Hawaiian or Other Pacific Islander 0 0 0 0 0 0 0 0 0 0 0 0
Black or African American 0 0 0 0 0 0 0 0 0 0 1 1
White 2 1 2 7 6 10 11 33 15 71 28 186
More than one race 0 0 0 0 0 0 0 0 0 0 0 0
Unknown or Not Reported 4 2 1 7 6 3 2 15 38 89 41 208
1.Primary Outcome
Title Recommended Phase 2 Dose (RP2D) of Tazemetostat as a Single-Agent and in Combination With Prednisolone (Phase 1 Only)
Hide Description Recommended Phase 2 dose (RP2D) of tazemetostat as administered orally twice daily (BID), continuously in 28-day cycles in subjects with advanced solid tumors or with relapsed and/or refractory B cell lymphomas as determined by incidence, seriousness, toxicity grade, and relatedness of treatment emergent dose limiting toxicities
Time Frame The first 28-day cycle of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase 1
Hide Arm/Group Description:
Patients in the Phase 1 portion of the study. Tazemetostat: Patients who received 100 mg to 1600 mg of tazemetostat, BID, administered in continuous 28-day cycles.
Overall Number of Participants Analyzed 64
Measure Type: Number
Unit of Measure: mg BID
800
2.Primary Outcome
Title Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) (Phase 2)
Hide Description Number of patients achieving an objective response (CR or PR)/number of patients treated x 100%. ORR was calculated as the percentage of patients with a confirmed complete response (CR) or partial response (PR) relative to the total number of patients in the analysis population per response evaluation criteria in solid tumors (RECIST) version (v)1.1. Complete Response (CR) was defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be <10 millimeter (mm) in the short axis. Partial Response (PR) was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.
Time Frame Radiologic tumor assessments performed at baseline(within 28 days before start of study treatment)and every 8 weeks during Cycles 2 to 6,and then every 12 weeks thereafter until confirmed disease progression (PD)/death,a maximum of approximately 82 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy
Hide Arm/Group Description:
Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients with R/R DLBCL received 800 mg of tazemetostat monotherapy, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. In addition, these patients also received prednisolone 40 mg/m^2 on Days 1 to 5 and 15 to 19 from Cycle 1 to Cycle 4 post which tazemetostat monotherapy was continued.
Overall Number of Participants Analyzed 48 54 163 71
Measure Type: Count of Participants
Unit of Measure: Participants
34 19 30 8
3.Secondary Outcome
Title Duration of Response for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only)
Hide Description The time (in months) from the date of the initial response (CR or PR, whichever was first) until the date of the first documented disease progression per an Independent Review Committee (for Groups 1 and 2), per Investigator (Group 3), or death due to any cause. Patients who were alive and progression free at the time of the analysis were censored at the last date where the patient was known to be in response. Note: the DOR was censored, meaning data collection was stopped early for analysis, making the top limit of the 95% confidence interval not estimable (NE). Per RECIST v.1.0, CR was defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be <10 mm in the short axis. The PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.
Time Frame Radiologic tumor assessments performed at baseline (within 28 days before start of study treatment) and every 8 weeks during Cycles 2 to 6, and then every 12 weeks thereafter until confirmed PD/death, a maximum of approximately 82 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who had a complete or partial response per an Independent Review Committee. Note: the DOR for some patients was censored, meaning data collection was stopped early for analysis making the top limit of the 95% confidence interval not estimable.
Arm/Group Title Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisone in R/R DLBCL Combination Therapy
Hide Arm/Group Description:
Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients with R/R DLBCL received 800 mg of tazemetostat monotherapy, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. In addition, these patients also received prednisolone 40 mg/m^2 on Days 1 to 5 and 15 to 19 from Cycle 1 to Cycle 4 post which tazemetostat monotherapy was continued.
Overall Number of Participants Analyzed 34 19 163 71
Median (95% Confidence Interval)
Unit of Measure: months
11.3 [1] 
(7.2 to NA)
13.0 [2] 
(5.6 to NA)
5.8
(3.7 to 12.8)
5.7 [2] 
(2.1 to NA)
[1]
NA indicates that upper limit of confidence interval (CI) was not estimable due to insufficient number of participants with events at study closure.
[2]
NA indicates that upper limit of CI was not estimable due to insufficient number of participants with events at study closure.
4.Secondary Outcome
Title Progression Free Survival for Tazemetostat as a Single Agent or in Combination With Prednisolone (Phase 2 Only)
Hide Description The time (in months) from the date of first dose of tazemetostat until the earliest date of disease progression or death from any cause. Per RECIST v1.0, CR was defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be <10 mm in the short axis. The PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.
Time Frame Radiologic tumor assessments performed at baseline (within 28 days before start of study treatment) and every 8 weeks during Cycles 2 to 6, and then every 12 weeks thereafter until confirmed PD/death, a maximum of approximately 82 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who had a response event per Independent Review Committee.
Arm/Group Title Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy
Hide Arm/Group Description:
Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients with R/R DLBCL received 800 mg of tazemetostat monotherapy, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent.
Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. In addition, these patients also received prednisolone 40 mg/m^2 on Days 1 to 5 and 15 to 19 from Cycle 1 to Cycle 4 post which tazemetostat monotherapy was continued.
Overall Number of Participants Analyzed 48 54 163 71
Median (95% Confidence Interval)
Unit of Measure: months
13.8
(10.9 to 22.1)
11.1
(3.7 to 14.6)
1.9
(1.8 to 3.2)
1.8
(1.6 to 2.0)
Time Frame Treatment-emergent adverse events are reported from the first dose of study drug (Day 1) until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. A maximum of approximately 40 months for Phase 1 and 82 months for Phase 2
Adverse Event Reporting Description The safety population included all patients in the Intent-to-treat (ITT) population set who had at least 1 post-dose safety observation recorded. MedDRA v17.1 for Phase 1 and MedDRA v18.1 for Phase 2.
 
Arm/Group Title Phase 1: Tazemetostat 100 mg Phase 1: Tazemetostat 200 mg Phase 1: Tazemetostat 400 mg Phase 1: Tazemetostat 800 mg Phase 1: Tazemetostat 1600 mg Phase 1: Food Effect (All Patients) Phase 1: Tazemetostat 800 mg + Midazolam 2 mg Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy
Hide Arm/Group Description Patients received tazemetostat 100 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 200 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 400 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 1600 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 200 mg as a single oral dose on Day -8 either after fasting for 8 hours before dosing or immediately after consuming a high-fat breakfast on Day -8. Following a 7-day washout period, patients crossed over to receive the second tazemetostat 200 mg single oral dose on Day -1 in the opposite condition (fed or fasted). Patients received tazemetostat 800 mg orally BID continuously starting on Day 1, with a single oral dose of midazolam 2 mg administered on Day -1 and then on Day 15. Post Day 15, patients continued to receive tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients with R/R FL with mutant EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients with R/R FL with wild-type EZH2 treated with tazemetostat as a single agent in Phase 2 of the study. Patients received 800 mg of tazemetostat, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients with R/R DLBCL received 800 mg of tazemetostat monotherapy, orally BID, administered in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Patients received tazemetostat 800 mg tablets orally BID in continuous 28-day treatment cycles until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. In addition, these patients also received prednisolone 40 mg/m^2 on Days 1 to 5 and 15 to 19 from Cycle 1 to Cycle 4 post which tazemetostat monotherapy was continued.
All-Cause Mortality
Phase 1: Tazemetostat 100 mg Phase 1: Tazemetostat 200 mg Phase 1: Tazemetostat 400 mg Phase 1: Tazemetostat 800 mg Phase 1: Tazemetostat 1600 mg Phase 1: Food Effect (All Patients) Phase 1: Tazemetostat 800 mg + Midazolam 2 mg Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy
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 (%) Affected / at Risk (%)
Total   2/6 (33.33%)   2/3 (66.67%)   3/3 (100.00%)   6/14 (42.86%)   7/12 (58.33%)   9/13 (69.23%)   5/13 (38.46%)   22/48 (45.83%)   23/54 (42.59%)   129/163 (79.14%)   59/71 (83.10%) 
Hide Serious Adverse Events
Phase 1: Tazemetostat 100 mg Phase 1: Tazemetostat 200 mg Phase 1: Tazemetostat 400 mg Phase 1: Tazemetostat 800 mg Phase 1: Tazemetostat 1600 mg Phase 1: Food Effect (All Patients) Phase 1: Tazemetostat 800 mg + Midazolam 2 mg Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy
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 (%) Affected / at Risk (%)
Total   1/6 (16.67%)   1/3 (33.33%)   2/3 (66.67%)   2/14 (14.29%)   5/12 (41.67%)   6/13 (46.15%)   2/13 (15.38%)   14/48 (29.17%)   16/54 (29.63%)   84/163 (51.53%)   47/71 (66.20%) 
Blood and lymphatic system disorders                       
Anaemia † 1  0/6 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  2/54 (3.70%)  3/163 (1.84%)  3/71 (4.23%) 
Thrombocytopenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  2/12 (16.67%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  8/163 (4.91%)  7/71 (9.86%) 
Febrile neutropenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  2/71 (2.82%) 
Neutropenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  12/163 (7.36%)  7/71 (9.86%) 
Histiocytosis haematophagic † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Lymphopenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  1/71 (1.41%) 
Pancytopenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Cardiac disorders                       
Arrhythmia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Atrial fibrillation † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Cardiac failure † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Diastolic dysfunction † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Pericardial effusion † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Pericarditis constrictive † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Tachycardia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Endocrine disorders                       
Hypercalcaemia of malignancy † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Gastrointestinal disorders                       
Abdominal pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  5/163 (3.07%)  1/71 (1.41%) 
Pancreatitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  1/13 (7.69%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Ascites † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  1/54 (1.85%)  0/163 (0.00%)  1/71 (1.41%) 
Constipation † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Diarrhoea † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Duodenal obstruction † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Gastric disorder † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Gastric ulcer † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Gastric ulcer perforation † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Gastrointestinal haemorrhage † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  1/71 (1.41%) 
Intestinal obstruction † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Large intestinal obstruction † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Melaena † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Nausea † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Pancreatitis acute † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  1/71 (1.41%) 
Small intestinal haemorrhage † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Small intestinal obstruction † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Subileus † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Vomiting † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  1/163 (0.61%)  0/71 (0.00%) 
General disorders                       
General physical health deterioration † 1  0/6 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  2/13 (15.38%)  0/13 (0.00%)  0/48 (0.00%)  2/54 (3.70%)  9/163 (5.52%)  8/71 (11.27%) 
Asthenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Pyrexia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  1/163 (0.61%)  3/71 (4.23%) 
Oedema peripheral † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  1/71 (1.41%) 
Generalised oedema † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Axillary pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Breakthrough pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Chills † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Fatigue † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Malaise † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Non-cardiac chest pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  2/71 (2.82%) 
Pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Hepatobiliary disorders                       
Bile duct obstruction † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Jaundice † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Jaundice cholestatic † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Portal hypertension † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Infections and infestations                       
Sepsis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  2/12 (16.67%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  1/54 (1.85%)  1/163 (0.61%)  2/71 (2.82%) 
Device related infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Empyema † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Lung infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  2/163 (1.23%)  1/71 (1.41%) 
Septic shock † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Pneumonia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  2/71 (2.82%) 
Herpes zoster † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Pneumocystis jirovecii pneumonia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Bronchitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
Bronchopneumonia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
Clostridium difficile colitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Clostridium difficile infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Encephalitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Febrile infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Influenza † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Lower respiratory tract infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  2/71 (2.82%) 
Neutropenic sepsis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Oesophageal candidiasis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Oral candidiasis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Respiratory syncytial virus infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Rhinovirus infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Skin infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Urinary tract infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Urosepsis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Injury, poisoning and procedural complications                       
Femoral neck fracture † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Hip fracture † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Post lumbar puncture syndrome † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Toxicity to various agents † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Investigations                       
Amylase increased † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Blood creatinine increased † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Blood uric acid increased † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Creatinine renal clearance abnormal † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Liver function test abnormal † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Neutrophil count decreased † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
General physical condition abnormal † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  1/71 (1.41%) 
Metabolism and nutrition disorders                       
Decreased appetite † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Dehydration † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Hyperamylasaemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Hypercalcaemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Hyperglycaemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
Hyperuricaemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  1/163 (0.61%)  1/71 (1.41%) 
Hypocalcaemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Hyponatraemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Lactic acidosis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Hypokalaemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  1/163 (0.61%)  0/71 (0.00%) 
Musculoskeletal and connective tissue disorders                       
Musculoskeletal pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Back Pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  3/163 (1.84%)  2/71 (2.82%) 
Bone pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Pain in extremity † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
Pain in jaw † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                       
Tumor pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Cancer pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  2/71 (2.82%) 
Acute myeloid leukaemia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Adenocarcinoma pancreas † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Lymphoma transformation † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Malignant melanoma † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Metastases to lung † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Myelodysplastic syndrome † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Tumour haemorrhage † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Nervous system disorders                       
Cervicobrachial syndrome † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  1/13 (7.69%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Neuralgia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
Osmotic demyelination syndrome † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Post herpetic neuralgia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Syncope † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Transient global amnesia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Cerebrovascular accident † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Dizziness † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  1/54 (1.85%)  0/163 (0.00%)  0/71 (0.00%) 
Encephalopathy † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Headache † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Lethargy † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Nervous system disorder † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Sciatica † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
Spinal cord compression † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
8th nerve paralysis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Psychiatric disorders                       
Anxiety † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Depression † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Confusional state † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Renal and urinary disorders                       
Renal colic † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Renal failure acute † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Renal failure chronic † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Anuria † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Haematuria † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Renal failure † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
Reproductive system and breast disorders                       
Pelvic pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Prostatitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Respiratory, thoracic and mediastinal disorders                       
Pulmonary embolism † 1  1/6 (16.67%)  0/3 (0.00%)  1/3 (33.33%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Respiratory distress † 1  0/6 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/14 (0.00%)  0/12 (0.00%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Acute respiratory distress syndrome † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Dyspnoea † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Hypoxia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Pleural effusion † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Acute pulmonary oedema † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Cough † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  2/71 (2.82%) 
Dyspnoea exertional † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Lung disorder † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Mediastinal disorder † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Pneumonitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  1/71 (1.41%) 
Respiratory failure † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Tonsillar hypertrophy † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Surgical and medical procedures                       
Pain management † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/12 (8.33%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Vascular disorders                       
Orthostatic hypotension † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  1/13 (7.69%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  0/71 (0.00%) 
Femoral artery occlusion † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Subclavian vein thrombosis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  1/48 (2.08%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Hypotension † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  1/163 (0.61%)  1/71 (1.41%) 
Superior vena cava syndrome † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  2/163 (1.23%)  0/71 (0.00%) 
1
Term from vocabulary, CTCAE v 4.03
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1: Tazemetostat 100 mg Phase 1: Tazemetostat 200 mg Phase 1: Tazemetostat 400 mg Phase 1: Tazemetostat 800 mg Phase 1: Tazemetostat 1600 mg Phase 1: Food Effect (All Patients) Phase 1: Tazemetostat 800 mg + Midazolam 2 mg Phase 2 Group 1: Tazemetostat in R/R FL With Mutant EZH2 Phase 2 Group 2: Tazemetostat in R/R FL With Wild-Type EZH2 Phase 2 Group 3: Tazemetostat in R/R DLBCL Monotherapy Phase 2 Group 4: Tazemetostat + Prednisolone in R/R DLBCL Combination Therapy
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 (%) Affected / at Risk (%)
Total   6/6 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   12/14 (85.71%)   11/12 (91.67%)   12/13 (92.31%)   13/13 (100.00%)   46/48 (95.83%)   53/54 (98.15%)   147/163 (90.18%)   56/71 (78.87%) 
Blood and lymphatic system disorders                       
Anaemia † 1  1/6 (16.67%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  1/12 (8.33%)  2/13 (15.38%)  6/13 (46.15%)  3/48 (6.25%)  10/54 (18.52%)  25/163 (15.34%)  13/71 (18.31%) 
Thrombocytopenia † 1  1/6 (16.67%)  0/3 (0.00%)  0/3 (0.00%)  3/14 (21.43%)  1/12 (8.33%)  4/13 (30.77%)  1/13 (7.69%)  4/48 (8.33%)  5/54 (9.26%)  37/163 (22.70%)  13/71 (18.31%) 
Neutropenia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  2/12 (16.67%)  1/13 (7.69%)  0/13 (0.00%)  4/48 (8.33%)  4/54 (7.41%)  16/163 (9.82%)  7/71 (9.86%) 
Gastrointestinal disorders                       
Nausea † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  6/12 (50.00%)  3/13 (23.08%)  2/13 (15.38%)  10/48 (20.83%)  14/54 (25.93%)  36/163 (22.09%)  9/71 (12.68%) 
Vomiting † 1  1/6 (16.67%)  1/3 (33.33%)  0/3 (0.00%)  3/14 (21.43%)  1/12 (8.33%)  2/13 (15.38%)  4/13 (30.77%)  5/48 (10.42%)  7/54 (12.96%)  23/163 (14.11%)  12/71 (16.90%) 
Constipation † 1  1/6 (16.67%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  2/12 (16.67%)  3/13 (23.08%)  3/13 (23.08%)  5/48 (10.42%)  3/54 (5.56%)  14/163 (8.59%)  4/71 (5.63%) 
Diarrhoea † 1  2/6 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  2/12 (16.67%)  0/13 (0.00%)  1/13 (7.69%)  11/48 (22.92%)  10/54 (18.52%)  28/163 (17.18%)  11/71 (15.49%) 
Abdominal pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/14 (21.43%)  0/12 (0.00%)  2/13 (15.38%)  1/13 (7.69%)  8/48 (16.67%)  5/54 (9.26%)  12/163 (7.36%)  12/71 (16.90%) 
Abdominal pain upper † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  5/48 (10.42%)  2/54 (3.70%)  8/163 (4.91%)  2/71 (2.82%) 
General disorders                       
Asthenia † 1  4/6 (66.67%)  1/3 (33.33%)  1/3 (33.33%)  10/14 (71.43%)  4/12 (33.33%)  7/13 (53.85%)  7/13 (53.85%)  7/48 (14.58%)  12/54 (22.22%)  16/163 (9.82%)  15/71 (21.13%) 
Oedema peripheral † 1  0/6 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/14 (0.00%)  0/12 (0.00%)  2/13 (15.38%)  1/13 (7.69%)  5/48 (10.42%)  3/54 (5.56%)  12/163 (7.36%)  8/71 (11.27%) 
Pyrexia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  3/12 (25.00%)  0/13 (0.00%)  0/13 (0.00%)  2/48 (4.17%)  8/54 (14.81%)  25/163 (15.34%)  7/71 (9.86%) 
Fatigue † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  9/48 (18.75%)  9/54 (16.67%)  23/163 (14.11%)  7/71 (9.86%) 
Infections and infestations                       
Urinary tract infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  1/12 (8.33%)  1/13 (7.69%)  2/13 (15.38%)  5/48 (10.42%)  2/54 (3.70%)  12/163 (7.36%)  3/71 (4.23%) 
Bronchitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/14 (21.43%)  0/12 (0.00%)  0/13 (0.00%)  1/13 (7.69%)  6/48 (12.50%)  9/54 (16.67%)  10/163 (6.13%)  5/71 (7.04%) 
Upper respiratory tract infection † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  13/48 (27.08%)  7/54 (12.96%)  8/163 (4.91%)  1/71 (1.41%) 
Nasopharyngitis † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  4/48 (8.33%)  5/54 (9.26%)  6/163 (3.68%)  2/71 (2.82%) 
Metabolism and nutrition disorders                       
Decreased appetite † 1  1/6 (16.67%)  1/3 (33.33%)  1/3 (33.33%)  3/14 (21.43%)  2/12 (16.67%)  3/13 (23.08%)  3/13 (23.08%)  6/48 (12.50%)  2/54 (3.70%)  13/163 (7.98%)  10/71 (14.08%) 
Hypophosphataemia † 1  1/6 (16.67%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  0/12 (0.00%)  2/13 (15.38%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Musculoskeletal and connective tissue disorders                       
Muscle spasms † 1  2/6 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  6/14 (42.86%)  2/12 (16.67%)  1/13 (7.69%)  3/13 (23.08%)  4/48 (8.33%)  6/54 (11.11%)  7/163 (4.29%)  2/71 (2.82%) 
Back pain † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  1/12 (8.33%)  2/13 (15.38%)  0/13 (0.00%)  7/48 (14.58%)  6/54 (11.11%)  16/163 (9.82%)  4/71 (5.63%) 
Nervous system disorders                       
Dysgeusia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  4/12 (33.33%)  0/13 (0.00%)  1/13 (7.69%)  6/48 (12.50%)  2/54 (3.70%)  7/163 (4.29%)  2/71 (2.82%) 
Headache † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  6/48 (12.50%)  8/54 (14.81%)  7/163 (4.29%)  2/71 (2.82%) 
Psychiatric disorders                       
Insomnia † 1  1/6 (16.67%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  1/12 (8.33%)  1/13 (7.69%)  1/13 (7.69%)  4/48 (8.33%)  3/54 (5.56%)  5/163 (3.07%)  0/71 (0.00%) 
Respiratory, thoracic and mediastinal disorders                       
Dyspnoea † 1  1/6 (16.67%)  0/3 (0.00%)  1/3 (33.33%)  1/14 (7.14%)  2/12 (16.67%)  2/13 (15.38%)  2/13 (15.38%)  3/48 (6.25%)  6/54 (11.11%)  7/163 (4.29%)  2/71 (2.82%) 
Cough † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  2/12 (16.67%)  1/13 (7.69%)  1/13 (7.69%)  7/48 (14.58%)  11/54 (20.37%)  32/163 (19.63%)  6/71 (8.45%) 
Dyspnoea exertional † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  2/12 (16.67%)  0/13 (0.00%)  0/13 (0.00%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Skin and subcutaneous tissue disorders                       
Dry skin † 1  1/6 (16.67%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  1/12 (8.33%)  2/13 (15.38%)  2/13 (15.38%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Night sweats † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/14 (21.43%)  1/12 (8.33%)  0/13 (0.00%)  1/13 (7.69%)  0/48 (0.00%)  0/54 (0.00%)  0/163 (0.00%)  0/71 (0.00%) 
Alopecia † 1  0/6 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/12 (0.00%)  0/13 (0.00%)  0/13 (0.00%)  11/48 (22.92%)  7/54 (12.96%)  6/163 (3.68%)  2/71 (2.82%) 
1
Term from vocabulary, CTCAE v 4.03
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Lead or Designee
Organization: Epizyme, Inc.
Phone: (855) 500-1011
EMail: clinicaltrials@epizyme.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Ipsen ( Epizyme, Inc. )
ClinicalTrials.gov Identifier: NCT01897571    
Other Study ID Numbers: E7438-G000-101
2012-004083-21 ( EudraCT Number )
First Submitted: June 21, 2013
First Posted: July 12, 2013
Results First Submitted: November 15, 2022
Results First Posted: August 4, 2023
Last Update Posted: March 26, 2024