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Safety Study of PLX108-01 in Patients With Solid Tumors

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: NCT01004861
Recruitment Status : Active, not recruiting
First Posted : October 30, 2009
Results First Posted : April 6, 2020
Last Update Posted : January 12, 2021
Sponsor:
Collaborator:
Plexxikon
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Solid Tumor
Intervention Drug: PLX3397
Enrollment 132
Recruitment Details The dose escalation phase administered ascending daily oral doses of PLX3397 to patients with solid tumors and evaluated PK and toxicity. Once the recommended phase 2 dose was reached, 6 extension cohorts were enrolled, consisting of a variety of tumor types.
Pre-assignment Details At least 3 participants and up to 6 participants were to be enrolled in each dose level using 100% dose increments for each level in the absence of Grade 2 or greater drug-attributable toxicity. Dose escalation was only permitted if adequate safety and tolerability were observed at the previous lower dose for 28 days for the first 3 participants.
Arm/Group Title Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) Dose Extension: MEC Cohort 1000 mg/Day (600mg AM, 400mg PM) Dose Extension: PVNS Cohort PVNS Cohort 1000 mg/Day (600mg A Dose Extension: GIST Cohort 1000 mg/Day (600mg AM, 400mg PM) Dose Extension: ATC Cohort 1000 mg/Day (600mg AM, 400mg PM) Dose Extension: Malignant Effusion Cohort 1000 mg/Day (600mg A Dose Extension: Other Tumors 1000 mg/Day (600mg AM, 400mg PM)
Hide Arm/Group Description Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day. Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day. Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day. Participants with advanced or recurrent mucoepidermoid carcinoma (MEC) who received PLX3397. Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397. Participants with advanced gastrointestinal stromal tumor (GIST) who received PLX3397. Participants with anaplastic thyroid carcinoma (ATC) who received PLX3397. Participants with advanced solid tumors with malignant effusion who received PLX3397. Participants with other solid tumor types who received PLX3397.
Period Title: Overall Study
Started 3 6 6 6 7 6 7 4 39 11 9 8 20
Completed 0 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 3 6 6 6 7 6 7 4 39 11 9 8 20
Reason Not Completed
Disease progression             3             4             5             4             4             4             5             1             4             7             6             3             8
Physician Decision             0             2             1             1             1             0             0             1             0             0             0             0             3
Adverse Event             0             0             0             1             0             2             1             1             13             1             1             0             2
Protocol Violation             0             0             0             0             1             0             0             0             0             0             0             0             0
Withdrawal by Subject             0             0             0             0             1             0             1             0             2             1             1             2             3
Lost to Follow-up             0             0             0             0             0             0             0             1             1             0             0             1             0
Non-compliance             0             0             0             0             0             0             0             0             5             0             0             0             1
Other             0             0             0             0             0             0             0             0             1             2             1             2             3
Ongoing (as of 31 Jan 2018)             0             0             0             0             0             0             0             0             13             0             0             0             0
Arm/Group Title Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day Dose Escalation Cohort 6: 1200 mg/Day Dose Escalation Cohort 7: 1000 mg/Day Dose Extension: MEC Cohort Dose Extension: PVNS Cohort Dose Extension: GIST Cohort Dose Extension: ATC Cohort Dose Extension: Malignant Effusion Cohort Dose Extension: Other Solid Tumor Type Cohort Total
Hide Arm/Group Description Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day. Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day. Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day. Participants with advanced mucoepidermoid carcinoma (MEC) who received PLX3397. Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397. Participants with advanced gastrointestinal stromal tumor (GIS) who received PLX3397. Participants with anaplastic thyroid carcinoma (ATC) who received PLX3397. Participants with advanced solid tumors with malignant effusion who received PLX3397. Participants with other solid tumor types who received PLX3397. Total of all reporting groups
Overall Number of Baseline Participants 3 6 6 6 7 6 7 4 39 11 9 8 20 132
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 6 participants 6 participants 6 participants 7 participants 6 participants 7 participants 4 participants 39 participants 11 participants 9 participants 8 participants 20 participants 132 participants
<=18 years
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%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
2
  66.7%
2
  33.3%
2
  33.3%
3
  50.0%
5
  71.4%
3
  50.0%
5
  71.4%
4
 100.0%
37
  94.9%
8
  72.7%
3
  33.3%
4
  50.0%
15
  75.0%
93
  70.5%
>=65 years
1
  33.3%
4
  66.7%
4
  66.7%
3
  50.0%
2
  28.6%
3
  50.0%
2
  28.6%
0
   0.0%
2
   5.1%
3
  27.3%
6
  66.7%
4
  50.0%
5
  25.0%
39
  29.5%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 6 participants 6 participants 6 participants 7 participants 6 participants 7 participants 4 participants 39 participants 11 participants 9 participants 8 participants 20 participants 132 participants
62.7  (10.1) 65.7  (2.3) 63.5  (8.6) 61.5  (19.1) 52.3  (15.0) 56.3  (17.1) 50.4  (19.8) 47.3  (18.4) 45.1  (14.0) 57.6  (12.1) 65.9  (14.7) 58.1  (13.3) 52.0  (15.1) 58.3  (14.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 6 participants 6 participants 6 participants 7 participants 6 participants 7 participants 4 participants 39 participants 11 participants 9 participants 8 participants 20 participants 132 participants
Female
2
  66.7%
4
  66.7%
3
  50.0%
3
  50.0%
4
  57.1%
3
  50.0%
6
  85.7%
1
  25.0%
22
  56.4%
6
  54.5%
4
  44.4%
5
  62.5%
5
  25.0%
68
  51.5%
Male
1
  33.3%
2
  33.3%
3
  50.0%
3
  50.0%
3
  42.9%
3
  50.0%
1
  14.3%
3
  75.0%
17
  43.6%
5
  45.5%
5
  55.6%
3
  37.5%
15
  75.0%
64
  48.5%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 3 participants 6 participants 6 participants 6 participants 7 participants 6 participants 7 participants 4 participants 39 participants 11 participants 9 participants 8 participants 20 participants 132 participants
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  16.7%
0
   0.0%
0
   0.0%
3
   7.7%
0
   0.0%
1
  11.1%
0
   0.0%
0
   0.0%
5
   3.8%
White
3
 100.0%
6
 100.0%
6
 100.0%
6
 100.0%
7
 100.0%
5
  83.3%
7
 100.0%
4
 100.0%
33
  84.6%
10
  90.9%
8
  88.9%
8
 100.0%
18
  90.0%
121
  91.7%
Black of African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
   7.7%
0
   0.0%
0
   0.0%
0
   0.0%
1
   5.0%
4
   3.0%
Native Hawaiian or Other Pacific Islander
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%
0
   0.0%
1
   5.0%
1
   0.8%
Multiple races
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%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 3 participants 6 participants 6 participants 6 participants 7 participants 6 participants 7 participants 4 participants 39 participants 11 participants 9 participants 8 participants 20 participants 132 participants
3 6 6 6 7 6 7 4 39 11 9 8 20 41
1.Primary Outcome
Title Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population)
Hide Description

Best overall tumor response (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]) is reported, including participants who were not evaluable (NE).

RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
Best overall tumor response was assessed in the Efficacy Evaluable Population.
Arm/Group Title Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) All Participants
Hide Arm/Group Description:
Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day.
All participants with advanced, incurable, solid tumors who received PL3397.
Overall Number of Participants Analyzed 3 5 5 5 6 5 6 35
Measure Type: Count of Participants
Unit of Measure: Participants
Censored participants
0
   0.0%
1
  20.0%
2
  40.0%
0
   0.0%
3
  50.0%
0
   0.0%
3
  50.0%
9
  25.7%
CR
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
PR
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  16.7%
1
   2.9%
SD
0
   0.0%
1
  20.0%
0
   0.0%
2
  40.0%
3
  50.0%
1
  20.0%
1
  16.7%
8
  22.9%
PD
3
 100.0%
4
  80.0%
3
  60.0%
3
  60.0%
2
  33.3%
4
  80.0%
3
  50.0%
22
  62.9%
NE
0
   0.0%
0
   0.0%
2
  40.0%
0
   0.0%
1
  16.7%
0
   0.0%
1
  16.7%
4
  11.4%
2.Primary Outcome
Title Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population)
Hide Description

Best overall tumor response (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]) is reported, including participants who were not evaluable (NE).

RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose)
Hide Outcome Measure Data
Hide Analysis Population Description
Best overall tumor response was assessed in the Efficacy Evaluable Population.
Arm/Group Title Dose Extension: MEC Cohort Dose Extension: PVNS Cohort Dose Extension: GIST Cohort Dose Extension: ATC Cohort Dose Extension: Malignant Effusion Cohort Dose Extension: Other Solid Tumor Type Cohort
Hide Arm/Group Description:
Participants with advanced mucoepidermoid carcinoma (MEC) who received PLX3397.
Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397.
Participants with advanced gastrointestinal stromal tumor (GIST) who received PLX3397.
Participants with anaplastic thyroid carcinoma (ATC) who received PLX3397.
Participants with advanced solid tumors with malignant effusion who received PLX3397.
Participants with other solid tumor types who received PLX3397.
Overall Number of Participants Analyzed 2 37 9 6 6 14
Measure Type: Count of Participants
Unit of Measure: Participants
CR 0 2 0 0 0 0
PR 0 22 0 0 0 1
SD 1 8 4 0 3 7
PD 1 1 5 6 2 6
NE 0 4 0 0 1 0
Overall response rate (CR or PR) 0 24 0 0 0 1
3.Primary Outcome
Title Duration of Response (Efficacy Evaluable Population) - Dose Extension
Hide Description Duration of Response (DOR) is defined as the number of days from the date of initial response (CR or PR confirmed at least 28 days later) to the date of first documented disease progression/relapse or death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, DOR is censored as of the date of their last imaging exam of target or non-target lesions prior to post-surgery and/or off-treatment scans.
Time Frame From initial response until disease progression or death, up to approximately 30 months postdose
Hide Outcome Measure Data
Hide Analysis Population Description
Duration of response was assessed among participants with response of CR or PR in the Efficacy Evaluable Population.
Arm/Group Title Dose Extension: MEC Cohort Dose Extension: PVNS Cohort Dose Extension: GIST Cohort Dose Extension: ATC Cohort Dose Extension: Malignant Effusion Cohort Dose Extension: Other Solid Tumor Type Cohort
Hide Arm/Group Description:
Participants with advanced mucoepidermoid carcinoma (MEC) who received PLX3397.
Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397.
Participants with advanced gastrointestinal stromal tumor (GIS) who received PLX3397.
Participants with anaplastic thyroid carcinoma (ATC) who received PLX3397.
Participants with advanced solid tumors with malignant effusion who received PLX3397.
Participants with other solid tumor types who received PLX3397.
Overall Number of Participants Analyzed 0 24 0 0 0 1
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(943 to NA)
115 [2] 
(NA to NA)
[1]
Lack of median value is due to <50% of the participants experiencing the event. In a Kaplan-Meir analysis, the curve would never fall below the 50% mark, and would continue to the largest observed censored time value.
[2]
There were not enough events to estimate a 95% confidence interval for the median survival time.
4.Primary Outcome
Title Progression-free Survival (Efficacy Evaluable Population) - Dose Extension
Hide Description Progression-Free Survival (PFS) is defined as the number of days from the first day of treatment to the first documented disease progression or date of death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, PFS is censored at the date of last evaluable tumor assessment.
Time Frame From Cycle 1 Day 1 to disease progression or death
Hide Outcome Measure Data
Hide Analysis Population Description
Progression-free survival was assessed in the Efficacy Evaluable Population.
Arm/Group Title Dose Extension: MEC Cohort Dose Extension: PVNS Cohort Dose Extension: GIST Cohort Dose Extension: ATC Cohort Dose Extension: Malignant Effusion Cohort Dose Extension: Other Solid Tumor Type Cohort
Hide Arm/Group Description:
Participants with advanced mucoepidermoid carcinoma (MEC) who received PLX3397.
Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397.
Participants with advanced gastrointestinal stromal tumor (GIST) who received PLX3397.
Participants with anaplastic thyroid carcinoma (ATC) who received PLX3397.
Participants with advanced solid tumors with malignant effusion who received PLX3397.
Participants with other solid tumor types who received PLX3397.
Overall Number of Participants Analyzed 2 37 9 6 6 14
Median (95% Confidence Interval)
Unit of Measure: days
NA [1] 
(43 to NA)
NA [1] 
(667 to NA)
54
(40 to 164)
50
(34 to 56)
78 [2] 
(51 to NA)
161
(54 to 504)
[1]
Insufficient number of events; Lack of median value is due to 50% or fewer participants experiencing the event. In a Kaplan-Meier analysis, the curve would never fall below the 50% mark, and would continue to the largest observed censored time value.
[2]
Missing upper bound is related to right-censored data. Last time point censored and estimate is essentially infinity, therefore it is NA.
5.Primary Outcome
Title Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension
Hide Description

Best overall tumor response (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]) is reported, including participants who were not evaluable (NE).

RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum). In addition, the sum must also demonstrate an absolute increase of at least 5 mm; SD, Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time Frame Every 2 months beginning Cycle 3, Day 1 until disease progression
Hide Outcome Measure Data
Hide Analysis Population Description
Best overall tumor response was assessed in the Efficacy Evaluable Population.
Arm/Group Title PVNS Cohort
Hide Arm/Group Description:
Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397.
Overall Number of Participants Analyzed 37
Measure Type: Count of Participants
Unit of Measure: Participants
CR
2
   5.4%
PR
22
  59.5%
SD
8
  21.6%
PD
1
   2.7%
NE
4
  10.8%
Overall response rate (CR or PR)
24
  64.9%
6.Primary Outcome
Title Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation
Hide Description Cycle 1 Day 15 pharmacokinetic (PK) timepoints taken are: For once daily (QD) dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For twice a day (BID) dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.
Time Frame Cycle 1, Day 15
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Hide Analysis Population Description
Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
Arm/Group Title Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)
Hide Arm/Group Description:
Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day.
Overall Number of Participants Analyzed 3 5 5 5 6 5 6
Median (Full Range)
Unit of Measure: ng/mL
1730
(1460 to 2900)
3630
(1360 to 5300)
3160
(2140 to 5210)
6570
(4000 to 14300)
6290
(5520 to 10400)
10600
(5070 to 12500)
6320
(5920 to 10100)
7.Primary Outcome
Title Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation
Hide Description Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.
Time Frame Cycle 1, Day 15
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Hide Analysis Population Description
Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
Arm/Group Title Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)
Hide Arm/Group Description:
Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day.
Overall Number of Participants Analyzed 3 5 5 5 6 5 6
Median (Full Range)
Unit of Measure: hour
2.00
(1.08 to 4.00)
1.97
(0.58 to 2.03)
0.98
(0.50 to 2.20)
1.04
(0.50 to 2.03)
2.00
(0 to 2.03)
1.05
(1.00 to 4.17)
2.03
(0 to 6.95)
8.Primary Outcome
Title Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation
Hide Description Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing, predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.
Time Frame Cycle 1, Day 15 (QD dosing: predose [morning] and 0.5, 1, 2, 4, and 8 hours postdose; BID dosing: predose [morning] and 1, 2, 4, and 7 hours postdose)
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Hide Analysis Population Description
Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
Arm/Group Title Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)
Hide Arm/Group Description:
Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD.
Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day.
Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day.
Overall Number of Participants Analyzed 3 5 5 5 6 5 6
Median (Full Range)
Unit of Measure: ng*hr/mL
26200
(13200 to 37100)
50400
(19500 to 83100)
40500
(29500 to 57300)
81000
(74300 to 166000)
107000
(68400 to 139000)
173000
(80200 to 190000)
115000
(105000 to 226000)
9.Primary Outcome
Title Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension
Hide Description The NRS for PVNS Symptoms instrument is a 5-item self-administered questionnaire to assess the "worst" of each of the symptoms pain, swelling, stiffness, instability and limited motion in the last 24 hours. A 0 to 10 NRS is provided for each symptom. For pain, 0 indicates "no pain" and 10 indicates "pain as bad as you can imagine". For the other 4 symptoms, 0 indicates "no (symptom)" and 10 indicates "(symptom) worst imaginable", e.g., "swelling - worst imaginable." Higher scores indicated worse outcome.
Time Frame Baseline, Cycle 1 Day 15, Cycle 2, Cycle 3, Cycle 12, Cycle 24, and Cycle 36
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Hide Analysis Population Description
NRS for PVNS symptoms were assessed in the Efficacy Evaluable Population.
Arm/Group Title NRS for PVNS Symptoms Evaluable Population
Hide Arm/Group Description:
Participants who were administered the NRS scale at baseline and monthly on treatment.
Overall Number of Participants Analyzed 39
Mean (Standard Deviation)
Unit of Measure: units on a scale
Pain; Baseline Number Analyzed 21 participants
5.2  (2.1)
Pain; Cycle 1 Day 15 Number Analyzed 21 participants
3.5  (2.9)
Pain; Cycle 2 Number Analyzed 21 participants
3.6  (2.6)
Pain; Cycle 3 Number Analyzed 20 participants
2.3  (1.9)
Pain; Cycle 12 Number Analyzed 16 participants
1.5  (1.9)
Pain; Cycle 24 Number Analyzed 11 participants
1.5  (1.4)
Pain; Cycle 36 Number Analyzed 10 participants
1.9  (2.7)
Swelling; Baseline Number Analyzed 21 participants
4.7  (2.9)
Swelling; Cycle 1 Day 15 Number Analyzed 21 participants
3.1  (2.5)
Swelling; Cycle 2 Number Analyzed 21 participants
2.6  (2.3)
Swelling; Cycle 3 Number Analyzed 20 participants
1.5  (1.4)
Swelling; Cycle 12 Number Analyzed 16 participants
1.0  (1.3)
Swelling; Cycle 24 Number Analyzed 11 participants
0.8  (0.8)
Swelling; Cycle 36 Number Analyzed 10 participants
1.1  (1.8)
Stiffness; Baseline Number Analyzed 21 participants
4.7  (2.9)
Stiffness; Cycle 1 Day 15 Number Analyzed 21 participants
3.6  (2.9)
Stiffness; Cycle 2 Number Analyzed 21 participants
3.1  (2.7)
Stiffness; Cycle 3 Number Analyzed 20 participants
2.2  (1.9)
Stiffness; Cycle 12 Number Analyzed 16 participants
1.7  (1.9)
Stiffness; Cycle 24 Number Analyzed 11 participants
1.2  (1.1)
Stiffness; Cycle 36 Number Analyzed 10 participants
1.5  (2.1)
Instability; Baseline Number Analyzed 21 participants
2.9  (2.6)
Instability; Cycle 1 Day 15 Number Analyzed 21 participants
2.1  (2.6)
Instability; Cycle 2 Number Analyzed 21 participants
2.1  (2.5)
Instability; Cycle 3 Number Analyzed 20 participants
1.2  (1.4)
Instability; Cycle 12 Number Analyzed 16 participants
0.9  (1.3)
Instability; Cycle 24 Number Analyzed 11 participants
0.4  (0.7)
Instability; Cycle 36 Number Analyzed 10 participants
0.3  (0.7)
Limited motion; Baseline Number Analyzed 21 participants
4.8  (2.8)
Limited motion; Cycle 1 Day 15 Number Analyzed 21 participants
3.2  (2.7)
Limited motion; Cycle 2 Number Analyzed 21 participants
3.0  (2.4)
Limited motion; Cycle 3 Number Analyzed 20 participants
1.9  (1.7)
Limited motion; Cycle 12 Number Analyzed 16 participants
1.6  (1.9)
Limited motion; Cycle 24 Number Analyzed 11 participants
1.0  (1.0)
Limited motion; Cycle 36 Number Analyzed 10 participants
1.6  (2.2)
Time Frame Adverse events (and serious adverse events) were recorded from the time the participant received the first dose of study drug up to 30 days after the last dose, up to approximately 30 months postdose.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) MEC Cohort 1000 mg/Day (600mg AM, 400mg PM) PVNS Cohort 1000 mg/Day (600mg AM, 400mg PM) GIST Cohort 1000 mg/Day (600mg AM, 400mg PM) ATC Cohort 1000 mg/Day (600mg AM, 400mg PM) Malignant Effusion Cohort 1000 mg/Day (600mg AM, 400mg PM) Other Solid Tumor Type Cohort 1000 mg/Day (600mg AM, 400mg PM)
Hide Arm/Group Description Participants with advanced, incurable, solid tumors who received PLX3397 200 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 300 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 400 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 600 mg QD. Participants with advanced, incurable, solid tumors who received PLX3397 900 mg/day. Participants with advanced, incurable, solid tumors who received PLX3397 1200 mg/day. Participants with advanced, incurable, solid tumors who received PLX3397 1000 mg/day. Participants with advanced or recurrent mucoepidermoid carcinoma (MEC) who received PLX3397. Participants with advanced pigmented villonodular synovitis (PVNS) who received PLX3397. Participants with advanced gastrointestinal stromal tumor (GIST) who received PLX3397. Participants with anaplastic thyroid carcinoma (ATC) who received PLX3397. Participants with advanced solid tumors with malignant effusion who received PLX3397. Participants with other solid tumor types who received PLX3397.
All-Cause Mortality
Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) MEC Cohort 1000 mg/Day (600mg AM, 400mg PM) PVNS Cohort 1000 mg/Day (600mg AM, 400mg PM) GIST Cohort 1000 mg/Day (600mg AM, 400mg PM) ATC Cohort 1000 mg/Day (600mg AM, 400mg PM) Malignant Effusion Cohort 1000 mg/Day (600mg AM, 400mg PM) Other Solid Tumor Type Cohort 1000 mg/Day (600mg AM, 400mg PM)
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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/3 (0.00%)   1/6 (16.67%)   1/6 (16.67%)   0/6 (0.00%)   0/7 (0.00%)   1/6 (16.67%)   0/7 (0.00%)   0/4 (0.00%)   0/39 (0.00%)   3/11 (27.27%)   1/9 (11.11%)   1/8 (12.50%)   1/20 (5.00%) 
Hide Serious Adverse Events
Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) MEC Cohort 1000 mg/Day (600mg AM, 400mg PM) PVNS Cohort 1000 mg/Day (600mg AM, 400mg PM) GIST Cohort 1000 mg/Day (600mg AM, 400mg PM) ATC Cohort 1000 mg/Day (600mg AM, 400mg PM) Malignant Effusion Cohort 1000 mg/Day (600mg AM, 400mg PM) Other Solid Tumor Type Cohort 1000 mg/Day (600mg AM, 400mg PM)
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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/3 (0.00%)   1/6 (16.67%)   0/6 (0.00%)   0/6 (0.00%)   1/7 (14.29%)   1/6 (16.67%)   3/7 (42.86%)   2/4 (50.00%)   5/39 (12.82%)   4/11 (36.36%)   1/9 (11.11%)   2/8 (25.00%)   3/20 (15.00%) 
Blood and lymphatic system disorders                           
Febrile neutropenia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Gastrointestinal disorders                           
Ascites † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Haematochezia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Small intestinal obstruction † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Diarrhoea † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
General disorders                           
Pyrexia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hepatobiliary disorders                           
Cholecystitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hepatic haemorrhage † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Infections and infestations                           
Pneumonia † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  2/20 (10.00%) 
Bacterial sepsis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Cellulitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Clostridium difficile colitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Sepsis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Upper respiratory tract infection † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Investigations                           
Transaminases increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Metabolism and nutrition disorders                           
Dehydration † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  1/20 (5.00%) 
Hyponatraemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Hypoglycaemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypomagnesaemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Musculoskeletal and connective tissue disorders                           
Neck pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                           
Renal cell carcinoma † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Nervous system disorders                           
Cerebrovascular accident † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Dizziness † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Psychiatric disorders                           
Mental status changes † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Renal and urinary disorders                           
Renal failure acute † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Respiratory, thoracic and mediastinal disorders                           
Acute respiratory failure † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypoxia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Pleural effusion † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Vascular disorders                           
Deep vein thrombosis † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
1
Term from vocabulary, MedDRA (12.1)
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dose Escalation Cohort 1: 200 mg QD Dose Escalation Cohort 2: 300 mg QD Dose Escalation Cohort 3: 400 mg QD Dose Escalation Cohort 4: 600 mg QD Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM) Dose Escalation Cohort 6: 1200 mg/Day (600mg BID) Dose Escalation Cohort 7: 1000 mg/Day (500mg BID) MEC Cohort 1000 mg/Day (600mg AM, 400mg PM) PVNS Cohort 1000 mg/Day (600mg AM, 400mg PM) GIST Cohort 1000 mg/Day (600mg AM, 400mg PM) ATC Cohort 1000 mg/Day (600mg AM, 400mg PM) Malignant Effusion Cohort 1000 mg/Day (600mg AM, 400mg PM) Other Solid Tumor Type Cohort 1000 mg/Day (600mg AM, 400mg PM)
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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)   6/6 (100.00%)   6/6 (100.00%)   6/6 (100.00%)   6/7 (85.71%)   6/6 (100.00%)   7/7 (100.00%)   4/4 (100.00%)   39/39 (100.00%)   11/11 (100.00%)   8/9 (88.89%)   8/8 (100.00%)   20/20 (100.00%) 
Blood and lymphatic system disorders                           
Anaemia † 1  0/3 (0.00%)  3/6 (50.00%)  4/6 (66.67%)  3/6 (50.00%)  2/7 (28.57%)  3/6 (50.00%)  2/7 (28.57%)  0/4 (0.00%)  7/39 (17.95%)  3/11 (27.27%)  0/9 (0.00%)  2/8 (25.00%)  6/20 (30.00%) 
Neutropenia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  1/20 (5.00%) 
Thrombocytopenia † 1  0/3 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Leukocytosis † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Lymphadenopathy † 1  1/3 (33.33%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Leukopenia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Lymphopenia † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Febrile neutropenia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Cardiac disorders                           
Angina pectoris † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Tachycardia † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Palpitations † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  2/9 (22.22%)  0/8 (0.00%)  0/20 (0.00%) 
Electromechanical dissociation † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Sinus bradycardia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  0/20 (0.00%) 
Ear and labyrinth disorders                           
Tinnitus † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Ear discomfort † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Endocrine disorders                           
Hypothyroidism † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Eye disorders                           
Conjunctival haemorrhage † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  1/9 (11.11%)  0/8 (0.00%)  1/20 (5.00%) 
Eye discharge † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Orbital oedema † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Vision blurred † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  6/39 (15.38%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  2/20 (10.00%) 
Visual impairment † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Diplopia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  2/20 (10.00%) 
Eye irritation † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Eye pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Eye pruritus † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Myodesopsia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Dry eye † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Gastrointestinal disorders                           
Nausea † 1  1/3 (33.33%)  3/6 (50.00%)  3/6 (50.00%)  4/6 (66.67%)  4/7 (57.14%)  2/6 (33.33%)  2/7 (28.57%)  1/4 (25.00%)  26/39 (66.67%)  4/11 (36.36%)  3/9 (33.33%)  5/8 (62.50%)  9/20 (45.00%) 
Diarrhoea † 1  0/3 (0.00%)  1/6 (16.67%)  2/6 (33.33%)  2/6 (33.33%)  0/7 (0.00%)  2/6 (33.33%)  2/7 (28.57%)  2/4 (50.00%)  14/39 (35.90%)  4/11 (36.36%)  2/9 (22.22%)  3/8 (37.50%)  2/20 (10.00%) 
Vomiting † 1  1/3 (33.33%)  3/6 (50.00%)  2/6 (33.33%)  3/6 (50.00%)  3/7 (42.86%)  1/6 (16.67%)  3/7 (42.86%)  1/4 (25.00%)  12/39 (30.77%)  1/11 (9.09%)  3/9 (33.33%)  2/8 (25.00%)  7/20 (35.00%) 
Dry mouth † 1  0/3 (0.00%)  2/6 (33.33%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  4/39 (10.26%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  2/20 (10.00%) 
Constipation † 1  0/3 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  1/6 (16.67%)  3/7 (42.86%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  11/39 (28.21%)  2/11 (18.18%)  4/9 (44.44%)  3/8 (37.50%)  6/20 (30.00%) 
Abdominal pain upper † 1  1/3 (33.33%)  1/6 (16.67%)  0/6 (0.00%)  2/6 (33.33%)  1/7 (14.29%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  3/39 (7.69%)  2/11 (18.18%)  1/9 (11.11%)  1/8 (12.50%)  1/20 (5.00%) 
Abdominal distension † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  2/6 (33.33%)  1/7 (14.29%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  3/39 (7.69%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Abdominal pain † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  2/39 (5.13%)  4/11 (36.36%)  0/9 (0.00%)  0/8 (0.00%)  2/20 (10.00%) 
Dyspepsia † 1  1/3 (33.33%)  0/6 (0.00%)  0/6 (0.00%)  2/6 (33.33%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  5/39 (12.82%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Retching † 1  1/3 (33.33%)  1/6 (16.67%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Ascites † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Stomatitis † 1  1/3 (33.33%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Abdominal discomfort † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Abdominal pain lower † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Aphthous stomatitis † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Eructation † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Faecal incontinence † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Flatulence † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Gastrooesophageal reflux disease † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  5/39 (12.82%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Gingival bleeding † 1  1/3 (33.33%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Haematemesis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Oesophageal stenosis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Proctalgia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Rectal haemorrhage † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Toothache † 1  1/3 (33.33%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Dysphagia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  2/9 (22.22%)  0/8 (0.00%)  1/20 (5.00%) 
Gingival pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Haematochezia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  2/20 (10.00%) 
Haemorrhoids † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Small intestine obstruction † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Tooth discolouration † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Upper gastrointestinal haemorrhage † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
General disorders                           
Fatigue † 1  0/3 (0.00%)  3/6 (50.00%)  1/6 (16.67%)  3/6 (50.00%)  5/7 (71.43%)  2/6 (33.33%)  3/7 (42.86%)  2/4 (50.00%)  36/39 (92.31%)  7/11 (63.64%)  5/9 (55.56%)  6/8 (75.00%)  12/20 (60.00%) 
Oedema peripheral † 1  1/3 (33.33%)  1/6 (16.67%)  1/6 (16.67%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  14/39 (35.90%)  2/11 (18.18%)  2/9 (22.22%)  0/8 (0.00%)  3/20 (15.00%) 
Face oedema † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  1/7 (14.29%)  0/4 (0.00%)  6/39 (15.38%)  0/11 (0.00%)  2/9 (22.22%)  1/8 (12.50%)  0/20 (0.00%) 
Mucosal inflammation † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  5/39 (12.82%)  0/11 (0.00%)  0/9 (0.00%)  2/8 (25.00%)  0/20 (0.00%) 
Swelling face † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Pyrexia † 1  0/3 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  2/6 (33.33%)  0/7 (0.00%)  2/6 (33.33%)  1/7 (14.29%)  0/4 (0.00%)  2/39 (5.13%)  1/11 (9.09%)  1/9 (11.11%)  1/8 (12.50%)  2/20 (10.00%) 
Chest pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  1/7 (14.29%)  0/4 (0.00%)  2/39 (5.13%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Chills † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  2/11 (18.18%)  1/9 (11.11%)  0/8 (0.00%)  1/20 (5.00%) 
Asthenia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  2/11 (18.18%)  0/9 (0.00%)  1/8 (12.50%)  2/20 (10.00%) 
Chest discomfort † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Infusion site pain † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Non-cardiac chest pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  1/20 (5.00%) 
Influenza like illness † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  4/39 (10.26%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Early satiety † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Feeling abnormal † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Gait disturbance † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Oedema † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Hepatobiliary disorders                           
Hepatic haemorrhage † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Immune system disorders                           
Hypersensitivity † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Infections and infestations                           
Upper respiratory tract infection † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  2/7 (28.57%)  0/4 (0.00%)  6/39 (15.38%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  3/20 (15.00%) 
Oral candidiasis † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Pneumonia † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  1/8 (12.50%)  2/20 (10.00%) 
Sinusitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Bronchitis † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Bronchitis viral † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Folliculitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Nasopharyngitis † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  4/39 (10.26%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Oesophageal candidiasis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Pharyngitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Sepsis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Urinary tract infection † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  3/11 (27.27%)  1/9 (11.11%)  1/8 (12.50%)  0/20 (0.00%) 
Influenza † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Candidiasis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Cellulitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  1/20 (5.00%) 
Lung infection † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Oral herpes † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Bacterial sepsis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Clostridium difficile colitis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Peritonitis bacterial † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Injury, poisoning and procedural complications                           
Contusion † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  1/9 (11.11%)  1/8 (12.50%)  1/20 (5.00%) 
Excoriation † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Fall † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  1/39 (2.56%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  0/20 (0.00%) 
Seroma † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Sunburn † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  5/39 (12.82%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Thermal burn † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Anaphylactic transfusion reaction † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Investigations                           
Alanine aminotransferase increased † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  7/39 (17.95%)  1/11 (9.09%)  0/9 (0.00%)  1/8 (12.50%)  1/20 (5.00%) 
Aspartate aminotransferase increased † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  1/7 (14.29%)  1/6 (16.67%)  1/7 (14.29%)  0/4 (0.00%)  7/39 (17.95%)  2/11 (18.18%)  0/9 (0.00%)  1/8 (12.50%)  1/20 (5.00%) 
Blood alkaline phosphatase increased † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  4/39 (10.26%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Activated partial thromboplastin time prolonged † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Blood cholesterol increased † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  2/11 (18.18%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Lymphocyte count decreased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
International normalised ratio increased † 1  0/3 (0.00%)  2/6 (33.33%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  2/20 (10.00%) 
Weight decreased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  1/4 (25.00%)  4/39 (10.26%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  4/20 (20.00%) 
Blood bilirubin increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Blood thyroid stimulating hormone increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Neutrophil count increased † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Occult blood positive † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Platelet count decreased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Prothrombin time prolonged † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
White blood cell count decreased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Lacrimation increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  1/11 (9.09%)  1/9 (11.11%)  1/8 (12.50%)  0/20 (0.00%) 
Blood creatinine increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Blood creatinine phosphokinase increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Blood glucose decreased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Troponin increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Metabolism and nutrition disorders                           
Decreased appetite † 1  1/3 (33.33%)  3/6 (50.00%)  1/6 (16.67%)  4/6 (66.67%)  2/7 (28.57%)  3/6 (50.00%)  4/7 (57.14%)  0/4 (0.00%)  9/39 (23.08%)  3/11 (27.27%)  5/9 (55.56%)  4/8 (50.00%)  9/20 (45.00%) 
Hypophosphataemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  9/39 (23.08%)  1/11 (9.09%)  1/9 (11.11%)  0/8 (0.00%)  4/20 (20.00%) 
Dehydration † 1  1/3 (33.33%)  3/6 (50.00%)  1/6 (16.67%)  2/6 (33.33%)  1/7 (14.29%)  0/6 (0.00%)  2/7 (28.57%)  0/4 (0.00%)  3/39 (7.69%)  1/11 (9.09%)  1/9 (11.11%)  1/8 (12.50%)  2/20 (10.00%) 
Hyperglycaemia † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypertriglyceridaemia † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypokalaemia † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  3/39 (7.69%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Abnormal loss of weight † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypercalcaemia † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hyponatraemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  2/8 (25.00%)  1/20 (5.00%) 
Tumour lysis syndrome † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Weight increased † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  6/39 (15.38%)  6/11 (54.55%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypomagnesaemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Fluid retention † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypercholesterolaemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypoalbuminaemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Hypoglycaemia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Malnutrition † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Musculoskeletal and connective tissue disorders                           
Back pain † 1  2/3 (66.67%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  2/6 (33.33%)  1/7 (14.29%)  1/4 (25.00%)  5/39 (12.82%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  4/20 (20.00%) 
Musculoskeletal pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  2/6 (33.33%)  2/7 (28.57%)  0/6 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  0/39 (0.00%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  4/20 (20.00%) 
Arthralgia † 1  1/3 (33.33%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  24/39 (61.54%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  4/20 (20.00%) 
Myalgia † 1  1/3 (33.33%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  4/39 (10.26%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Muscle spasms † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  4/39 (10.26%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Musculoskeletal chest pain † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  2/20 (10.00%) 
Pain in extremity † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  10/39 (25.64%)  0/11 (0.00%)  1/9 (11.11%)  1/8 (12.50%)  2/20 (10.00%) 
Bone pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Bunion † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Muscular weakness † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Joint swelling † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  6/39 (15.38%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Joint stiffness † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Arthritis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Fibromyalgia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Groin pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Muscle twitching † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Pain in jaw † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  0/20 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                           
Tumour pain † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Melanocytic naevus † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/39 (7.69%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Tumour associated fever † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Nervous system disorders                           
Dysgeusia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  3/6 (50.00%)  1/7 (14.29%)  0/6 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  14/39 (35.90%)  2/11 (18.18%)  1/9 (11.11%)  2/8 (25.00%)  2/20 (10.00%) 
Headache † 1  0/3 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  3/6 (50.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  13/39 (33.33%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  5/20 (25.00%) 
Cognitive disorder † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  7/39 (17.95%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Dizziness † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  2/6 (33.33%)  1/7 (14.29%)  1/6 (16.67%)  2/7 (28.57%)  1/4 (25.00%)  11/39 (28.21%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  2/20 (10.00%) 
Aphasia † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Balance disorder † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Memory impairment † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  5/39 (12.82%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Burning sensation † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hypoaesthesia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Hypogeusia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Lethargy † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Neuropathy peripheral † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  4/39 (10.26%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  1/20 (5.00%) 
Paraesthesia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  3/39 (7.69%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  0/20 (0.00%) 
Parosmia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Sedation † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Syncope † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Tremor † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Amnesia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  4/39 (10.26%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Somnolence † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  1/39 (2.56%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Disturbance in attention † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Migraine † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Cerebrovascular accident † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Mental impairment † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Presyncope † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  1/20 (5.00%) 
Psychiatric disorders                           
Insomnia † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  1/6 (16.67%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  7/39 (17.95%)  4/11 (36.36%)  2/9 (22.22%)  2/8 (25.00%)  2/20 (10.00%) 
Anxiety † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  4/39 (10.26%)  1/11 (9.09%)  1/9 (11.11%)  0/8 (0.00%)  3/20 (15.00%) 
Depression † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/6 (33.33%)  0/7 (0.00%)  1/4 (25.00%)  5/39 (12.82%)  1/11 (9.09%)  2/9 (22.22%)  0/8 (0.00%)  2/20 (10.00%) 
Agitation † 1  0/3 (0.00%)  0/6 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  1/9 (11.11%)  0/8 (0.00%)  0/20 (0.00%) 
Confusional state † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  1/4 (25.00%)  3/39 (7.69%)  1/11 (9.09%)  1/9 (11.11%)  1/8 (12.50%)  0/20 (0.00%) 
Disorientation † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Distractibility † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Impulsive behaviour † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Mental status changes † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Abnormal dreams † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/39 (5.13%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hallucination † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Mood altered † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Sleep talking † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  1/8 (12.50%)  0/20 (0.00%) 
Renal and urinary disorders                           
Haematuria † 1  0/3 (0.00%)  1/6 (16.67%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  5/39 (12.82%)  1/11 (9.09%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Hydronephrosis † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Micturition urgency † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/4 (0.00%)  1/39 (2.56%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Nocturia † 1  0/3 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/6 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/39 (0.00%)  0/11 (0.00%)  0/9 (0.00%)  0/8 (0.00%)  0/20 (0.00%) 
Pollakiuria