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Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies

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: NCT01781429
Recruitment Status : Completed
First Posted : February 1, 2013
Results First Posted : March 20, 2020
Last Update Posted : March 20, 2020
Sponsor:
Information provided by (Responsible Party):
BioMed Valley Discoveries, Inc

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Advanced Solid Tumors
Intervention Drug: BVD-523
Enrollment 136
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion Group 1 Cohort-expansion Group 2 Cohort-expansion Group 3 Cohort-expansion Group 4 Cohort-expansion Group 5 Cohort-expansion Group 6 Cohort-expansion Group 7
Hide Arm/Group Description Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with BRAF mutated colorectal cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with BRAF mutated melanoma who had progressed or were refractory to BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with NRAS mutated melanoma, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with MEK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with BRAF mutated non-small cell lung cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with ERK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Period Title: Overall Study
Started 1 1 1 1 1 4 7 4 7 24 18 21 22 8 16 0
Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 1 1 1 1 1 4 7 4 7 24 18 21 22 8 16 0
Reason Not Completed
Death             0             0             0             0             0             0             0             0             0             1             0             0             1             0             1             0
Withdrawal by Subject             0             0             0             0             0             0             0             0             1             3             1             1             5             2             3             0
Disease Progression             1             0             1             1             1             4             7             4             6             15             15             15             15             4             11             0
Unacceptable Toxicity             0             0             0             0             0             0             0             0             0             0             0             2             0             0             0             0
Patient Condition Changed             0             0             0             0             0             0             0             0             0             4             0             1             0             1             0             0
Other - as entered by PI in eCRF             0             1             0             0             0             0             0             0             0             1             1             2             1             1             1             0
Enrolled, but not treated             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0             0
Arm/Group Title Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion Group 1 Cohort-expansion Group 2 Cohort-expansion Group 3 Cohort-expansion Group 4 Cohort-expansion Group 5 Cohort-expansion Group 6 Total
Hide Arm/Group Description Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with BRAF mutated colorectal cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with BRAF mutated melanoma who had progressed or were refractory to BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with NRAS mutated melanoma, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with MEK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients with BRAF mutated non-small cell lung cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Total of all reporting groups
Overall Number of Baseline Participants 1 1 1 1 1 4 7 4 7 24 17 21 22 8 16 135
Hide Baseline Analysis Population Description
One patient from Cohort-expansion group 2 was enrolled, but not treated. Therefore, they were not included in the baseline characteristics or study results.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1 participants 1 participants 1 participants 1 participants 1 participants 4 participants 7 participants 4 participants 7 participants 24 participants 17 participants 21 participants 22 participants 8 participants 16 participants 135 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%
0
   0.0%
0
   0.0%
Between 18 and 65 years
0
   0.0%
1
 100.0%
1
 100.0%
0
   0.0%
0
   0.0%
0
   0.0%
3
  42.9%
3
  75.0%
6
  85.7%
12
  50.0%
7
  41.2%
16
  76.2%
11
  50.0%
6
  75.0%
6
  37.5%
72
  53.3%
>=65 years
1
 100.0%
0
   0.0%
0
   0.0%
1
 100.0%
1
 100.0%
4
 100.0%
4
  57.1%
1
  25.0%
1
  14.3%
12
  50.0%
10
  58.8%
5
  23.8%
11
  50.0%
2
  25.0%
10
  62.5%
63
  46.7%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1 participants 1 participants 1 participants 1 participants 1 participants 4 participants 7 participants 4 participants 7 participants 24 participants 17 participants 21 participants 22 participants 8 participants 16 participants 135 participants
Female
1
 100.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
5
  71.4%
1
  25.0%
5
  71.4%
8
  33.3%
7
  41.2%
9
  42.9%
5
  22.7%
1
  12.5%
9
  56.3%
52
  38.5%
Male
0
   0.0%
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
3
  75.0%
2
  28.6%
3
  75.0%
2
  28.6%
16
  66.7%
10
  58.8%
12
  57.1%
17
  77.3%
7
  87.5%
7
  43.8%
83
  61.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1 participants 1 participants 1 participants 1 participants 1 participants 4 participants 7 participants 4 participants 7 participants 24 participants 17 participants 21 participants 22 participants 8 participants 16 participants 135 participants
Hispanic or Latino
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%
3
  13.6%
0
   0.0%
0
   0.0%
3
   2.2%
Not Hispanic or Latino
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
4
 100.0%
7
 100.0%
4
 100.0%
7
 100.0%
19
  79.2%
15
  88.2%
21
 100.0%
16
  72.7%
8
 100.0%
15
  93.8%
121
  89.6%
Unknown or Not Reported
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%
5
  20.8%
2
  11.8%
0
   0.0%
3
  13.6%
0
   0.0%
1
   6.3%
11
   8.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1 participants 1 participants 1 participants 1 participants 1 participants 4 participants 7 participants 4 participants 7 participants 24 participants 17 participants 21 participants 22 participants 8 participants 16 participants 135 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
2
   8.3%
1
   5.9%
0
   0.0%
0
   0.0%
2
  25.0%
0
   0.0%
6
   4.4%
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%
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
   0.0%
0
   0.0%
1
  25.0%
0
   0.0%
0
   0.0%
1
  14.3%
2
   8.3%
0
   0.0%
0
   0.0%
1
   4.5%
0
   0.0%
1
   6.3%
6
   4.4%
White
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
3
  75.0%
7
 100.0%
4
 100.0%
5
  71.4%
19
  79.2%
15
  88.2%
20
  95.2%
18
  81.8%
6
  75.0%
15
  93.8%
117
  86.7%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
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
   4.2%
1
   5.9%
1
   4.8%
3
  13.6%
0
   0.0%
0
   0.0%
6
   4.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 1 participants 1 participants 1 participants 1 participants 1 participants 4 participants 7 participants 4 participants 7 participants 24 participants 17 participants 21 participants 22 participants 8 participants 16 participants 135 participants
1 1 1 1 1 4 7 4 7 24 17 21 22 8 16 135
1.Primary Outcome
Title Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT).
Hide Description

DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in:

  1. ≥Grade 4 hematologic toxicity for >1 day;
  2. Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding;
  3. ≥Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain and rash (these become DLTs if the adverse event (AE) persists despite adequate treatment), a doubling of aspartate transaminase (AST)/alanine transaminase (ALT) in patients with grade 2 ALT/AST at baseline;
  4. A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for > 7 days) due to BVD-523-related toxicity.
Time Frame As indicated by safety and tolerability during study conduct; ~42 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort
Hide Arm/Group Description:
Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Overall Number of Participants Analyzed 1 1 1 1 1 4 7 4 7
Measure Type: Count of Participants
Unit of Measure: Participants
Any DLT Yes
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
2
  50.0%
2
  28.6%
No
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
4
 100.0%
6
  85.7%
2
  50.0%
5
  71.4%
Grade 3 Hematologic Toxicity with Complications Yes
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  25.0%
2
  28.6%
No
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
4
 100.0%
7
 100.0%
3
  75.0%
5
  71.4%
≥Grade 3 Non-Hematologic Toxicity Yes
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
2
  50.0%
2
  28.6%
No
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
1
 100.0%
4
 100.0%
6
  85.7%
2
  50.0%
5
  71.4%
2.Secondary Outcome
Title Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites.
Hide Description Data provided is for BVD-523.
Time Frame Samples will be collected on day 1 and day 15 of Cycle 1
Hide Outcome Measure Data
Hide Analysis Population Description
Day 1 - Dose-escalation 10mg b.i.d. patient was not calculable. Cohort-expansion numbers do not include those patients that were dose reduced and/or were not at a steady state with 600mg b.i.d. for the Day 15 draw.
Arm/Group Title Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion Group 1 Cohort-expansion Group 2 Cohort-expansion Group 3 Cohort-expansion Group 4 Cohort-expansion Group 5 Cohort-expansion Group 6
Hide Arm/Group Description:
Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated colorectal cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated melanoma who had progressed or were refractory to BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with NRAS mutated melanoma, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with MEK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated non-small cell lung cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 1 1 1 1 1 4 7 4 7 24 18 21 22 8 16
Mean (Standard Deviation)
Unit of Measure: ng/mL
Cmax Day 1 Number Analyzed 1 participants 1 participants 1 participants 1 participants 1 participants 4 participants 7 participants 4 participants 7 participants 23 participants 17 participants 19 participants 20 participants 8 participants 16 participants
NA [1]  14.9 100 133 216 765  (234) 1110  (589) 1450  (539) 1430  (1010) 1180  (501) 1260  (474) 1190  (467) 1230  (840) 1140  (423) 1560  (885)
Cmax Day 15 Number Analyzed 1 participants 1 participants 1 participants 1 participants 1 participants 3 participants 7 participants 3 participants 3 participants 17 participants 12 participants 11 participants 15 participants 4 participants 12 participants
45.7 15.8 191 326 459 586  (257) 3090  (1570) 2290  (1790) 1730  (401) 2440  (900) 1890  (953) 2340  (962) 1890  (1060) 2050  (1570) 2680  (1520)
[1]
Day 1 - Dose-escalation 10mg b.i.d. patient was not calculable.
3.Secondary Outcome
Title Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam.
Hide Description At enrollment, all study patients had metastatic or advanced-stage malignant tumor for which no curative therapy was known to exist. Patients entering Part 2 additionally had to have measurable disease by RECIST version 1.1. Data shown is best response.
Time Frame Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is completion. The best responses presented occurred at different time points for each patient.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion Group 1 Cohort-expansion Group 2 Cohort-expansion Group 3 Cohort-expansion Group 4 Cohort-expansion Group 5 Cohort-expansion Group 6
Hide Arm/Group Description:
Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.
Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated colorectal cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated melanoma who had progressed or were refractory to BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with NRAS mutated melanoma, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with MEK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated non-small cell lung cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 1 1 1 1 1 4 7 4 7 22 13 15 19 5 14
Measure Type: Count of Participants
Unit of Measure: Participants
Complete Response
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%
0
   0.0%
Partial Response
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
1
  25.0%
1
  14.3%
4
  18.2%
0
   0.0%
1
   6.7%
3
  15.8%
0
   0.0%
3
  21.4%
Stable Disease
1
 100.0%
1
 100.0%
0
   0.0%
1
 100.0%
1
 100.0%
2
  50.0%
5
  71.4%
0
   0.0%
4
  57.1%
14
  63.6%
8
  61.5%
6
  40.0%
7
  36.8%
2
  40.0%
9
  64.3%
Progressive Disease
0
   0.0%
0
   0.0%
1
 100.0%
0
   0.0%
0
   0.0%
2
  50.0%
1
  14.3%
3
  75.0%
2
  28.6%
4
  18.2%
5
  38.5%
8
  53.3%
9
  47.4%
3
  60.0%
2
  14.3%
4.Other Pre-specified Outcome
Title Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK)
Hide Description RSK1, a member of the RSK serine/threonine kinase family, is a direct substrate of the MAP Kinases ERK1 & ERK2. RSK1 and ERK1/2 form an inactive complex in unstimulated cells. Upon activation of the mitogenic pathway, ERK1/2 phosphorylates Thr573, Thr359 and Ser363 on RSK1. Thr573 resides in the activation loop of the carboxy terminal kinase domain of RSK1 and once phosphorylated, enables RSK1 to autophosphorylate Ser380. Phosphorylation of Ser380 on RSK1 can therefore be used as a target biomarker for ERK1 and ERK2 activity. BVD-523 inhibits the activity of ERK. In this study, phosphorylation of RSK1 Ser 380 (pRSK) was used as a target biomarker for assessment of ERK inhibition by BVD-523 in human whole blood samples.
Time Frame Patients will be evaluated at baseline and on ~day 15 of Cycle 1
Hide Outcome Measure Data
Hide Analysis Population Description
The protocol was amended to stop collecting PD samples unless the patient consented to a tumor biopsy. Therefore, some patients did not have PD samples collected or did not consent to optional research tests involving collection of tumor tissue and blood/plasma samples.
Arm/Group Title Cohort-expansion Group 1 Cohort-expansion Group 2 Cohort-expansion Group 3 Cohort-expansion Group 4 Cohort-expansion Group 5 Cohort-expansion Group 6
Hide Arm/Group Description:
Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated colorectal cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated melanoma who had progressed or were refractory to BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with NRAS mutated melanoma, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with MEK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients with BRAF mutated non-small cell lung cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 24 17 21 22 8 16
Mean (Standard Deviation)
Unit of Measure: Enzyme inhibition (%)
Cycle 1, Day 1; pre-dose Number Analyzed 18 participants 6 participants 18 participants 14 participants 6 participants 10 participants
0.000  (0) 0.000  (0) 0.000  (0) 0.000  (0) 0.000  (0) 0.000  (0)
Cycle 1, Day 1; 4 hours post-dose Number Analyzed 18 participants 6 participants 15 participants 14 participants 4 participants 9 participants
82.162  (27.3012) 69.989  (36.9362) 87.563  (26.8634) 96.868  (5.8054) 93.910  (12.1800) 80.214  (28.9393)
Cycle 1, Day 15; pre-dose Number Analyzed 16 participants 3 participants 11 participants 11 participants 3 participants 7 participants
94.607  (9.9291) 66.667  (57.7350) 78.679  (37.6286) 91.955  (21.5915) 89.050  (18.9660) 99.447  (1.4627)
Cycle 1, Day 15; 4 hours post-dose Number Analyzed 16 participants 4 participants 10 participants 10 participants 3 participants 8 participants
91.419  (13.9282) 56.554  (51.2962) 87.624  (26.0916) 98.902  (3.4722) 92.640  (12.7479) 85.329  (27.2781)
Time Frame The reporting period of an AE began from the time that the patient provided informed consent through and including 30 calendar days after the last administration of BVD-523 (or at the time when a patient begins a new anti-cancer therapy). Anticipated fluctuations of preexisting conditions, including the disease under study that did not represent a clinically significant exacerbation or worsening, did not need to be considered AEs. AEs were collected/assessed at each study visit.
Adverse Event Reporting Description A TEAE is any AE temporally assoc. with the use of BVD-523 related or not. If the onset of an AE was missing & the AE resolution date was either after the initial BVD-523 dose date or missing, then the AE was considered TE. A patient who reported multiple AEs that map to a common PT/SOC was counted only once for that PT/SOC at the highest severity reported & at the greatest relationship to study drug. AEs were assessed for all participants in Part 2 combined.
 
Arm/Group Title Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion
Hide Arm/Group Description Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
All-Cause Mortality
Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion
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   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/4 (0.00%)   0/7 (0.00%)   0/4 (0.00%)   0/7 (0.00%)   3/108 (2.78%) 
Hide Serious Adverse Events
Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion
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   0/1 (0.00%)   1/1 (100.00%)   1/1 (100.00%)   1/1 (100.00%)   1/1 (100.00%)   2/4 (50.00%)   2/7 (28.57%)   1/4 (25.00%)   5/7 (71.43%)   57/108 (52.78%) 
Blood and lymphatic system disorders                     
ANAEMIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
LEUKOCYTOSIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
FACTOR VIII INHIBITION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
THROMBOCYTOPENIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
THROMBOTIC THROMBOCYTOPENIC PURPURA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Cardiac disorders                     
ATRIAL FIBRILLATION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
CARDIAC ARREST  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
CARDIAC FAILURE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
TACHYCARDIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Congenital, familial and genetic disorders                     
PERICARDIAL EFFUSION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Endocrine disorders                     
ADRENAL INSUFFICIENCY  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Eye disorders                     
OPTIC NERVE DISORDER  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
RETINAL VEIN OCCLUSION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Gastrointestinal disorders                     
DIARRHOEA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  6/108 (5.56%) 
DIVERTICULUM  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
NAUSEA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
SMALL INTESTINAL OBSTRUCTION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
GASTROINTESTINAL HAEMORRHAGE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
VOMITING  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
ABDOMINAL PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
ABDOMINAL PAIN UPPER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
GASTRIC ULCER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
LARGE INTESTINAL ULCER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
OESOPHAGITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
PANCREATITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
PERITONEAL HAEMORRHAGE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
RETROPERITONEAL HAEMORRHAGE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
INTESTINAL OBSTRUCTION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
LARGE INTESTINAL OBSTRUCTION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
UPPER GASTROINTESTINAL HAEMORRHAGE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
PANCREATITIS ACUTE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
General disorders                     
DISEASE PROGRESSION  1  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  9/108 (8.33%) 
PYREXIA  1  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  5/108 (4.63%) 
ASTHENIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/108 (0.93%) 
FATIGUE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
CHEST PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
DEATH  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
OEDEMA PERIPHERAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Hepatobiliary disorders                     
CHOLANGITIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
CHOLECYSTITIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
GALLBLADDER OBSTRUCTION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
JAUNDICE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Infections and infestations                     
URINARY TRACT INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  0/7 (0.00%)  0/108 (0.00%) 
BACTERAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
GASTROENTERITIS VIRAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
PNEUMONIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
SEPSIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
CELLULITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
FUNGAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
RESPIRATORY TRACT INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
SKIN INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
VIRAL INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
ESCHERICHIA BACTERAEMIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
BACTERIAL SEPSIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
UROSEPSIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Injury, poisoning and procedural complications                     
FALL  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
OVERDOSE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
TOXICITY TO VARIOUS AGENTS  1 [1]  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
WOUND HAEMORRHAGE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
FRACTURE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
SPINAL FRACTURE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Investigations                     
BLOOD CREATININE INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  0/108 (0.00%) 
ALANINE AMINOTRANSFERASE INCREASED  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
LIPASE INCREASED  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Metabolism and nutrition disorders                     
DEHYDRATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  4/108 (3.70%) 
HYPOGLYCAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/108 (0.93%) 
ELECTROLYTE IMBALANCE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
HYPONATRAEMIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
HYPOALBUMINAEMIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
Musculoskeletal and connective tissue disorders                     
PATHOLOGICAL FRACTURE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
BACK PAIN  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
FLANK PAIN  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
ARTHRALGIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                     
RECTAL CANCER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
CARDIAC NEOPLASM UNSPECIFIED  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Nervous system disorders                     
CEREBELLAR INFARCTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
CONVULSION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
ATAXIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
CEREBRAL HAEMORRHAGE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
HEADACHE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
HEMIPARESIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
PETIT MAL EPILEPSY  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
SYNCOPE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Psychiatric disorders                     
CONFUSIONAL STATE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
DELIRIUM  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Renal and urinary disorders                     
RENAL FAILURE ACUTE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
HAEMATURIA  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Respiratory, thoracic and mediastinal disorders                     
DYSPNOEA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
PLEURAL EFFUSION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
PULMONARY EMBOLISM  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
CHRONIC OBSTRUCTIVE PULMONARY DISEASE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
HAEMOPTYSIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
PNEUMONITIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
PNEUMOTHORAX  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
STRIDOR  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Skin and subcutaneous tissue disorders                     
RASH MACULO-PAPULAR  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
DERMATITIS ACNEIFORM  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
RASH  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
SWELLING FACE  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Vascular disorders                     
HYPOTENSION  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  4/108 (3.70%) 
THROMBOSIS  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
HYPOVOLAEMIC SHOCK  1  /1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
1
Term from vocabulary, CTCAE 4, MedDRA 16
Indicates events were collected by systematic assessment
[1]
TOXICITY TO VARIOUS AGENTS
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dose-escalation 10mg b.i.d. Cohort Dose-escalation 20mg b.i.d. Cohort Dose-escalation 40mg b.i.d. Cohort Dose-escalation 75mg b.i.d. Cohort Dose-escalation 150mg b.i.d. Cohort Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Dose-escalation 900mg b.i.d. Cohort Cohort-expansion
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   1/1 (100.00%)   1/1 (100.00%)   1/1 (100.00%)   1/1 (100.00%)   1/1 (100.00%)   4/4 (100.00%)   7/7 (100.00%)   4/4 (100.00%)   7/7 (100.00%)   107/108 (99.07%) 
Blood and lymphatic system disorders                     
ANAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  1/1 (100.00%)  1/4 (25.00%)  1/7 (14.29%)  1/4 (25.00%)  3/7 (42.86%)  21/108 (19.44%) 
LYMPHOPENIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
THROMBOCYTOPENIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
Cardiac disorders                     
PALPITATIONS  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
TACHYCARDIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  6/108 (5.56%) 
ATRIAL FIBRILLATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
CONDUCTION DISORDER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
Eye disorders                     
VISION BLURRED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  7/108 (6.48%) 
VISUAL IMPAIRMENT  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  10/108 (9.26%) 
ABNORMAL SENSATION IN EYE  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
BLEPHARITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
CHALAZION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
CHORIORETINOPATHY  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
EYE DISCHARGE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/108 (0.93%) 
MYDRIASIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
PHOTOPHOBIA  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
Gastrointestinal disorders                     
ABDOMINAL DISTENSION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  2/7 (28.57%)  1/108 (0.93%) 
ABDOMINAL PAIN  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  12/108 (11.11%) 
CONSTIPATION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  1/4 (25.00%)  3/7 (42.86%)  25/108 (23.15%) 
DIARRHOEA  1  1/1 (100.00%)  1/1 (100.00%)  1/1 (100.00%)  1/1 (100.00%)  1/1 (100.00%)  0/4 (0.00%)  3/7 (42.86%)  3/4 (75.00%)  6/7 (85.71%)  59/108 (54.63%) 
DRY MOUTH  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  7/108 (6.48%) 
GASTROOESOPHAGEAL REFLUX DISEASE  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  9/108 (8.33%) 
NAUSEA  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  1/4 (25.00%)  4/7 (57.14%)  1/4 (25.00%)  6/7 (85.71%)  49/108 (45.37%) 
ORAL PAIN  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/108 (0.93%) 
STOMATITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  6/108 (5.56%) 
VOMITING  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  3/7 (42.86%)  3/4 (75.00%)  5/7 (71.43%)  31/108 (28.70%) 
ABDOMINAL PAIN UPPER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  6/108 (5.56%) 
ABDOMINAL DISCOMFORT  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  3/108 (2.78%) 
ABDOMINAL PAIN LOWER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
ANAL FISSURE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
ASCITES  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/108 (0.93%) 
CHEILITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
DIVERTICULUM  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
DYSPHAGIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
FLATULENCE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
GINGIVAL BLEEDING  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
LOWER GASTROINTESTINAL HAEMORRHAGE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  2/108 (1.85%) 
MELAENA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/108 (0.93%) 
PAINFUL DEFAECATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
PERITONEAL DISORDER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
SMALL INTESTINAL OBSTRUCTION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
UPPER GASTROINTESTINAL HAEMORRHAGE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
General disorders                     
ASTHENIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  2/7 (28.57%)  5/108 (4.63%) 
CHILLS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  6/108 (5.56%) 
FATIGUE  1  0/1 (0.00%)  1/1 (100.00%)  1/1 (100.00%)  1/1 (100.00%)  1/1 (100.00%)  2/4 (50.00%)  5/7 (71.43%)  1/4 (25.00%)  7/7 (100.00%)  54/108 (50.00%) 
MUCOSAL INFLAMMATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  2/108 (1.85%) 
OEDEMA PERIPHERAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  1/1 (100.00%)  0/4 (0.00%)  2/7 (28.57%)  0/4 (0.00%)  2/7 (28.57%)  28/108 (25.93%) 
PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  7/108 (6.48%) 
PYREXIA  1  0/1 (0.00%)  1/1 (100.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  1/4 (25.00%)  3/7 (42.86%)  20/108 (18.52%) 
DISEASE PROGRESSION  1  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  9/108 (8.33%) 
APPLICATION SITE RASH  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
CHEST DISCOMFORT  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
MALAISE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
THIRST  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
CHEST PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  6/108 (5.56%) 
Hepatobiliary disorders                     
HYPERBILIRUBINAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
Immune system disorders                     
SEASONAL ALLERGY  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
Infections and infestations                     
BRONCHITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
UPPER RESPIRATORY TRACT INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  0/7 (0.00%)  4/108 (3.70%) 
URINARY TRACT INFECTION  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  1/4 (25.00%)  1/7 (14.29%)  3/108 (2.78%) 
GASTROENTERITIS VIRAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
BACTERAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
BACTERIAL SEPSIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/108 (0.93%) 
CANDIDIASIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/108 (0.93%) 
FOLLICULITIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
INFLUENZA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
KIDNEY INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
NAIL INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
ONYCHOMYCOSIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
ORAL CANDIDIASIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
ORAL HERPES  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
PERITONITIS BACTERIAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
PNEUMONIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  7/108 (6.48%) 
RESPIRATORY TRACT INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
RESPIRATORY TRACT INFECTION VIRAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
SINUSITIS  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
STAPHYLOCOCCAL INFECTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
VIRAL INFECTION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
VIRAL UPPER RESPIRATORY TRACT INFECTION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
Injury, poisoning and procedural complications                     
FALL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  2/7 (28.57%)  5/108 (4.63%) 
EXCORIATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
EYE CONTUSION  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
INCISION SITE COMPLICATION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
LACERATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
LIP INJURY  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
UPPER LIMB FRACTURE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
Investigations                     
ALANINE AMINOTRANSFERASE INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  1/7 (14.29%)  5/108 (4.63%) 
ASPARTATE AMINOTRANSFERASE INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  2/7 (28.57%)  8/108 (7.41%) 
BLOOD CREATININE INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  2/4 (50.00%)  0/7 (0.00%)  1/4 (25.00%)  3/7 (42.86%)  13/108 (12.04%) 
WEIGHT DECREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  11/108 (10.19%) 
LYMPHOCYTE COUNT DECREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  5/108 (4.63%) 
BLOOD ALKALINE PHOSPHATASE INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  3/108 (2.78%) 
BLOOD BILIRUBIN INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  3/108 (2.78%) 
BLOOD PHOSPHORUS INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
BODY TEMPERATURE INCREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
LIVER FUNCTION TEST ABNORMAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
OCCULT BLOOD POSITIVE  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
PLATELET COUNT DECREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
PROTEIN TOTAL DECREASED  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
Metabolism and nutrition disorders                     
DECREASED APPETITE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  3/4 (75.00%)  5/7 (71.43%)  38/108 (35.19%) 
DEHYDRATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  2/7 (28.57%)  0/4 (0.00%)  4/7 (57.14%)  19/108 (17.59%) 
HYPERGLYCAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  7/108 (6.48%) 
HYPOALBUMINAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  10/108 (9.26%) 
HYPOCALCAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  7/108 (6.48%) 
HYPOKALAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  0/4 (0.00%)  1/7 (14.29%)  8/108 (7.41%) 
HYPOMAGNESAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  4/108 (3.70%) 
HYPONATRAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  13/108 (12.04%) 
HYPERKALAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  4/108 (3.70%) 
HYPOGLYCAEMIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
Musculoskeletal and connective tissue disorders                     
ARTHRALGIA  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  12/108 (11.11%) 
BACK PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  8/108 (7.41%) 
FLANK PAIN  1  1/1 (100.00%)  1/1 (100.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
MUSCULOSKELETAL CHEST PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  3/108 (2.78%) 
MUSCULOSKELETAL PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  4/108 (3.70%) 
MYALGIA  1  1/1 (100.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  4/108 (3.70%) 
NECK PAIN  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  5/108 (4.63%) 
JOINT SWELLING  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
MUSCLE SPASMS  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  4/108 (3.70%) 
MUSCLE TIGHTNESS  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
MUSCLE TWITCHING  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/108 (0.00%) 
MUSCULAR WEAKNESS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
MUSCULOSKELETAL DISCOMFORT  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
PAIN IN EXTREMITY  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
PATHOLOGICAL FRACTURE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                     
KERATOACANTHOMA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
RECTAL CANCER  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
SEBORRHOEIC KERATOSIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
TUMOUR PAIN  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
Nervous system disorders                     
DIZZINESS  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  16/108 (14.81%) 
DYSGEUSIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  12/108 (11.11%) 
HEADACHE  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  3/7 (42.86%)  10/108 (9.26%) 
SOMNOLENCE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
ATAXIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
CEREBELLAR INFARCTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
CEREBROVASCULAR ACCIDENT  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
HYPOAESTHESIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
LETHARGY  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
PARAESTHESIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  1/4 (25.00%)  0/7 (0.00%)  1/108 (0.93%) 
TENSION HEADACHE  1  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
SYNCOPE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  5/108 (4.63%) 
Psychiatric disorders                     
ANXIETY  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  2/7 (28.57%)  0/4 (0.00%)  1/7 (14.29%)  2/108 (1.85%) 
INSOMNIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  8/108 (7.41%) 
AGITATION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
MENTAL STATUS CHANGES  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  1/108 (0.93%) 
Renal and urinary disorders                     
HAEMATURIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  9/108 (8.33%) 
PROTEINURIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  5/108 (4.63%) 
DYSURIA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  2/108 (1.85%) 
HYDRONEPHROSIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
RENAL FAILURE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
URINARY INCONTINENCE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
RENAL FAILURE ACUTE  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  6/108 (5.56%) 
Reproductive system and breast disorders                     
ERECTILE DYSFUNCTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
VULVOVAGINAL ERYTHEMA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/108 (0.00%) 
Respiratory, thoracic and mediastinal disorders                     
COUGH  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  3/7 (42.86%)  1/4 (25.00%)  1/7 (14.29%)  10/108 (9.26%) 
DYSPNOEA  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  3/4 (75.00%)  2/7 (28.57%)  1/4 (25.00%)  1/7 (14.29%)  20/108 (18.52%) 
OROPHARYNGEAL PAIN  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  4/108 (3.70%) 
PLEURAL EFFUSION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/4 (25.00%)  1/7 (14.29%)  0/4 (0.00%)  2/7 (28.57%)  7/108 (6.48%) 
RHINORRHOEA  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  1/4 (25.00%)  0/7 (0.00%)  1/108 (0.93%) 
DYSPNOEA EXERTIONAL  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  1/7 (14.29%)  6/108 (5.56%) 
EPISTAXIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
HAEMOPTYSIS  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
HICCUPS  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  4/108 (3.70%) 
NASAL CONGESTION  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  3/108 (2.78%) 
PRODUCTIVE COUGH  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
PULMONARY EMBOLISM  1  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/7 (14.29%)  0/4 (0.00%)  0/7 (0.00%)  3/108 (2.78%) 
THROAT IRRITATION  1  0/1 (0.00%)  1/1 (100.00%)  0/1 (0.00%)  0/1 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/4 (0.00%)  0/7 (0.00%)  0/108 (0.00%) 
Skin and subcutaneous tissue disorders