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

• 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: BioMed Valley Discoveries, Inc
• 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

Participant Flow

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
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

Baseline Characteristics

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
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
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

Outcome Measures

1. Primary Outcome

Title	Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT).
Description	DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in: ≥Grade 4 hematologic toxicity for >1 day;; Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding;; ≥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;; 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

Outcome Measure Data

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
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.
Description	Data provided is for BVD-523.
Time Frame	Samples will be collected on day 1 and day 15 of Cycle 1

Outcome Measure Data

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
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.
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.

Outcome Measure Data

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
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)
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

Outcome Measure Data

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
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)

Adverse Events

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
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%)
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
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