A Phase 2 Study of Sitravatinib in Combination With PD-(L)1 Checkpoint Inhibitor Regimens in Patients With Advanced or Metastatic Urothelial Carcinoma

• ClinicalTrials.gov Identifier: NCT03606174
• Recruitment Status: Terminated
• First Posted: July 30, 2018
• Results First Posted: August 24, 2023
• Last Update Posted: August 24, 2023
• Sponsor: Mirati Therapeutics Inc.
• Information provided by (Responsible Party): Mirati Therapeutics Inc.

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Urothelial Carcinoma; Urothelial Carcinoma Bladder; Urothelial Carcinoma Ureter; Urothelial Carcinoma of the Renal Pelvis and Ureter; Urothelial Carcinoma Urethra
• Interventions: Drug: Sitravatinib; Drug: Nivolumab; Drug: Pembrolizumab; Drug: Enfortumab vedotin
• Enrollment: 260

Participant Flow

Recruitment Details	260 participants were enrolled into this study at investigative sites in the United States.
Pre-assignment Details	Screening tests and procedures were performed within the 28 days preceding administration of the first dose.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9 Dose Level 1	Cohort 9 Dose Level 2	Cohort 9 Dose Level 3
Arm/Group Description	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.
Period Title: Overall Study
Started	49	23	18	9	53	27	56	9	8	4	4
Started Cohort 9 Lead-in Dose-escalation Part	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	8	4	4
Started Cohort 9 Dose-expansion Part	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	0 [1]	0	0	0
Completed	0	0	0	0	0	0	0	0	0	0	0
Not Completed	49	23	18	9	53	27	56	9	8	4	4
Reason Not Completed
Death	37	15	15	7	35	12	35	8	5	3	0
Lost to Follow-up	0	0	0	0	1	1	0	0	0	0	0
Withdrawal by Subject	6	0	0	1	2	1	4	0	0	0	1
Study Terminated by Sponsor	5	7	3	0	11	6	12	1	3	1	2
Miscellaneous	1	1	0	1	4	7	5	0	0	0	1
[1] N/A for Cohorts 1-8

Baseline Characteristics

Arm/Group Title		Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9 Dose Level 1	Cohort 9 Dose Level 2	Cohort 9 Dose Level 3	Total
Arm/Group Description		Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.	Total of all reporting groups
Overall Number of Baseline Participants		49	23	18	9	53	27	56	9	8	4	4	260
Baseline Analysis Population Description		Measured in the safety population, which included all participants who received ≥ 1 dose of any study treatment (sitravatinib, nivolumab, pembrolizumab, or enfortumab vedotin).
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	49 participants	23 participants	18 participants	9 participants	53 participants	27 participants	56 participants	9 participants	8 participants	4 participants	4 participants	260 participants
		67.3 (9.63)	72.3 (7.94)	67.6 (12.89)	75.1 (7.62)	65.2 (8.34)	70.0 (8.23)	67.1 (9.07)	78.0 (7.02)	65.1 (6.40)	69.0 (8.00)	75.8 (9.54)	68.3 (9.39)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants	23 participants	18 participants	9 participants	53 participants	27 participants	56 participants	9 participants	8 participants	4 participants	4 participants	260 participants
	Female	13 26.5%	7 30.4%	6 33.3%	1 11.1%	10 18.9%	10 37.0%	17 30.4%	4 44.4%	0 0.0%	1 25.0%	1 25.0%	70 26.9%
	Male	36 73.5%	16 69.6%	12 66.7%	8 88.9%	43 81.1%	17 63.0%	39 69.6%	5 55.6%	8 100.0%	3 75.0%	3 75.0%	190 73.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants	23 participants	18 participants	9 participants	53 participants	27 participants	56 participants	9 participants	8 participants	4 participants	4 participants	260 participants
	Hispanic or Latino	4 8.2%	0 0.0%	0 0.0%	2 22.2%	1 1.9%	0 0.0%	2 3.6%	1 11.1%	0 0.0%	0 0.0%	0 0.0%	10 3.8%
	Not Hispanic or Latino	44 89.8%	23 100.0%	18 100.0%	7 77.8%	52 98.1%	27 100.0%	53 94.6%	8 88.9%	8 100.0%	4 100.0%	4 100.0%	248 95.4%
	Unknown or Not Reported	1 2.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	1 1.8%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	2 0.8%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	49 participants	23 participants	18 participants	9 participants	53 participants	27 participants	56 participants	9 participants	8 participants	4 participants	4 participants	260 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%
	Asian	0 0.0%	0 0.0%	2 11.1%	0 0.0%	1 1.9%	0 0.0%	4 7.1%	1 11.1%	0 0.0%	1 25.0%	1 25.0%	10 3.8%
	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%
	Black or African American	2 4.1%	2 8.7%	1 5.6%	0 0.0%	5 9.4%	1 3.7%	2 3.6%	0 0.0%	0 0.0%	1 25.0%	0 0.0%	14 5.4%
	White	46 93.9%	21 91.3%	15 83.3%	9 100.0%	46 86.8%	26 96.3%	48 85.7%	8 88.9%	8 100.0%	2 50.0%	3 75.0%	232 89.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	1 2.0%	0 0.0%	0 0.0%	0 0.0%	1 1.9%	0 0.0%	2 3.6%	0 0.0%	0 0.0%	0 0.0%	0 0.0%	4 1.5%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	ORR was defined as the number of participants documented to have a confirmed investigator-assessed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions.
Time Frame	Up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants were enrolled to 3 dose levels of sitravatinib in combination with pembrolizumab and enfortumab vedotin. Sitravatinib was received orally via capsules QD in 21-day cycles at doses 35 mg and 70 mg. Pembrolizumab was received as an IV infusion over approximately 30 minutes (± 5 minutes) at 200 mg every 3 weeks (Q3W), in accordance with the current pembrolizumab USPI. Enfortumab vedotin dosing was based on participant weight, starting at 1.25 mg/kg up to 125 mg/kg QD, with a dose de-escalation step to 1 mg/kg. Enfortumab vedotin was received as an IV infusion over approximately 30 minutes (± 5 minutes) on Days 1 and 8 of a 21-day cycle.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	16
Measure Type: Count of Participants; Unit of Measure: Participants
	6 12.2%	5 21.7%	4 22.2%	0 0.0%	17 32.1%	9 33.3%	3 5.4%	0 0.0%	4 25.0%

2. Secondary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An AE was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial, regardless of treatment group or suspected causal relationship to study treatment. Any clinically significant changes from baseline in laboratory results were recorded as AEs.
Time Frame	Day 1 up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the safety population, which included all participants who received ≥ 1 dose of any study treatment (sitravatinib, nivolumab, pembrolizumab, or enfortumab vedotin).

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9 Dose Level 1	Cohort 9 Dose Level 2	Cohort 9 Dose Level 3
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	8	4	4
Measure Type: Count of Participants; Unit of Measure: Participants
	49 100.0%	23 100.0%	18 100.0%	9 100.0%	53 100.0%	27 100.0%	56 100.0%	9 100.0%	8 100.0%	4 100.0%	4 100.0%

3. Secondary Outcome

Title	Number of Participants Who Experienced a Serious Adverse Event (SAE)
Description	An SAE was defined as any event that resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/permanent damage (substantial disruption of the ability to conduct normal life functions), a congenital anomaly/birth defect, or may have jeopardized the participant and may have required medical or surgical intervention to prevent intensive treatment in an emergency room or at home (e.g. for allergic bronchospasm, blood dyscrasias or convulsions) that do not result in inpatient hospitalization, development of drug dependency or drug abuse.
Time Frame	Day 1 up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the safety population, which included all participants who received ≥ 1 dose of any study treatment (sitravatinib, nivolumab, pembrolizumab, or enfortumab vedotin).

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9 Dose Level 1	Cohort 9 Dose Level 2	Cohort 9 Dose Level 3
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	8	4	4
Measure Type: Count of Participants; Unit of Measure: Participants
	35 71.4%	15 65.2%	10 55.6%	4 44.4%	26 49.1%	14 51.9%	23 41.1%	3 33.3%	5 62.5%	1 25.0%	3 75.0%

4. Secondary Outcome

Title	Number of Participants Who Experienced a Treatment-related Adverse Event
Description	A treatment-related adverse event was defined as an adverse event determined to have a possible causal relationship to the study treatment(s) by the investigator. An adverse event was defined as any reaction, side effect or other undesirable medical event that occurred during participation in a clinical trial. Any clinically significant changes from baseline in laboratory results were recorded as adverse events.
Time Frame	Day 1 up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the safety population, which included all participants who received ≥ 1 dose of any study treatment (sitravatinib, nivolumab, pembrolizumab, or enfortumab vedotin).

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9 Dose Level 1	Cohort 9 Dose Level 2	Cohort 9 Dose Level 3
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	8	4	4
Measure Type: Count of Participants; Unit of Measure: Participants
Sitravatinib Related	43 87.8%	23 100.0%	18 100.0%	8 88.9%	51 96.2%	26 96.3%	52 92.9%	9 100.0%	8 100.0%	4 100.0%	3 75.0%
Nivolumab Related	41 83.7%	23 100.0%	15 83.3%	7 77.8%	41 77.4%	24 88.9%	35 62.5%	4 44.4%	NA [1]	NA [1]	NA [1]
Pembrolizumab Related	NA [2]	NA [2]	NA [2]	NA [2]	NA [2]	NA [2]	NA [2]	NA [2]	6 75.0%	3 75.0%	3 75.0%
Enfortumab Vedotin Related	NA [3]	NA [3]	NA [3]	NA [3]	NA [3]	NA [3]	NA [3]	NA [3]	7 87.5%	4 100.0%	4 100.0%

[1]

As pre-specified, participants did not receive nivolumab treatment in this Cohort.

[2]

As pre-specified, participants did not receive pembrolizumab treatment in this Cohort.

[3]

As pre-specified, participants did not receive enfortumab vedotin treatment in this Cohort.

5. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of objective progression of disease (PD) per RECIST V1.1, or to death due to any cause in the absence of documented PD. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm. Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.
Time Frame	Up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the Clinical Activity Evaluable Population-confirmed Response Subset, which included participants who achieved an objective response, received ≥1 dose of study treatment drug, had an evaluable baseline tumor assessment and ≥1 post-baseline tumor assessment. One participant in Cohort 6 who experienced a response wasn't included in DOR analysis because they didn't receive ≥1 dose of study treatment, have an evaluable baseline tumor assessment or ≥1 post-baseline tumor assessment.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants were enrolled to 3 dose levels of sitravatinib in combination with pembrolizumab and enfortumab vedotin. Sitravatinib was received orally via capsules QD in 21-day cycles at doses 35 mg and 70 mg. Pembrolizumab was received as an IV infusion over approximately 30 minutes (± 5 minutes) at 200 mg every 3 weeks (Q3W), in accordance with the current pembrolizumab USPI. Enfortumab vedotin dosing was based on participant weight, starting at 1.25 mg/kg up to 125 mg/kg QD, with a dose de-escalation step to 1 mg/kg. Enfortumab vedotin was received as an IV infusion over approximately 30 minutes (± 5 minutes) on Days 1 and 8 of a 21-day cycle.
Overall Number of Participants Analyzed	6	5	4	0	17	8	3	0	4
Median (95% Confidence Interval); Unit of Measure: months
	5.585 [1]; (3.844 to NA)	9.478 [1]; (5.782 to NA)	11.762 [1]; (7.392 to NA)		7.326; (5.520 to 12.977)	16.361 [1]; (5.552 to NA)	7.425 [1]; (5.552 to NA)		11.8 [1]; (4.70 to NA)

[1]

Upper confidence intervals could not be calculated due to the low number of participants with a response.

6. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	Clinical Benefit Rate (CBR) was defined as the number of participants documented to have a confirmed CR, PR, or stable disease (SD), per RECIST V1.1, documented during at least 1 on-study assessment. CR was defined as complete disappearance of all target lesions with the exception of nodal disease. All target nodes must have decreased to normal size (short axis < 10 mm). PR was defined as a greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. SD was defined as target lesions increasing by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds.
Time Frame	Up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants were enrolled to 3 dose levels of sitravatinib in combination with pembrolizumab and enfortumab vedotin. Sitravatinib was received orally via capsules QD in 21-day cycles at doses 35 mg and 70 mg. Pembrolizumab was received as an IV infusion over approximately 30 minutes (± 5 minutes) at 200 mg every 3 weeks (Q3W), in accordance with the current pembrolizumab USPI. Enfortumab vedotin dosing was based on participant weight, starting at 1.25 mg/kg up to 125 mg/kg QD, with a dose de-escalation step to 1 mg/kg. Enfortumab vedotin was received as an IV infusion over approximately 30 minutes (± 5 minutes) on Days 1 and 8 of a 21-day cycle.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	16
Measure Type: Count of Participants; Unit of Measure: Participants
	32 65.3%	19 82.6%	12 66.7%	7 77.8%	35 66.0%	17 63.0%	33 58.9%	6 66.7%	10 62.5%

7. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as the time from date of first study treatment to first PD per RECIST V1.1, or death due to any cause in the absence of documented PD.
Time Frame	Up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants were enrolled to 3 dose levels of sitravatinib in combination with pembrolizumab and enfortumab vedotin. Sitravatinib was received orally via capsules QD in 21-day cycles at doses 35 mg and 70 mg. Pembrolizumab was received as an IV infusion over approximately 30 minutes (± 5 minutes) at 200 mg every 3 weeks (Q3W), in accordance with the current pembrolizumab USPI. Enfortumab vedotin dosing was based on participant weight, starting at 1.25 mg/kg up to 125 mg/kg QD, with a dose de-escalation step to 1 mg/kg. Enfortumab vedotin was received as an IV infusion over approximately 30 minutes (± 5 minutes) on Days 1 and 8 of a 21-day cycle.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	16
Median (95% Confidence Interval); Unit of Measure: months
	3.877; (2.497 to 5.487)	7.786; (3.943 to 14.620)	3.910; (1.873 to 9.133)	3.515 [1]; (1.971 to NA)	3.943; (3.450 to 5.651)	5.421; (3.220 to 18.168)	3.680; (2.234 to 5.520)	3.713 [1]; (1.840 to NA)	4.0; (2.04 to 6.51)

[1]

Upper confidence intervals could not be calculated due to the low number of participants with a documented PD or death.

8. Secondary Outcome

Title	1-Year Survival Rate
Description	Survival was defined as the time from date of first study treatment to death due to any cause. Kaplan-Meier (product limit) estimates of the percentage of participants who died at 1-year was calculated to estimate the 1-year survival rate, defined as the percentage of participants alive at 1 year. Confidence Intervals were calculated based on Greenwood's formula. Participants who discontinued prior to 1-year were censored on the last date that they were known to be alive. For participants with no follow-up after first dose of study drug, survival rate was censored at the date of first dose (Day 1).
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants were enrolled to 3 dose levels of sitravatinib in combination with pembrolizumab and enfortumab vedotin. Sitravatinib was received orally via capsules QD in 21-day cycles at doses 35 mg and 70 mg. Pembrolizumab was received as an IV infusion over approximately 30 minutes (± 5 minutes) at 200 mg every 3 weeks (Q3W), in accordance with the current pembrolizumab USPI. Enfortumab vedotin dosing was based on participant weight, starting at 1.25 mg/kg up to 125 mg/kg QD, with a dose de-escalation step to 1 mg/kg. Enfortumab vedotin was received as an IV infusion over approximately 30 minutes (± 5 minutes) on Days 1 and 8 of a 21-day cycle.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	16
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	42.5; (27.9 to 56.4)	56.5; (34.3 to 73.8)	55.6; (30.5 to 74.8)	44.4; (13.6 to 71.9)	53.9; (39.5 to 66.3)	57.1; (36.0 to 73.6)	32.6; (19.5 to 46.3)	16.7; (1.1 to 49.3)	41.5; (15.4 to 66.1)

9. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from date of first study treatment to death due to any cause.
Time Frame	Up to approximately 3 years

Outcome Measure Data

Analysis Population Description

Measured in the Full Analysis Set, which included participants who received ≥ 1 dose of each study treatment drug (ie, ≥ 1 dose of both sitravatinib and nivolumab for Cohorts 1 to 8, or ≥ 1 dose each of sitravatinib, pembrolizumab, and enfortumab vedotin for Cohort 9). Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare efficacy endpoints across Cohort 9 dose levels.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9
Arm/Group Description:	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants were enrolled to 3 dose levels of sitravatinib in combination with pembrolizumab and enfortumab vedotin. Sitravatinib was received orally via capsules QD in 21-day cycles at doses 35 mg and 70 mg. Pembrolizumab was received as an IV infusion over approximately 30 minutes (± 5 minutes) at 200 mg every 3 weeks (Q3W), in accordance with the current pembrolizumab USPI. Enfortumab vedotin dosing was based on participant weight, starting at 1.25 mg/kg up to 125 mg/kg QD, with a dose de-escalation step to 1 mg/kg. Enfortumab vedotin was received as an IV infusion over approximately 30 minutes (± 5 minutes) on Days 1 and 8 of a 21-day cycle.
Overall Number of Participants Analyzed	49	23	18	9	53	27	56	9	16
Median (95% Confidence Interval); Unit of Measure: months
	8.049; (4.632 to 15.967)	15.639 [1]; (7.655 to NA)	12.945; (5.618 to 22.439)	5.092; (1.971 to 24.279)	13.405; (5.782 to 21.290)	NA [1]; (5.947 to NA)	8.969; (7.359 to 10.809)	7.556; (2.825 to 9.922)	10.8 [1]; (2.69 to NA)

[1]

Data could not be calculated as too few participants experienced an event.

10. Secondary Outcome

Title	Geometric Mean Blood Plasma Concentration of Sitravatinib
Description	Blood draws for analysis of blood plasma concentrations of sitravatinib were collected following electrocardiograms and assessment of vital signs. Concentration data below the limit of quantification were set to 0.
Time Frame	Cycle(C)1 Day(D)1 pre-dose, 30min, 2,4,6,7,8,24hr post-dose, C1D15 pre-dose, 30min,2,4,6,7,8,24hr post-dose, C2D1 pre-dose,7hr post-dose, C2D8,C3D1,C3D8,C5D1,C6D8 pre-dose (28 day cycles Cohorts 1-8, 21 day cycles Cohort 9)

Outcome Measure Data

Analysis Population Description

Measured in the Pharmacokinetic (PK) Evaluable Population, which included all participants who received treatment with sitravatinib and had available data at each timepoint. Per the statistical analysis plan (SAP), Cohort 9 arms are grouped as pre-specified as there was never intent to compare PK endpoints across Cohort 9 dose levels.

Arm/Group Title		Cohort 1	Cohort 2	Cohort 3	Cohort 4	Cohort 5	Cohort 6	Cohort 7	Cohort 8	Cohort 9
Arm/Group Description:		Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).	Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants were enrolled to 3 dose levels of sitravatinib in combination with pembrolizumab and enfortumab vedotin. Sitravatinib was received orally via capsules QD in 21-day cycles at doses 35 mg and 70 mg. Pembrolizumab was received as an IV infusion over approximately 30 minutes (± 5 minutes) at 200 mg every 3 weeks (Q3W), in accordance with the current pembrolizumab USPI. Enfortumab vedotin dosing was based on participant weight, starting at 1.25 mg/kg up to 125 mg/kg QD, with a dose de-escalation step to 1 mg/kg. Enfortumab vedotin was received as an IV infusion over approximately 30 minutes (± 5 minutes) on Days 1 and 8 of a 21-day cycle.
Overall Number of Participants Analyzed		49	23	17	9	53	27	56	9	16
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
Cycle 1 Day 1 Pre-dose	Number Analyzed	46 participants	21 participants	16 participants	9 participants	50 participants	24 participants	46 participants	8 participants	16 participants
		0; (0%)	0; (0%)	0; (0%)	0; (0%)	0; (0%)	0; (0%)	0; (0%)	0; (0%)	0; (0%)
Cycle 1 Day 1 30 Min Post-Dose	Number Analyzed	34 participants	15 participants	15 participants	6 participants	41 participants	18 participants	42 participants	7 participants	12 participants
		1.85; (300.88%)	0.82; (10.95%)	1.56; (176.68%)	0.91; (499.94%)	1.25; (266.58%)	1.28; (231.33%)	1.40; (268.79%)	0.25; (248.74%)	0.40; (172.86%)
Cycle 1 Day 1 2 Hours Post-Dose	Number Analyzed	7 participants	0 participants	1 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		5.69; (117.10%)		6.94 [1]; (NA%)		24.90 [1]; (NA%)
Cycle 1 Day 1 4 Hours Post-Dose	Number Analyzed	44 participants	12 participants	10 participants	5 participants	26 participants	0 participants	1 participants	0 participants	0 participants
		16.55; (168.43%)	21.46; (122.57%)	31.21; (80.61%)	18.33; (158.02%)	23.72; (104.51%)		35.20 [1]; (NA%)
Cycle 1 Day 1 6 Hours Post-Dose	Number Analyzed	7 participants	0 participants	1 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		23.16; (69.50%)		11.70 [1]; (NA%)		15.50 [1]; (NA%)
Cycle 1 Day 1 7 Hours Post-Dose	Number Analyzed	1 participants	6 participants	2 participants	4 participants	13 participants	7 participants	21 participants	5 participants	11 participants
		27.40 [1]; (NA%)	22.90; (121.87%)	20.08; (167.73%)	15.36; (108.29%)	23.13; (167.10%)	23.13; (126.44%)	37.99; (50.79%)	31.21; (39.99%)	10.56; (41.43%)
Cycle 1 Day 1 8 Hours Post-Dose	Number Analyzed	6 participants	0 participants	1 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		26.08; (72.20%)		12.10 [1]; (NA%)		23.00 [1]; (NA%)
Cycle 1 Day 1 24 Hours Post-Dose	Number Analyzed	6 participants	0 participants	0 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		24.82; (71.41%)				26.30 [1]; (NA%)
Cycle 1 Day 15 Pre-Dose	Number Analyzed	37 participants	15 participants	12 participants	8 participants	34 participants	9 participants	34 participants	4 participants	0 participants
		66.00; (52.30%)	50.21; (92.49%)	42.03; (232.08%)	55.22; (34.39%)	50.58; (51.48%)	70.11; (67.12%)	49.94; (60.28%)	47.01; (39.78%)
Cycle 1 Day 15 30 Min Post-Dose	Number Analyzed	6 participants	0 participants	0 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		54.47; (77.06%)				75.00 [1]; (NA%)
Cycle 1 Day 15 2 Hours Post-Dose	Number Analyzed	8 participants	0 participants	0 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		62.50; (44.94%)				67.80 [1]; (NA%)
Cycle 1 Day 15 4 Hours Post-Dose	Number Analyzed	34 participants	7 participants	10 participants	4 participants	21 participants	3 participants	2 participants	1 participants	0 participants
		70.90; (49.99%)	68.77; (23.87%)	52.36; (111.45%)	95.35; (3.65%)	68.67; (52.79%)	45.27; (21.03%)	50.71; (33.36%)	55.30 [1]; (NA%)
Cycle 1 Day 15 6 Hours Post-Dose	Number Analyzed	7 participants	0 participants	0 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		67.45; (55.03%)				82.90 [1]; (NA%)
Cycle 1 Day 15 7 Hours Post-Dose	Number Analyzed	0 participants	3 participants	2 participants	4 participants	9 participants	3 participants	19 participants	2 participants	0 participants
			89.19; (10.73%)	81.09; (85.63%)	62.78; (22.36%)	75.08; (45.43%)	104.61; (26.97%)	76.70; (51.05%)	86.04; (2.22%)
Cycle 1 Day 15 8 Hours Post-Dose	Number Analyzed	7 participants	0 participants	0 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		72.12; (58.96%)				95.20 [1]; (NA%)
Cycle 1 Day 15 24 Hours Post-Dose	Number Analyzed	6 participants	0 participants	0 participants	0 participants	1 participants	0 participants	0 participants	0 participants	0 participants
		59.88; (52.20%)				85.20 [1]; (NA%)
Cycle 2 Day 1 Pre-Dose	Number Analyzed	31 participants	17 participants	16 participants	7 participants	33 participants	19 participants	34 participants	6 participants	11 participants
		28.06; (184.46%)	36.81; (107.98%)	27.15; (459.38%)	48.24; (19.63%)	39.39; (101.75%)	32.81; (156.63%)	32.38; (155.83%)	46.89; (30.61%)	8.15; (274.13%)
Cycle 2 Day 1 7 Hours Post-Dose	Number Analyzed	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	5 participants
										26.28; (68.42%)
Cycle 2 Day 8 Pre-Dose	Number Analyzed	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	7 participants
										12.43; (476.36%)
Cycle 3 Day 1 Pre-Dose	Number Analyzed	23 participants	15 participants	8 participants	4 participants	25 participants	12 participants	30 participants	5 participants	0 participants
		29.10; (190.09%)	37.99; (126.82%)	32.32; (56.61%)	56.40; (45.32%)	39.28; (48.02%)	20.02; (422.49%)	29.21; (140.39%)	19.39; (259.86%)
Cycle 3 Day 8 Pre-Dose	Number Analyzed	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	5 participants
										7.53; (823.64%)
Cycle 5 Day 1 Pre-Dose	Number Analyzed	16 participants	9 participants	8 participants	3 participants	18 participants	10 participants	23 participants	2 participants	0 participants
		33.41; (41.39%)	40.39; (20.19%)	44.45; (42.23%)	28.04; (81.00%)	26.48; (121.54%)	42.98; (39.16%)	37.55; (47.23%)	38.47; (20.17%)
Cycle 6 Day 8 Pre-Dose	Number Analyzed	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	5 participants
										17.87; (105.74%)

[1]

Geometric coefficient of variation could not be calculated as there was only 1 participant with evaluable PK samples at this time point.

11. Secondary Outcome

Title	Cohort 9 Lead-in Dose Escalation Part Only: Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
Description	A DLT was defined as any of the following events considered to be causally related to treatment with sitravatinib in combination with pembrolizumab and enfortumab in the lead-in dose escalation part of Cohort 9 (as pre-specified): hematological DLTs (Grade 4 neutropenia, thrombocytopenia, anemia unexplained by underlying disease, ≥Grade 3 febrile neutropenia or neutropenia with significant clinical sequelae, or any requirement for a platelet transfusion), non-hematological DLTs (≥Grade 4 infusion related reaction, non-hematological toxicity, Grade 3 infusion related reaction that does not resolve within 24 hours, hypertension that cannot be controlled with medical therapy), other Grade 3 non-hematologic toxicity lasting for >3 days, with exceptions, Grade 2 pneumonitis or colitis, ≥Grade 3 non-hematological laboratory abnormalities, alanine transaminase>3 x upper limit of normal (ULN) with bilirubin> 2xULN, and other related toxic effects may have been assessed as DLTs.
Time Frame	Cycle 1 Day 1 through pre-dose Cycle 2 Day 1 (cycle for Cohort 9 was 21 days)

Outcome Measure Data

Analysis Population Description

Measured in the DLT evaluable population, which, as pre-specified in the statistical analysis plan, was defined as participants who enrolled in the lead-in dose escalation portion of Cohort 9, who experienced a DLT or who cleared the DLT period.

Arm/Group Title	Cohort 9 Dose Level 1	Cohort 9 Dose Level 2	Cohort 9 Dose Level 3
Arm/Group Description:	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.	Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.
Overall Number of Participants Analyzed	8	4	4
Measure Type: Count of Participants; Unit of Measure: Participants
	2 25.0%	0 0.0%	2 50.0%

Adverse Events

Time Frame	Day 1 up to approximately 3 years
Adverse Event Reporting Description	All cause mortality, serious adverse events and other adverse events are reported for all enrolled participants.
Arm/Group Title	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5		Cohort 6		Cohort 7		Cohort 8		Cohort 9 Dose Level 1		Cohort 9 Dose Level 2		Cohort 9 Dose Level 3
Arm/Group Description	Participants with locally advanced or metastatic urothelial carcinoma (UC) with documented disease progression on or after previous anti-programmed cell death (PD)-ligand(L)-1 as most recent treatment, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 1. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules once daily (QD) in 28-day cycles. Nivolumab was received via an intravenous (IV) infusion over approximately 30 minutes (± 5 minutes) at 240 mg once every 2 weeks (Q2W) or 480 mg once every 4 weeks (Q4W), at the discretion of the Investigator and in accordance with the current nivolumab US Prescribing Information (USPI).		Participants with locally advanced or metastatic UC with documented disease progression on or after previous anti-PD-L-1 as most recent treatment, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 2. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.		Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 3. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.		Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti-PD-(L)1 as the most recent treatment, who previously received (in combination or separately) other selected immunotherapies, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 4. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.		Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 5. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.		Participants with locally advanced or metastatic UC who had not previously received an anti-PD-(L)1, and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 6. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 120 mg capsules QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.		Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and antibody-drug conjugate (ADC) (in combination or separately, and in any order), and who were previously treated with a platinum-based chemotherapy were enrolled into Cohort 7. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.		Participants with locally advanced or metastatic UC with documented disease progression on or after a previous anti PD-(L)1 and ADC (in combination or separately, and in any order), and who were considered ineligible for platinum-based chemotherapy were enrolled into Cohort 8. Participants received sitravatinib in combination with nivolumab. Sitravatinib was received orally via 100 mg malate capsules, or 120 mg free base capsule formulation QD in 28-day cycles. Nivolumab was received via an IV infusion over approximately 30 minutes (± 5 minutes) at 240 mg Q2W or 480 mg Q4W, at the discretion of the Investigator and in accordance with the current nivolumab USPI.		Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 1 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.25 mg/kg IV infusion on Days 1 and 8 every 3 weeks (Q3W), and pembrolizumab 200 mg Q3W as an IV infusion.		Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 2 were enrolled to receive sitravatinib 35 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.		Participants with locally advanced or metastatic UC who had previously received a PD-(L)1 checkpoint inhibitor (CPI) and a platinum-based chemotherapy were enrolled into Cohort 9, which included a lead-in dose-escalation part. A dose-expansion part was planned, but was not enrolled. During the lead-in dose-escalation part, participants in Cohort 9 Dose Level 3 were enrolled to receive sitravatinib 70 mg QD orally via capsules in 21-day cycles, enfortumab vedotin 1.0 mg/kg IV infusion on Days 1 and 8 Q3W, and pembrolizumab 200 mg Q3W as an IV infusion.
All-Cause Mortality
	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5		Cohort 6		Cohort 7		Cohort 8		Cohort 9 Dose Level 1		Cohort 9 Dose Level 2		Cohort 9 Dose Level 3
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	37/49 (75.51%)		15/23 (65.22%)		15/18 (83.33%)		7/9 (77.78%)		35/53 (66.04%)		12/27 (44.44%)		36/56 (64.29%)		8/9 (88.89%)		5/8 (62.50%)		3/4 (75.00%)		0/4 (0.00%)
Serious Adverse Events
	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5		Cohort 6		Cohort 7		Cohort 8		Cohort 9 Dose Level 1		Cohort 9 Dose Level 2		Cohort 9 Dose Level 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/49 (71.43%)		15/23 (65.22%)		10/18 (55.56%)		4/9 (44.44%)		26/53 (49.06%)		14/27 (51.85%)		23/56 (41.07%)		3/9 (33.33%)		5/8 (62.50%)		1/4 (25.00%)		3/4 (75.00%)
Blood and lymphatic system disorders
Anaemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Leukocytosis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Thrombocytopenia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Cardiac disorders
Cardiac failure congestive † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Atrial fibrillation † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Endocrine disorders
Adrenal insufficiency † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperthyroidism † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypothyroidism † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Gastrointestinal disorders
Abdominal distension † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Abdominal pain † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Abdominal pain upper † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	2/27 (7.41%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Ascites † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Constipation † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Diarrhoea † 1	3/49 (6.12%)	3	2/23 (8.70%)	2	0/18 (0.00%)	0	1/9 (11.11%)	2	2/53 (3.77%)	2	1/27 (3.70%)	1	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Dysphagia † 1	2/49 (4.08%)	2	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Large intestinal obstruction † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Nausea † 1	3/49 (6.12%)	3	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pancreatitis † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	2/18 (11.11%)	3	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Rectal haemorrhage † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Vomiting † 1	3/49 (6.12%)	4	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
General disorders
Asthenia † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Chills † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Fatigue † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Influenza like illness † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Infusion site extravasation † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Non-cardiac chest pain † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pyrexia † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Infections and infestations
Cellulitis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Corona virus infection † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Kidney infection † 1	2/49 (4.08%)	2	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pneumonia † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Sepsis † 1	2/49 (4.08%)	3	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	2	1/27 (3.70%)	1	3/56 (5.36%)	3	0/9 (0.00%)	0	2/8 (25.00%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin infection † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Urinary tract infection † 1	3/49 (6.12%)	3	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	6/53 (11.32%)	6	2/27 (7.41%)	2	3/56 (5.36%)	4	1/9 (11.11%)	1	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Injury, poisoning and procedural complications
Fall † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Amylase increased † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Aspartate aminotransferase increased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood bilirubin increased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood creatinine increased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Ejection fraction decreased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Lipase increased † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Metabolism and nutrition disorders
Dehydration † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperglycaemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypocalcaemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypokalaemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypomagnesaemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyponatraemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Bone pain † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Flank pain † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Muscular weakness † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Musculoskeletal pain † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Nervous system disorders
Dizziness † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Headache † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Syncope † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	2/8 (25.00%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	2/49 (4.08%)	2	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	1/27 (3.70%)	1	1/56 (1.79%)	2	1/9 (11.11%)	2	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Haematuria † 1	2/49 (4.08%)	2	1/23 (4.35%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	2/8 (25.00%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Urinary incontinence † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Urinary retention † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Urinary tract obstruction † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Dyspnoea † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	4	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Epistaxis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pneumonitis † 1	1/49 (2.04%)	1	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pulmonary embolism † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	2	0/9 (0.00%)	0	3/53 (5.66%)	3	0/27 (0.00%)	0	3/56 (5.36%)	3	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Vascular disorders
Embolism † 1	2/49 (4.08%)	3	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypertension † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Orthostatic hypotension † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
1 Term from vocabulary, MedDRA 21.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Cohort 1		Cohort 2		Cohort 3		Cohort 4		Cohort 5		Cohort 6		Cohort 7		Cohort 8		Cohort 9 Dose Level 1		Cohort 9 Dose Level 2		Cohort 9 Dose Level 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/49 (100.00%)		23/23 (100.00%)		18/18 (100.00%)		9/9 (100.00%)		53/53 (100.00%)		27/27 (100.00%)		56/56 (100.00%)		9/9 (100.00%)		8/8 (100.00%)		4/4 (100.00%)		4/4 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	13/49 (26.53%)	27	10/23 (43.48%)	14	2/18 (11.11%)	4	2/9 (22.22%)	3	10/53 (18.87%)	21	10/27 (37.04%)	27	10/56 (17.86%)	18	1/9 (11.11%)	2	2/8 (25.00%)	3	1/4 (25.00%)	2	1/4 (25.00%)	1
Iron deficiency anaemia † 1	0/49 (0.00%)	0	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Leukocytosis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Lymphadenopathy † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	2	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Lymphopenia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Neutropenia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	4	0/4 (0.00%)	0	0/4 (0.00%)	0
Polycythaemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Thrombocytopenia † 1	2/49 (4.08%)	5	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Thrombocytosis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Cardiac disorders
Bradycardia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Cardiac failure congestive † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Cardiomegaly † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Palpitations † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	2	0/9 (0.00%)	0	0/53 (0.00%)	0	2/27 (7.41%)	2	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Pericardial effusion † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	2/8 (25.00%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Sinus tachycardia † 1	3/49 (6.12%)	3	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Supraventricular extrasystoles † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Tachycardia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	6/53 (11.32%)	6	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Ear and labyrinth disorders
Deafness unilateral † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Ear haemorrhage † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Tinnitus † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	4/53 (7.55%)	4	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Endocrine disorders
Adrenal insufficiency † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Androgen deficiency † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperthyroidism † 1	4/49 (8.16%)	5	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	3/53 (5.66%)	4	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypogonadism male † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypothyroidism † 1	19/49 (38.78%)	20	9/23 (39.13%)	9	8/18 (44.44%)	9	4/9 (44.44%)	4	14/53 (26.42%)	15	8/27 (29.63%)	9	13/56 (23.21%)	14	2/9 (22.22%)	3	1/8 (12.50%)	1	1/4 (25.00%)	1	0/4 (0.00%)	0
Eye disorders
Dry eye † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	3/53 (5.66%)	3	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Eye disorder † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Eye pain † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Eyelid margin crusting † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Scleral discolouration † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Vision blurred † 1	3/49 (6.12%)	4	1/23 (4.35%)	1	0/18 (0.00%)	0	1/9 (11.11%)	1	3/53 (5.66%)	3	1/27 (3.70%)	1	3/56 (5.36%)	3	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Vitreous floaters † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	2	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Gastrointestinal disorders
Abdominal distension † 1	3/49 (6.12%)	3	0/23 (0.00%)	0	2/18 (11.11%)	3	0/9 (0.00%)	0	4/53 (7.55%)	5	1/27 (3.70%)	1	3/56 (5.36%)	3	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Abdominal pain † 1	8/49 (16.33%)	8	4/23 (17.39%)	6	8/18 (44.44%)	10	1/9 (11.11%)	1	9/53 (16.98%)	13	12/27 (44.44%)	16	6/56 (10.71%)	8	1/9 (11.11%)	1	2/8 (25.00%)	3	1/4 (25.00%)	1	1/4 (25.00%)	1
Abdominal pain lower † 1	1/49 (2.04%)	1	1/23 (4.35%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	2/56 (3.57%)	2	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Abdominal pain upper † 1	2/49 (4.08%)	2	1/23 (4.35%)	1	1/18 (5.56%)	2	0/9 (0.00%)	0	2/53 (3.77%)	3	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Anal haemorrhage † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Ascites † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	2	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Constipation † 1	16/49 (32.65%)	20	9/23 (39.13%)	10	5/18 (27.78%)	7	0/9 (0.00%)	0	17/53 (32.08%)	26	12/27 (44.44%)	16	17/56 (30.36%)	18	2/9 (22.22%)	2	4/8 (50.00%)	4	1/4 (25.00%)	1	2/4 (50.00%)	2
Diarrhoea † 1	29/49 (59.18%)	66	20/23 (86.96%)	52	13/18 (72.22%)	24	4/9 (44.44%)	12	34/53 (64.15%)	109	18/27 (66.67%)	33	31/56 (55.36%)	66	3/9 (33.33%)	11	4/8 (50.00%)	7	3/4 (75.00%)	4	1/4 (25.00%)	4
Dry mouth † 1	3/49 (6.12%)	3	6/23 (26.09%)	7	3/18 (16.67%)	3	2/9 (22.22%)	2	4/53 (7.55%)	4	6/27 (22.22%)	7	7/56 (12.50%)	7	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Duodenal ulcer † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Dyspepsia † 1	3/49 (6.12%)	3	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	5/56 (8.93%)	5	0/9 (0.00%)	0	1/8 (12.50%)	1	1/4 (25.00%)	1	0/4 (0.00%)	0
Dysphagia † 1	4/49 (8.16%)	4	3/23 (13.04%)	4	3/18 (16.67%)	4	0/9 (0.00%)	0	5/53 (9.43%)	5	1/27 (3.70%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Faeces discoloured † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Flatulence † 1	1/49 (2.04%)	1	3/23 (13.04%)	4	0/18 (0.00%)	0	1/9 (11.11%)	1	2/53 (3.77%)	2	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Gastrooesophageal reflux disease † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	2/18 (11.11%)	2	0/9 (0.00%)	0	5/53 (9.43%)	5	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Gingival pain † 1	3/49 (6.12%)	3	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Haemorrhoidal haemorrhage † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	3/27 (11.11%)	4	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Haemorrhoids † 1	0/49 (0.00%)	0	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	2/27 (7.41%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Large intestinal obstruction † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	2	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Nausea † 1	20/49 (40.82%)	37	12/23 (52.17%)	18	7/18 (38.89%)	9	3/9 (33.33%)	3	19/53 (35.85%)	26	13/27 (48.15%)	18	17/56 (30.36%)	23	5/9 (55.56%)	6	2/8 (25.00%)	7	3/4 (75.00%)	4	1/4 (25.00%)	1
Odynophagia † 1	2/49 (4.08%)	5	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Oral dysaesthesia † 1	6/49 (12.24%)	9	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Oral pain † 1	2/49 (4.08%)	3	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	3	2/27 (7.41%)	2	5/56 (8.93%)	5	1/9 (11.11%)	1	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Pancreatitis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	1/9 (11.11%)	1	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Rectal haemorrhage † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Retching † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Small intestinal obstruction † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	2/27 (7.41%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Stomatitis † 1	11/49 (22.45%)	19	4/23 (17.39%)	7	7/18 (38.89%)	9	2/9 (22.22%)	2	7/53 (13.21%)	11	7/27 (25.93%)	12	10/56 (17.86%)	18	3/9 (33.33%)	3	1/8 (12.50%)	1	1/4 (25.00%)	1	0/4 (0.00%)	0
Vomiting † 1	15/49 (30.61%)	23	7/23 (30.43%)	9	2/18 (11.11%)	2	1/9 (11.11%)	1	16/53 (30.19%)	22	7/27 (25.93%)	12	11/56 (19.64%)	14	4/9 (44.44%)	5	1/8 (12.50%)	3	0/4 (0.00%)	0	1/4 (25.00%)	1
General disorders
Asthenia † 1	2/49 (4.08%)	2	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	2/53 (3.77%)	2	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Axillary pain † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	2	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Chest discomfort † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Chills † 1	5/49 (10.20%)	5	1/23 (4.35%)	1	1/18 (5.56%)	1	1/9 (11.11%)	1	8/53 (15.09%)	8	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Face oedema † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Fatigue † 1	35/49 (71.43%)	67	19/23 (82.61%)	46	15/18 (83.33%)	28	4/9 (44.44%)	5	32/53 (60.38%)	54	17/27 (62.96%)	27	24/56 (42.86%)	33	1/9 (11.11%)	1	3/8 (37.50%)	7	3/4 (75.00%)	11	2/4 (50.00%)	7
Feeling cold † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Gait disturbance † 1	1/49 (2.04%)	5	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Influenza like illness † 1	1/49 (2.04%)	2	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	2/53 (3.77%)	2	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Infusion site extravasation † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	2	0/4 (0.00%)	0
Localised oedema † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Malaise † 1	0/49 (0.00%)	0	1/23 (4.35%)	3	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Mucosal inflammation † 1	4/49 (8.16%)	4	1/23 (4.35%)	1	3/18 (16.67%)	5	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Non-cardiac chest pain † 1	1/49 (2.04%)	1	2/23 (8.70%)	4	2/18 (11.11%)	2	0/9 (0.00%)	0	2/53 (3.77%)	2	1/27 (3.70%)	1	4/56 (7.14%)	4	1/9 (11.11%)	1	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Oedema peripheral † 1	13/49 (26.53%)	14	9/23 (39.13%)	15	2/18 (11.11%)	2	1/9 (11.11%)	1	7/53 (13.21%)	7	4/27 (14.81%)	7	5/56 (8.93%)	6	3/9 (33.33%)	3	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Pyrexia † 1	6/49 (12.24%)	9	6/23 (26.09%)	7	2/18 (11.11%)	2	1/9 (11.11%)	1	5/53 (9.43%)	7	3/27 (11.11%)	4	8/56 (14.29%)	9	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Temperature intolerance † 1	3/49 (6.12%)	5	1/23 (4.35%)	1	2/18 (11.11%)	2	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Infections and infestations
Bronchitis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Candida infection † 1	2/49 (4.08%)	2	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Cellulitis † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	0/18 (0.00%)	0	1/9 (11.11%)	1	1/53 (1.89%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Conjunctivitis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Corona virus infection † 1	1/49 (2.04%)	2	2/23 (8.70%)	2	0/18 (0.00%)	0	1/9 (11.11%)	1	1/53 (1.89%)	1	3/27 (11.11%)	3	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Cystitis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Ear infection † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Fungal skin infection † 1	0/49 (0.00%)	0	1/23 (4.35%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	2/27 (7.41%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hand-foot-and-mouth disease † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Kidney infection † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Onychomycosis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Oral candidiasis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Pneumonia † 1	0/49 (0.00%)	0	3/23 (13.04%)	4	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Rash pustular † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Sepsis † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	4	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Sinusitis † 1	0/49 (0.00%)	0	2/23 (8.70%)	3	0/18 (0.00%)	0	0/9 (0.00%)	0	4/53 (7.55%)	5	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin infection † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	2/56 (3.57%)	4	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Tooth infection † 1	2/49 (4.08%)	2	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	3	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Urinary tract infection † 1	8/49 (16.33%)	16	8/23 (34.78%)	13	4/18 (22.22%)	5	1/9 (11.11%)	1	8/53 (15.09%)	14	6/27 (22.22%)	7	7/56 (12.50%)	10	3/9 (33.33%)	5	1/8 (12.50%)	1	2/4 (50.00%)	2	2/4 (50.00%)	2
Injury, poisoning and procedural complications
Fall † 1	6/49 (12.24%)	6	4/23 (17.39%)	5	0/18 (0.00%)	0	2/9 (22.22%)	3	6/53 (11.32%)	7	6/27 (22.22%)	8	2/56 (3.57%)	4	0/9 (0.00%)	0	2/8 (25.00%)	3	1/4 (25.00%)	1	0/4 (0.00%)	0
Infusion related reaction † 1	0/49 (0.00%)	0	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Medication error † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Muscle strain † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Procedural pain † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin abrasion † 1	0/49 (0.00%)	0	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Stoma site haemorrhage † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Subarachnoid haemorrhage † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Subdural haematoma † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Upper limb fracture † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	17/49 (34.69%)	22	8/23 (34.78%)	14	3/18 (16.67%)	3	2/9 (22.22%)	3	23/53 (43.40%)	40	14/27 (51.85%)	23	15/56 (26.79%)	16	1/9 (11.11%)	1	2/8 (25.00%)	3	1/4 (25.00%)	1	1/4 (25.00%)	1
Amylase increased † 1	10/49 (20.41%)	15	5/23 (21.74%)	5	3/18 (16.67%)	3	2/9 (22.22%)	3	3/53 (5.66%)	7	6/27 (22.22%)	17	4/56 (7.14%)	8	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Aspartate aminotransferase increased † 1	14/49 (28.57%)	19	9/23 (39.13%)	11	5/18 (27.78%)	5	2/9 (22.22%)	2	18/53 (33.96%)	26	14/27 (51.85%)	32	17/56 (30.36%)	18	1/9 (11.11%)	1	3/8 (37.50%)	8	2/4 (50.00%)	2	1/4 (25.00%)	1
Blood albumin decreased † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood alkaline phosphatase increased † 1	8/49 (16.33%)	9	5/23 (21.74%)	13	3/18 (16.67%)	3	0/9 (0.00%)	0	8/53 (15.09%)	10	6/27 (22.22%)	7	6/56 (10.71%)	10	1/9 (11.11%)	1	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood bilirubin increased † 1	2/49 (4.08%)	3	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	3/53 (5.66%)	3	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood creatinine increased † 1	10/49 (20.41%)	21	9/23 (39.13%)	10	2/18 (11.11%)	2	1/9 (11.11%)	1	17/53 (32.08%)	27	8/27 (29.63%)	13	6/56 (10.71%)	6	2/9 (22.22%)	2	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Blood glucose increased † 1	3/49 (6.12%)	4	2/23 (8.70%)	2	2/18 (11.11%)	2	0/9 (0.00%)	0	2/53 (3.77%)	3	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood thyroid stimulating hormone decreased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood thyroid stimulating hormone increased † 1	1/49 (2.04%)	1	6/23 (26.09%)	6	0/18 (0.00%)	0	0/9 (0.00%)	0	8/53 (15.09%)	9	7/27 (25.93%)	7	3/56 (5.36%)	3	1/9 (11.11%)	1	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Blood triglycerides increased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Blood urea increased † 1	2/49 (4.08%)	5	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	2	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Ejection fraction decreased † 1	3/49 (6.12%)	3	2/23 (8.70%)	2	1/18 (5.56%)	1	0/9 (0.00%)	0	5/53 (9.43%)	6	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Lipase increased † 1	10/49 (20.41%)	22	6/23 (26.09%)	7	5/18 (27.78%)	9	2/9 (22.22%)	6	6/53 (11.32%)	13	6/27 (22.22%)	24	10/56 (17.86%)	14	1/9 (11.11%)	2	1/8 (12.50%)	5	0/4 (0.00%)	0	1/4 (25.00%)	2
Lymphocyte count decreased † 1	5/49 (10.20%)	6	4/23 (17.39%)	7	3/18 (16.67%)	5	1/9 (11.11%)	2	5/53 (9.43%)	8	3/27 (11.11%)	6	3/56 (5.36%)	7	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Neutrophil count decreased † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Platelet count decreased † 1	5/49 (10.20%)	7	3/23 (13.04%)	5	4/18 (22.22%)	10	1/9 (11.11%)	1	7/53 (13.21%)	10	3/27 (11.11%)	3	3/56 (5.36%)	3	1/9 (11.11%)	3	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Troponin T increased † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Weight decreased † 1	15/49 (30.61%)	25	13/23 (56.52%)	20	4/18 (22.22%)	10	2/9 (22.22%)	2	14/53 (26.42%)	26	11/27 (40.74%)	15	12/56 (21.43%)	14	0/9 (0.00%)	0	2/8 (25.00%)	3	3/4 (75.00%)	3	1/4 (25.00%)	1
White blood cell count decreased † 1	2/49 (4.08%)	4	0/23 (0.00%)	0	2/18 (11.11%)	2	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Metabolism and nutrition disorders
Cachexia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Decreased appetite † 1	23/49 (46.94%)	41	18/23 (78.26%)	26	12/18 (66.67%)	21	3/9 (33.33%)	3	32/53 (60.38%)	51	14/27 (51.85%)	18	17/56 (30.36%)	24	1/9 (11.11%)	1	2/8 (25.00%)	4	3/4 (75.00%)	3	2/4 (50.00%)	2
Dehydration † 1	5/49 (10.20%)	6	3/23 (13.04%)	3	1/18 (5.56%)	1	2/9 (22.22%)	2	8/53 (15.09%)	9	2/27 (7.41%)	2	5/56 (8.93%)	5	0/9 (0.00%)	0	1/8 (12.50%)	1	2/4 (50.00%)	2	1/4 (25.00%)	1
Glucose tolerance impaired † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Hypercalcaemia † 1	1/49 (2.04%)	1	3/23 (13.04%)	3	0/18 (0.00%)	0	0/9 (0.00%)	0	4/53 (7.55%)	7	1/27 (3.70%)	1	2/56 (3.57%)	3	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperglycaemia † 1	6/49 (12.24%)	9	3/23 (13.04%)	7	2/18 (11.11%)	7	1/9 (11.11%)	1	4/53 (7.55%)	5	7/27 (25.93%)	14	2/56 (3.57%)	2	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperkalaemia † 1	3/49 (6.12%)	11	3/23 (13.04%)	4	1/18 (5.56%)	2	1/9 (11.11%)	4	5/53 (9.43%)	8	6/27 (22.22%)	7	2/56 (3.57%)	2	3/9 (33.33%)	6	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Hyperlipidaemia † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypertriglyceridaemia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperuricaemia † 1	4/49 (8.16%)	6	3/23 (13.04%)	5	2/18 (11.11%)	2	2/9 (22.22%)	2	7/53 (13.21%)	8	7/27 (25.93%)	7	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Hypoalbuminaemia † 1	9/49 (18.37%)	14	7/23 (30.43%)	10	3/18 (16.67%)	6	2/9 (22.22%)	3	8/53 (15.09%)	11	8/27 (29.63%)	9	5/56 (8.93%)	6	0/9 (0.00%)	0	1/8 (12.50%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypocalcaemia † 1	3/49 (6.12%)	7	2/23 (8.70%)	2	1/18 (5.56%)	1	0/9 (0.00%)	0	4/53 (7.55%)	5	2/27 (7.41%)	3	3/56 (5.36%)	4	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypoglycaemia † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	2/56 (3.57%)	2	0/9 (0.00%)	0	1/8 (12.50%)	1	1/4 (25.00%)	1	0/4 (0.00%)	0
Hypokalaemia † 1	3/49 (6.12%)	3	2/23 (8.70%)	2	1/18 (5.56%)	1	1/9 (11.11%)	1	8/53 (15.09%)	9	4/27 (14.81%)	4	4/56 (7.14%)	11	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	1/4 (25.00%)	1
Hypomagnesaemia † 1	6/49 (12.24%)	8	4/23 (17.39%)	7	1/18 (5.56%)	4	2/9 (22.22%)	2	8/53 (15.09%)	10	3/27 (11.11%)	3	6/56 (10.71%)	13	1/9 (11.11%)	1	0/8 (0.00%)	0	1/4 (25.00%)	2	1/4 (25.00%)	1
Hyponatraemia † 1	6/49 (12.24%)	12	4/23 (17.39%)	6	5/18 (27.78%)	10	2/9 (22.22%)	2	16/53 (30.19%)	29	7/27 (25.93%)	10	8/56 (14.29%)	10	3/9 (33.33%)	5	1/8 (12.50%)	1	0/4 (0.00%)	0	1/4 (25.00%)	1
Hypophosphataemia † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	1/9 (11.11%)	2	2/53 (3.77%)	2	2/27 (7.41%)	3	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Iron deficiency † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Vitamin B12 deficiency † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	11/49 (22.45%)	16	3/23 (13.04%)	4	1/18 (5.56%)	2	1/9 (11.11%)	1	10/53 (18.87%)	14	3/27 (11.11%)	3	11/56 (19.64%)	14	0/9 (0.00%)	0	1/8 (12.50%)	5	0/4 (0.00%)	0	0/4 (0.00%)	0
Arthritis † 1	0/49 (0.00%)	0	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Back pain † 1	6/49 (12.24%)	6	6/23 (26.09%)	7	4/18 (22.22%)	7	1/9 (11.11%)	1	11/53 (20.75%)	13	5/27 (18.52%)	6	8/56 (14.29%)	12	2/9 (22.22%)	3	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Bone pain † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Coccydynia † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Flank pain † 1	4/49 (8.16%)	4	4/23 (17.39%)	4	2/18 (11.11%)	2	0/9 (0.00%)	0	3/53 (5.66%)	4	2/27 (7.41%)	2	2/56 (3.57%)	2	0/9 (0.00%)	0	1/8 (12.50%)	3	0/4 (0.00%)	0	0/4 (0.00%)	0
Gouty arthritis † 1	1/49 (2.04%)	2	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Joint swelling † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Muscle spasms † 1	2/49 (4.08%)	2	4/23 (17.39%)	4	1/18 (5.56%)	1	0/9 (0.00%)	0	2/53 (3.77%)	4	1/27 (3.70%)	1	2/56 (3.57%)	2	0/9 (0.00%)	0	2/8 (25.00%)	3	0/4 (0.00%)	0	0/4 (0.00%)	0
Muscular weakness † 1	2/49 (4.08%)	2	7/23 (30.43%)	12	1/18 (5.56%)	1	3/9 (33.33%)	3	3/53 (5.66%)	3	5/27 (18.52%)	5	3/56 (5.36%)	4	1/9 (11.11%)	1	2/8 (25.00%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Musculoskeletal chest pain † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	3	1/27 (3.70%)	1	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Musculoskeletal pain † 1	2/49 (4.08%)	2	3/23 (13.04%)	3	1/18 (5.56%)	1	0/9 (0.00%)	0	7/53 (13.21%)	18	0/27 (0.00%)	0	2/56 (3.57%)	2	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Musculoskeletal stiffness † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Myalgia † 1	3/49 (6.12%)	3	0/23 (0.00%)	0	1/18 (5.56%)	1	2/9 (22.22%)	3	6/53 (11.32%)	8	3/27 (11.11%)	3	1/56 (1.79%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Neck pain † 1	1/49 (2.04%)	1	2/23 (8.70%)	2	1/18 (5.56%)	1	0/9 (0.00%)	0	3/53 (5.66%)	4	1/27 (3.70%)	1	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pain in extremity † 1	2/49 (4.08%)	2	2/23 (8.70%)	7	3/18 (16.67%)	3	1/9 (11.11%)	1	5/53 (9.43%)	13	3/27 (11.11%)	3	2/56 (3.57%)	2	0/9 (0.00%)	0	2/8 (25.00%)	5	0/4 (0.00%)	0	0/4 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain † 1	5/49 (10.20%)	8	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	1/27 (3.70%)	2	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Nervous system disorders
Amnesia † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	1/9 (11.11%)	2	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Ataxia † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Disturbance in attention † 1	2/49 (4.08%)	2	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Dizziness † 1	8/49 (16.33%)	11	6/23 (26.09%)	9	0/18 (0.00%)	0	1/9 (11.11%)	1	14/53 (26.42%)	16	12/27 (44.44%)	12	11/56 (19.64%)	11	2/9 (22.22%)	2	3/8 (37.50%)	5	0/4 (0.00%)	0	1/4 (25.00%)	1
Dysarthria † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Dysgeusia † 1	10/49 (20.41%)	18	5/23 (21.74%)	5	4/18 (22.22%)	5	4/9 (44.44%)	4	4/53 (7.55%)	4	5/27 (18.52%)	6	4/56 (7.14%)	4	0/9 (0.00%)	0	2/8 (25.00%)	4	2/4 (50.00%)	3	2/4 (50.00%)	2
Headache † 1	8/49 (16.33%)	9	2/23 (8.70%)	3	3/18 (16.67%)	4	0/9 (0.00%)	0	9/53 (16.98%)	13	5/27 (18.52%)	5	9/56 (16.07%)	12	1/9 (11.11%)	1	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperreflexia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Lethargy † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	3	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Memory impairment † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Migraine † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Neuropathy peripheral † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	4/53 (7.55%)	7	0/27 (0.00%)	0	3/56 (5.36%)	4	1/9 (11.11%)	1	1/8 (12.50%)	1	1/4 (25.00%)	2	1/4 (25.00%)	2
Paraesthesia † 1	3/49 (6.12%)	3	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	3/27 (11.11%)	3	2/56 (3.57%)	5	1/9 (11.11%)	1	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Peripheral sensory neuropathy † 1	1/49 (2.04%)	2	2/23 (8.70%)	3	2/18 (11.11%)	2	1/9 (11.11%)	1	1/53 (1.89%)	2	2/27 (7.41%)	2	3/56 (5.36%)	4	0/9 (0.00%)	0	2/8 (25.00%)	6	2/4 (50.00%)	2	1/4 (25.00%)	1
Seizure † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	3	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Syncope † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	3/8 (37.50%)	3	0/4 (0.00%)	0	0/4 (0.00%)	0
Psychiatric disorders
Anxiety † 1	2/49 (4.08%)	2	0/23 (0.00%)	0	2/18 (11.11%)	2	0/9 (0.00%)	0	4/53 (7.55%)	4	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Confusional state † 1	3/49 (6.12%)	4	1/23 (4.35%)	1	3/18 (16.67%)	3	1/9 (11.11%)	1	2/53 (3.77%)	2	3/27 (11.11%)	3	3/56 (5.36%)	3	2/9 (22.22%)	2	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Delirium † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	1/9 (11.11%)	1	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Depression † 1	5/49 (10.20%)	5	1/23 (4.35%)	1	2/18 (11.11%)	2	0/9 (0.00%)	0	4/53 (7.55%)	4	1/27 (3.70%)	1	3/56 (5.36%)	3	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	1/4 (25.00%)	1
Insomnia † 1	10/49 (20.41%)	11	6/23 (26.09%)	7	1/18 (5.56%)	1	2/9 (22.22%)	2	7/53 (13.21%)	7	1/27 (3.70%)	2	3/56 (5.36%)	3	1/9 (11.11%)	1	1/8 (12.50%)	1	1/4 (25.00%)	1	0/4 (0.00%)	0
Irritability † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Tangentiality † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	0/49 (0.00%)	0	2/23 (8.70%)	2	1/18 (5.56%)	1	0/9 (0.00%)	0	2/53 (3.77%)	2	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Bladder spasm † 1	4/49 (8.16%)	5	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Chromaturia † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	1/56 (1.79%)	3	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Chronic kidney disease † 1	2/49 (4.08%)	3	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Cystitis noninfective † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Dysuria † 1	1/49 (2.04%)	1	3/23 (13.04%)	3	0/18 (0.00%)	0	1/9 (11.11%)	1	5/53 (9.43%)	5	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	2/8 (25.00%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Haematuria † 1	12/49 (24.49%)	14	3/23 (13.04%)	3	2/18 (11.11%)	2	2/9 (22.22%)	2	11/53 (20.75%)	19	1/27 (3.70%)	3	10/56 (17.86%)	15	2/9 (22.22%)	2	5/8 (62.50%)	7	0/4 (0.00%)	0	1/4 (25.00%)	2
Micturition urgency † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	2/27 (7.41%)	2	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Nephritis † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Nocturia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	1/27 (3.70%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Pollakiuria † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	6/53 (11.32%)	6	3/27 (11.11%)	3	3/56 (5.36%)	3	0/9 (0.00%)	0	1/8 (12.50%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Proteinuria † 1	7/49 (14.29%)	13	2/23 (8.70%)	3	1/18 (5.56%)	2	0/9 (0.00%)	0	2/53 (3.77%)	3	2/27 (7.41%)	2	2/56 (3.57%)	2	1/9 (11.11%)	1	1/8 (12.50%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Renal pain † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Urinary incontinence † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	3	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Urinary retention † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	2	0/4 (0.00%)	0	0/4 (0.00%)	0
Urinary tract obstruction † 1	2/49 (4.08%)	2	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	3	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Urine flow decreased † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pelvic pain † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	2/18 (11.11%)	2	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Penile pain † 1	2/49 (4.08%)	2	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	3	0/4 (0.00%)	0	0/4 (0.00%)	0
Penile swelling † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Perineal pain † 1	0/49 (0.00%)	0	2/23 (8.70%)	5	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Scrotal swelling † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Testicular pain † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Vaginal haemorrhage † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	1/18 (5.56%)	2	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Cough † 1	7/49 (14.29%)	7	4/23 (17.39%)	6	3/18 (16.67%)	3	2/9 (22.22%)	2	12/53 (22.64%)	16	7/27 (25.93%)	7	7/56 (12.50%)	8	2/9 (22.22%)	2	3/8 (37.50%)	4	3/4 (75.00%)	3	0/4 (0.00%)	0
Dysphonia † 1	19/49 (38.78%)	23	15/23 (65.22%)	19	9/18 (50.00%)	10	4/9 (44.44%)	4	21/53 (39.62%)	28	9/27 (33.33%)	13	23/56 (41.07%)	23	5/9 (55.56%)	5	1/8 (12.50%)	1	1/4 (25.00%)	1	0/4 (0.00%)	0
Dyspnoea † 1	7/49 (14.29%)	9	9/23 (39.13%)	11	4/18 (22.22%)	7	3/9 (33.33%)	3	19/53 (35.85%)	30	5/27 (18.52%)	5	7/56 (12.50%)	8	0/9 (0.00%)	0	2/8 (25.00%)	2	1/4 (25.00%)	1	0/4 (0.00%)	0
Dyspnoea exertional † 1	3/49 (6.12%)	3	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	0/27 (0.00%)	0	0/56 (0.00%)	0	1/9 (11.11%)	1	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Epistaxis † 1	1/49 (2.04%)	1	2/23 (8.70%)	2	1/18 (5.56%)	1	0/9 (0.00%)	0	2/53 (3.77%)	2	2/27 (7.41%)	2	1/56 (1.79%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hiccups † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Nasal congestion † 1	3/49 (6.12%)	5	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	1/27 (3.70%)	1	3/56 (5.36%)	3	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Nasal inflammation † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Oropharyngeal pain † 1	6/49 (12.24%)	6	4/23 (17.39%)	10	2/18 (11.11%)	2	1/9 (11.11%)	1	4/53 (7.55%)	5	0/27 (0.00%)	0	2/56 (3.57%)	2	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Paranasal sinus hypersecretion † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Pneumonitis † 1	1/49 (2.04%)	1	3/23 (13.04%)	4	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	1/27 (3.70%)	2	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Productive cough † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Pulmonary embolism † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
Pulmonary oedema † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Rhinitis allergic † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	2/27 (7.41%)	2	1/56 (1.79%)	1	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Rhinorrhoea † 1	1/49 (2.04%)	1	2/23 (8.70%)	2	0/18 (0.00%)	0	0/9 (0.00%)	0	1/53 (1.89%)	2	1/27 (3.70%)	1	1/56 (1.79%)	1	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Sleep apnoea syndrome † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Upper-airway cough syndrome † 1	0/49 (0.00%)	0	3/23 (13.04%)	3	0/18 (0.00%)	0	0/9 (0.00%)	0	3/53 (5.66%)	4	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Wheezing † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin and subcutaneous tissue disorders
Alopecia † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	1/53 (1.89%)	1	1/27 (3.70%)	1	2/56 (3.57%)	2	0/9 (0.00%)	0	2/8 (25.00%)	2	0/4 (0.00%)	0	1/4 (25.00%)	1
Blister † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Dermatitis acneiform † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	3/53 (5.66%)	3	1/27 (3.70%)	3	1/56 (1.79%)	1	0/9 (0.00%)	0	2/8 (25.00%)	3	1/4 (25.00%)	2	0/4 (0.00%)	0
Dry skin † 1	6/49 (12.24%)	6	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	7/53 (13.21%)	8	3/27 (11.11%)	3	2/56 (3.57%)	2	1/9 (11.11%)	1	0/8 (0.00%)	0	1/4 (25.00%)	1	0/4 (0.00%)	0
Erythema multiforme † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Hyperkeratosis † 1	0/49 (0.00%)	0	3/23 (13.04%)	3	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	1/27 (3.70%)	1	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Lichen planus † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Night sweats † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Palmar-plantar erythrodysaesthesia syndrome † 1	10/49 (20.41%)	20	5/23 (21.74%)	11	7/18 (38.89%)	16	3/9 (33.33%)	4	13/53 (24.53%)	17	5/27 (18.52%)	6	5/56 (8.93%)	12	2/9 (22.22%)	6	0/8 (0.00%)	0	2/4 (50.00%)	4	1/4 (25.00%)	1
Pruritus † 1	4/49 (8.16%)	4	4/23 (17.39%)	4	2/18 (11.11%)	3	1/9 (11.11%)	1	7/53 (13.21%)	7	3/27 (11.11%)	3	6/56 (10.71%)	6	0/9 (0.00%)	0	2/8 (25.00%)	3	1/4 (25.00%)	4	2/4 (50.00%)	2
Rash † 1	6/49 (12.24%)	10	3/23 (13.04%)	5	2/18 (11.11%)	2	0/9 (0.00%)	0	3/53 (5.66%)	3	1/27 (3.70%)	2	3/56 (5.36%)	3	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Rash erythematous † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	2
Rash maculo-papular † 1	4/49 (8.16%)	4	6/23 (26.09%)	7	3/18 (16.67%)	3	0/9 (0.00%)	0	11/53 (20.75%)	15	6/27 (22.22%)	7	5/56 (8.93%)	5	1/9 (11.11%)	1	1/8 (12.50%)	1	0/4 (0.00%)	0	3/4 (75.00%)	3
Rash papular † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	1/9 (11.11%)	2	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Rosacea † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin exfoliation † 1	1/49 (2.04%)	1	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin hyperpigmentation † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	0/18 (0.00%)	0	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin lesion † 1	2/49 (4.08%)	3	1/23 (4.35%)	1	2/18 (11.11%)	3	0/9 (0.00%)	0	1/53 (1.89%)	1	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	2
Skin mass † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	1/8 (12.50%)	1	0/4 (0.00%)	0	0/4 (0.00%)	0
Skin ulcer † 1	2/49 (4.08%)	3	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	5/53 (9.43%)	6	0/27 (0.00%)	0	2/56 (3.57%)	3	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Vascular disorders
Embolism † 1	3/49 (6.12%)	3	1/23 (4.35%)	1	0/18 (0.00%)	0	1/9 (11.11%)	1	2/53 (3.77%)	2	2/27 (7.41%)	2	2/56 (3.57%)	2	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Haematoma † 1	0/49 (0.00%)	0	0/23 (0.00%)	0	1/18 (5.56%)	1	0/9 (0.00%)	0	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Hypertension † 1	14/49 (28.57%)	32	12/23 (52.17%)	19	6/18 (33.33%)	16	4/9 (44.44%)	5	21/53 (39.62%)	29	12/27 (44.44%)	15	27/56 (48.21%)	43	4/9 (44.44%)	4	0/8 (0.00%)	0	0/4 (0.00%)	0	3/4 (75.00%)	3
Hypotension † 1	1/49 (2.04%)	1	1/23 (4.35%)	1	0/18 (0.00%)	0	0/9 (0.00%)	0	2/53 (3.77%)	2	3/27 (11.11%)	3	1/56 (1.79%)	1	1/9 (11.11%)	2	0/8 (0.00%)	0	0/4 (0.00%)	0	0/4 (0.00%)	0
Orthostatic hypotension † 1	0/49 (0.00%)	0	1/23 (4.35%)	1	0/18 (0.00%)	0	1/9 (11.11%)	1	0/53 (0.00%)	0	0/27 (0.00%)	0	0/56 (0.00%)	0	0/9 (0.00%)	0	0/8 (0.00%)	0	0/4 (0.00%)	0	1/4 (25.00%)	1
1 Term from vocabulary, MedDRA 21.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Director, Clinical Operations
• Organization: Mirati Therapeutics
• Phone: 858-381-5289
• EMail: LatvenL@Mirati.com

• Responsible Party: Mirati Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT03606174
• Other Study ID Numbers: 516-003
• First Submitted: July 20, 2018
• First Posted: July 30, 2018
• Results First Submitted: August 3, 2023
• Results First Posted: August 24, 2023
• Last Update Posted: August 24, 2023