Trial Outcomes & Findings for Varlitinib in Combination With Capecitabine for Advanced or Metastatic Biliary Tract Cancer (NCT NCT03093870)

NCT ID: NCT03093870

Last Updated: 2021-08-03

Results Overview

Part 1: The ORR was defined as the number (%) of subjects with ≥ 1 visit response of complete response (CR) or partial response (PR). Data obtained up until progression, or until last evaluable assessment in the absence of progression, was included in the assessment of ORR, regardless of whether subjects discontinued treatment or received a subsequent therapy prior to progression. Best overall RECIST Response (BOR) was calculated based on the overall visit responses from each RECIST assessment, i.e. the best response a subject had following randomization and prior to RECIST progression or the last evaluable assessment in the absence of RECIST progression. Categorization of BOR was based on the RECIST criteria using the following response categories: CR, PR, stable disease (SD), progressive disease (PD) and not evaluable (NE).

• Recruitment status: COMPLETED
• Study phase: PHASE2/PHASE3
• Target enrollment: 151 participants
• Primary outcome timeframe: Data obtained up until progression, or until last evaluable assessment in the absence of progression, regardless of whether subjects discontinued treatment or received a subsequent therapy prior to progression, up to 2 years.
• Results posted on: 2021-08-03

Participant Flow

Period 1: Safety lead-in, N=24. Period 2: Part 1, N=127

Period 1: Safety lead-in phase had only 1 arm (Varlitinib and Capecitabine). Period 2: Part 1 phase had 2 arms (Varlitinib and Capecitabine vs Placebo and Capecitabine)

Participant milestones

Measure	Varlitinib and Capecitabine - Safety Lead-In Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Varlitinib and Capecitabine - Part 1 Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine - Part 1 Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Overall Study STARTED	24	64	63
Overall Study COMPLETED	0	23	22
Overall Study NOT COMPLETED	24	41	41

Reasons for withdrawal

Measure	Varlitinib and Capecitabine - Safety Lead-In Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Varlitinib and Capecitabine - Part 1 Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine - Part 1 Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Overall Study Withdrawal by Subject	2	6	5
Overall Study Death	1	35	35
Overall Study Radiographic disease progression	10	0	0
Overall Study Clinical disease progression	1	0	0
Overall Study Physician Decision	2	0	0
Overall Study Adverse Event	7	0	0
Overall Study Patient withdrew from treatment voluntarily due to intermittent constipation and anorexia	1	0	0
Overall Study Lost to Follow-up	0	0	1

Baseline Characteristics

The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)

Baseline characteristics by cohort

Measure	Varlitinib and Capecitabine - Safety Lead-In n=24 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Varlitinib and Capecitabine - Part 1 n=64 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine - Part 1 n=63 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Total n=151 Participants Total of all reporting groups
Age, Continuous Safety Lead-In	58.5 years STANDARD_DEVIATION 9.68 • n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	—	—	58.5 years STANDARD_DEVIATION 9.68 • n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)
Age, Continuous Part 1	—	61.6 years STANDARD_DEVIATION 10.39 • n=64 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	62.7 years STANDARD_DEVIATION 11.19 • n=63 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	62.1 years STANDARD_DEVIATION 10.76 • n=127 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)
Sex: Female, Male Safety Lead-In · Female	13 Participants n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	—	—	13 Participants n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)
Sex: Female, Male Safety Lead-In · Male	11 Participants n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	—	—	11 Participants n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)
Sex: Female, Male Part 1 · Female	—	20 Participants n=64 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	30 Participants n=63 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	50 Participants n=127 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)
Sex: Female, Male Part 1 · Male	—	44 Participants n=64 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	33 Participants n=63 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	77 Participants n=127 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)
Ethnicity (NIH/OMB) Overall Study · Hispanic or Latino	4 Participants n=24 Participants	1 Participants n=64 Participants	1 Participants n=63 Participants	6 Participants n=151 Participants
Ethnicity (NIH/OMB) Overall Study · Not Hispanic or Latino	20 Participants n=24 Participants	63 Participants n=64 Participants	62 Participants n=63 Participants	145 Participants n=151 Participants
Ethnicity (NIH/OMB) Overall Study · Unknown or Not Reported	0 Participants n=24 Participants	0 Participants n=64 Participants	0 Participants n=63 Participants	0 Participants n=151 Participants
Race (NIH/OMB) Overall Study · American Indian or Alaska Native	0 Participants n=24 Participants	0 Participants n=64 Participants	0 Participants n=63 Participants	0 Participants n=151 Participants
Race (NIH/OMB) Overall Study · Asian	9 Participants n=24 Participants	42 Participants n=64 Participants	47 Participants n=63 Participants	98 Participants n=151 Participants
Race (NIH/OMB) Overall Study · Native Hawaiian or Other Pacific Islander	0 Participants n=24 Participants	0 Participants n=64 Participants	0 Participants n=63 Participants	0 Participants n=151 Participants
Race (NIH/OMB) Overall Study · Black or African American	0 Participants n=24 Participants	1 Participants n=64 Participants	0 Participants n=63 Participants	1 Participants n=151 Participants
Race (NIH/OMB) Overall Study · White	12 Participants n=24 Participants	21 Participants n=64 Participants	16 Participants n=63 Participants	49 Participants n=151 Participants
Race (NIH/OMB) Overall Study · More than one race	2 Participants n=24 Participants	0 Participants n=64 Participants	0 Participants n=63 Participants	2 Participants n=151 Participants
Race (NIH/OMB) Overall Study · Unknown or Not Reported	1 Participants n=24 Participants	0 Participants n=64 Participants	0 Participants n=63 Participants	1 Participants n=151 Participants
Region of Enrollment South Korea	4 Participants n=24 Participants	23 Participants n=64 Participants	26 Participants n=63 Participants	53 Participants n=151 Participants
Region of Enrollment Hungary	0 Participants n=24 Participants	1 Participants n=64 Participants	3 Participants n=63 Participants	4 Participants n=151 Participants
Region of Enrollment United States	14 Participants n=24 Participants	7 Participants n=64 Participants	6 Participants n=63 Participants	27 Participants n=151 Participants
Region of Enrollment Japan	0 Participants n=24 Participants	15 Participants n=64 Participants	13 Participants n=63 Participants	28 Participants n=151 Participants
Region of Enrollment Taiwan	0 Participants n=24 Participants	3 Participants n=64 Participants	7 Participants n=63 Participants	10 Participants n=151 Participants
Region of Enrollment Poland	0 Participants n=24 Participants	3 Participants n=64 Participants	1 Participants n=63 Participants	4 Participants n=151 Participants
Region of Enrollment Australia	0 Participants n=24 Participants	5 Participants n=64 Participants	2 Participants n=63 Participants	7 Participants n=151 Participants
Region of Enrollment Spain	0 Participants n=24 Participants	7 Participants n=64 Participants	5 Participants n=63 Participants	12 Participants n=151 Participants
Region of Enrollment Singapore	6 Participants n=24 Participants	0 Participants n=64 Participants	0 Participants n=63 Participants	6 Participants n=151 Participants
BMI BMI - Safety Lead-in	36.85 kg/m^2 STANDARD_DEVIATION 58.381 • n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	—	—	36.85 kg/m^2 STANDARD_DEVIATION 58.381 • n=24 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)
BMI BMI - Part 1	—	24.6 kg/m^2 STANDARD_DEVIATION 4.69 • n=64 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	23.8 kg/m^2 STANDARD_DEVIATION 4.52 • n=63 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)	24.2 kg/m^2 STANDARD_DEVIATION 4.60 • n=127 Participants • The study consists of Safety Lead-In (24 patients in Varlitinib + Capecitabine group) and Part 1 (64 patients in Varlitinib + Capecitabine group, 63 patients in Placebo + Capecitabine group)

PRIMARY outcome

Timeframe: Data obtained up until progression, or until last evaluable assessment in the absence of progression, regardless of whether subjects discontinued treatment or received a subsequent therapy prior to progression, up to 2 years.

Part 1: The ORR was defined as the number (%) of subjects with ≥ 1 visit response of complete response (CR) or partial response (PR). Data obtained up until progression, or until last evaluable assessment in the absence of progression, was included in the assessment of ORR, regardless of whether subjects discontinued treatment or received a subsequent therapy prior to progression. Best overall RECIST Response (BOR) was calculated based on the overall visit responses from each RECIST assessment, i.e. the best response a subject had following randomization and prior to RECIST progression or the last evaluable assessment in the absence of RECIST progression. Categorization of BOR was based on the RECIST criteria using the following response categories: CR, PR, stable disease (SD), progressive disease (PD) and not evaluable (NE).

Outcome measures

Measure	Varlitinib and Capecitabine n=64 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=63 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Objective Response Rate (ORR) - Part 1 Responders - CR	0 Participants	0 Participants
Objective Response Rate (ORR) - Part 1 Responders - PR	6 Participants	3 Participants
Objective Response Rate (ORR) - Part 1 Non-Responders - SD	29 Participants	34 Participants
Objective Response Rate (ORR) - Part 1 Non-Responders - PD	24 Participants	24 Participants
Objective Response Rate (ORR) - Part 1 Non-Responders - NE	5 Participants	2 Participants

PRIMARY outcome

Timeframe: Time from randomization until date of objective disease progression or death (by any cause in absence of disease progression) regardless of whether subject withdrew from randomized therapy or received another antitumor therapy prior to PD, up to 2 years.

Part 1: Progression-free survival (PFS) was defined as the time from randomization (or starting treatment for the Safety Lead-in) until the date of objective disease progression or death (by any cause in the absence of disease progression) regardless of whether the subject withdrew from randomized therapy or received another antitumor therapy prior to disease progression. Subjects who did not experience disease progression or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. However, if the patient progressed or died after ≥ 2 missed visits (12 weeks ± 5 days maximum), the subject was censored at the time of the latest evaluable RECIST assessment. The PFS time was based on the scan/assessment dates rather than visit dates.

Outcome measures

Measure	Varlitinib and Capecitabine n=49 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=47 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Progression-free Survival (PFS) - Part 1	2.83 Months Interval 1.48 to 5.62	2.79 Months Interval 1.41 to 4.24

SECONDARY outcome

Timeframe: Data obtained up until progression, or until last evaluable assessment in absence of progression, regardless of whether subjects discontinued treatment or received a subsequent therapy prior to progression, up to 2 years.

The ORR rate was defined as the number (%) of subjects with ≥ 1 visit response of complete response (CR) or partial response (PR). Data obtained up until progression, or until last evaluable assessment in the absence of progression, was included in the assessment of ORR, regardless of whether subjects discontinued treatment or received a subsequent therapy prior to progression. In all study parts, the primary assessment of ORR was based on the Full Analysis Set (FAS).

Outcome measures

Measure	Varlitinib and Capecitabine n=24 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Object Response Rates (ORR) - Safety Lead-In Responders - CR	0 Participants	—
Object Response Rates (ORR) - Safety Lead-In Responders - PR	1 Participants	—
Object Response Rates (ORR) - Safety Lead-In Non-Responders - SD	5 Participants	—
Object Response Rates (ORR) - Safety Lead-In Non-Responders - PD	9 Participants	—
Object Response Rates (ORR) - Safety Lead-In Non-Responders - NE	9 Participants	—

SECONDARY outcome

Timeframe: Time from the date of randomization until death due to any cause, up to 2 years

Part 1: Overall survival (OS) was defined as the time from the date of randomization until death due to any cause. Any subject not known to have died at the time of the data cut-off was censored based on the last recorded date on which the subject was known to be alive.

Outcome measures

Measure	Varlitinib and Capecitabine n=35 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=35 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Overall Survival (OS) - Part 1	7.8 Months Interval 4.5 to 11.5	7.5 Months Interval 5.3 to The 75th percentile is Not Evaluable (NE), because the 75th percentile has not been reached yet (i.e. the data are too immature for that arm)

SECONDARY outcome

Timeframe: Time from the date of randomization until death due to any cause, up to 2 years

Part 1: Overall survival (OS) was defined as the time from the date of randomization until death due to any cause. Any subject not known to have died at the time of the data cut-off was censored based on the last recorded date on which the subject was known to be alive.

Outcome measures

Measure	Varlitinib and Capecitabine n=24 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Overall Survival (OS) - Safety Lead-In Alive	17 Participants	—
Overall Survival (OS) - Safety Lead-In Withdrew Consent	2 Participants	—
Overall Survival (OS) - Safety Lead-In Dead	4 Participants	—
Overall Survival (OS) - Safety Lead-In Withdrew due to AE	1 Participants	—

SECONDARY outcome

Timeframe: Time from the date of first documented response until the date of documented PD or death in the absence of disease progression, up to 2 years

Population: Kaplan Meier median is presented for DoR. At the time of reporting, there were 3 censored observations in the V+C arm, none in the P+C arm. The observed number of responders in the trial was much lower than anticipated; 9 responders in total, 6 for varlitinib and 3 for placebo. Based on results of the primary endpoints, the follow-up analysis to provide more long-term efficacy data planned for when 70% of patients had experienced an OS event was not undertaken based on pre-specified criteria.

Part 1: Duration of response (DoR) was defined as the time from the date of first documented response until the date of documented PD or death in the absence of disease progression. The end of the response should have coincided with the date of disease progression or death from any cause used for the PFS endpoint.

For Part 1, DoR was calculated based on data from the ICR of radiological data.

Outcome measures

Measure	Varlitinib and Capecitabine n=6 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=3 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Duration of Response (DoR) - Part 1	158 Days Interval 43.0 to 158.0	90 Days Interval 48.0 to 246.0

SECONDARY outcome

Timeframe: Number (%) of subjects with ≥ 1 visit response of CR or PR, or with SD for a minimum of 12 weeks (± 5 days) from randomization.

Part 1: DCR rate was defined as the number (%) of subjects with ≥ 1 visit response of CR or PR, or with SD for a minimum of 12 weeks (± 5 days) from randomization. Data obtained up until progression, or until last evaluable assessment in the absence of progression, were included in the assessment of DCR, regardless of whether subjects discontinued treatment or received a subsequent therapy prior to progression. For all study parts, the primary assessment of DCR was based on the FAS.

For Part 1, DCR was calculated based on data from the ICR

Outcome measures

Measure	Varlitinib and Capecitabine n=64 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=63 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Disease Control Rate DCR - Part 1 Disease Control - CR	0 Participants	0 Participants
Disease Control Rate DCR - Part 1 Disease Control - PR	6 Participants	3 Participants
Disease Control Rate DCR - Part 1 Disease Control - SD for 12 weeks	12 Participants	16 Participants
Disease Control Rate DCR - Part 1 No Disease Control - SD < 12 weeks	17 Participants	18 Participants
Disease Control Rate DCR - Part 1 No Disease Control - PD	24 Participants	24 Participants
Disease Control Rate DCR - Part 1 No Disease Control - NE	5 Participants	2 Participants

SECONDARY outcome

Timeframe: Week 12

Part 1: The percentage change from baseline in tumor size at Week 12 (%ΔTSWk12) was a secondary endpoint for Part 1 and was used to present waterfall plots of the target lesion data in the Evaluable for Response (EFR) Population

Outcome measures

Measure	Varlitinib and Capecitabine n=51 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=51 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Tumor Size - Part 1	18.1 Percentage change from Baseline Standard Deviation 39.46	22.6 Percentage change from Baseline Standard Deviation 36.11

SECONDARY outcome

Timeframe: Subject screening visit to 28 days post last study drug administration

Population: No subjects reported with any CS values across majority of the hematologic, clinical chemistry, urinalysis parameters during the Safety Lead-In of the study

Clinical laboratory tests (hematology, clinical chemistry, urinalysis) - Number of Participants with Clinically Significant Laboratory Tests.

Outcome measures

Measure	Varlitinib and Capecitabine n=24 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With Clinically Significant Laboratory Tests- Safety Lead-in	0 Participants	—

SECONDARY outcome

Timeframe: Subject screening visit to 28 days post last study drug administration

Population: No subjects reported with any CS values across majority of the hematologic, clinical chemistry and urinalysis parameters at the end of treatment.

Clinical laboratory tests (hematology, clinical chemistry, urinalysis) - Number of Participants with Clinically Significant Laboratory Tests.

Outcome measures

Measure	Varlitinib and Capecitabine n=64 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=63 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With Clinically Significant Laboratory Tests - Part 1	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Subject screening visit to 28 days post last study drug administration

Number of participants with clinically significant change in vital signs (blood pressure [diastolic and systolic], heart rate, respiratory rate, body temperature) and physical examination.

Outcome measures

Measure	Varlitinib and Capecitabine n=24 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With Clinically Significant Change in Vital Signs and Physical Examinations - Safety Lead-In	0 Participants	—

SECONDARY outcome

Timeframe: Subject screening visit to 28 days post last study drug administration

Number of participants with clinically significant change in vital signs (blood pressure [diastolic and systolic], heart rate, respiratory rate, body temperature) and physical examination.

Outcome measures

Measure	Varlitinib and Capecitabine n=64 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=63 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With Clinically Significant Change in Vital Signs and Physical Examinations - Part 1	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Subject screening visit to 28 days post last study drug administration

Number of participants with ECG parameters of interest: Max. on-treatment QTcF Value: >450 to 480 msec, max. on-treatment QTcF Value: >480 to 500 msec, max. on-treatment QTcF Value: >500 msec, max. on-treatment QTcB Value: >450 to 480 msec, max. on-treatment QTcB Value: >480 to 500 msec, max. on-treatment QTcB Value: >500 msec, max. QTcF CFB Value: >30 to 60 msec, max. QTcF CFB Value: >60 msec, max. QTcB CFB Value: >30 to 60 msec, max. QTcB CFB Value: >60 msec.

Outcome measures

Measure	Varlitinib and Capecitabine n=24 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum on-treatment QTcF Value: >450 to 480 msec	8 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum on-treatment QTcF Value: >480 to 500 msec	0 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum on-treatment QTcF Value: >500 msec	0 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum on-treatment QTcB Value: >450 to 480 msec	10 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum on-treatment QTcB Value: >480 to 500 msec	2 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum on-treatment QTcB Value: >500 msec	0 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum QTcF CFB Value: >30 to 60 msec	8 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum QTcF CFB Value: >60 msec	1 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum QTcB CFB Value: >30 to 60 msec	6 participants	—
Number of Participants With ECG Parameters of Interest - Safety Lead-In Maximum QTcB CFB Value: >60 msec	1 participants	—

SECONDARY outcome

Timeframe: Subject screening visit to 28 days post last study drug administration

Number of participants with ECG parameters of interest: Max. on-treatment QTcF Value: <=450 msec, max. on-treatment QTcF Value: >450 to 480 msec, max. on-treatment QTcF Value: >480 to 500 msec, max. on-treatment QTcF Value: >500 msec, max. on-treatment QTcB Value: <=450 msec, max. on-treatment QTcB Value: >450 to 480 msec, max. on-treatment QTcB Value: >480 to 500 msec, max. on-treatment QTcB Value: >500 msec, max. QTcF CFB Value: <=30 msec, max. QTcF CFB Value: >30 to 60 msec, max. QTcF CFB Value: >60 msec, max. QTcB CFB Value: <=30 msec, max. QTcB CFB Value: >30 to 60 msec, max. QTcB CFB Value: >60 msec.

Outcome measures

Measure	Varlitinib and Capecitabine n=64 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=63 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcF Value: <=450 msec	53 Participants	57 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcF Value: >450 to 480 msec	10 Participants	6 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcF Value: >480 to 500 msec	0 Participants	0 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcF Value: >500 msec	1 Participants	0 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcB Value: <=450 msec	42 Participants	40 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcB Value: >450 to 480 msec	21 Participants	22 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcB Value: >480 to 500 msec	0 Participants	1 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum on-treatment QTcB Value: >500 msec	1 Participants	0 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum QTcF CFB Value: <=30 msec	56 Participants	57 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum QTcF CFB Value: >30 to 60 msec	7 Participants	4 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum QTcF CFB Value: >60 msec	0 Participants	1 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum QTcB CFB Value: <=30 msec	55 Participants	54 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum QTcB CFB Value: >30 to 60 msec	8 Participants	7 Participants
Number of Participants With ECG Parameters of Interest - Part 1 Maximum QTcB CFB Value: >60 msec	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Subject screening visit to 28 days post last study drug administration

Population: For the Varlitinib 300 mg BID + Capecitabine treatment group, ECOG Performance Status scores ranged from 0 to 3 at EOT. For the Placebo + Capecitabine treatment group, ECOG Performance Status scores ranged from 0 to 3 at EOT.

Eastern Cooperative Oncology Group (ECOG) Performance was clinically graded based on the following:

Grade 0 = Normal activity. Fully active, able to carry on all pre-disease performance without restriction.

Grade 1 = Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work).

Grade 2 = In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours.

Grade 3 = In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.

Grade 4 = 100% bedridden. Completely disabled. Cannot carry on any self- care. Totally confined to bed or chair.

Grade 5 = Death

Outcome measures

Measure	Varlitinib and Capecitabine n=64 Participants Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine n=63 Participants Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
ECOG Performance Status - Part 1 Baseline Value Grade 0 - EOT Value Grade 0	16 Participants	11 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 0 - EOT Value Grade 1	13 Participants	10 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 0 - EOT Value Grade 2	0 Participants	2 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 0 - EOT Value Grade 3	4 Participants	1 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 0 - EOT Value Not done	4 Participants	2 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 1 - EOT Value Grade 0	1 Participants	5 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 1 - EOT Value Grade 1	10 Participants	25 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 1 - EOT Value Grade 2	5 Participants	2 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 1 - EOT Value Grade 3	0 Participants	0 Participants
ECOG Performance Status - Part 1 Baseline Value Grade 1 - EOT Value Not done	11 Participants	5 Participants

Adverse Events

Varlitinib and Capecitabine - Safety Lead-In

Serious events: 13 serious events

Other events: 24 other events

Deaths: 2 deaths

Varlitinib and Capecitabine - Part 1

Serious events: 25 serious events

Other events: 64 other events

Deaths: 35 deaths

Placebo and Capecitabine - Part 1

Serious events: 27 serious events

Other events: 59 other events

Deaths: 35 deaths

Serious adverse events

Measure	Varlitinib and Capecitabine - Safety Lead-In n=24 participants at risk Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Varlitinib and Capecitabine - Part 1 n=64 participants at risk Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine - Part 1 n=63 participants at risk Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Renal and urinary disorders Acute kidney injury	8.3% 2/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Bile duct obstruction	8.3% 2/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Enterocolitis	8.3% 2/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Abdominal Pain	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Aspiration	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Asthenia	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Cardiac disorders Cardiac arrest	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Cholangitis	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Constipation	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Dehydration	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Diarrhoea	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Haematemesis	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Hyperbilirubinaemia	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hypercalcaemia	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hyponatremia	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Hypoxic-ischaemic encephalopathy	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Ischaemic stroke	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Lung Infection	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Metabolic acidosis	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Nausea	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Pyrexia	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Skin and subcutaneous tissue disorders Rash generalized	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Respiratory Failure	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Septic shock	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Small intestinal obstruction	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Spinal cord compression	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Toxic leukoencephalopathy	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Vomiting	4.2% 1/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Blood bilirubin increased	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.9% 5/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Disease progression	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Pneumonia	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Hepatobiliary infection	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Blood creatinine increased	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Oedema peripheral	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Blood and lymphatic system disorders Anemia	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Biliary tract infection	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Skin and subcutaneous tissue disorders Erythema multiforme	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Hemobilia	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Renal and urinary disorders Hematuria	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Blood and lymphatic system disorders Embolism	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Bile duct stenosis	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Biliary dilatation	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Biliary sepsis	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Blood and lymphatic system disorders Blood culture positive	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Cerebrovascular accident	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Dyspnoea	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Haemorrhoidal haemorrhage	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Renal and urinary disorders Hernia	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Jaundice	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Liver abscess	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Peritonitis bacterial	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Injury, poisoning and procedural complications Procedural complication	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Small intestinal haemorrhage	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Biloma	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Cholangiolitis	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Cholecystitis	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders General physical health deterioration	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Inguinal hernia	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Jaundice cholestatic	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Pain	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.

Other adverse events

Measure	Varlitinib and Capecitabine - Safety Lead-In n=24 participants at risk Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Varlitinib and Capecitabine - Part 1 n=64 participants at risk Varlitinib: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Placebo and Capecitabine - Part 1 n=63 participants at risk Placebo (for Varlitinib): oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Capecitabine: 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Gastrointestinal disorders Nausea	62.5% 15/24 • Number of events 29 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	51.6% 33/64 • Number of events 58 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	22.2% 14/63 • Number of events 19 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Diarrhoea	54.2% 13/24 • Number of events 31 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	40.6% 26/64 • Number of events 43 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	25.4% 16/63 • Number of events 19 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Vomiting	45.8% 11/24 • Number of events 27 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	34.4% 22/64 • Number of events 30 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	17.5% 11/63 • Number of events 18 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Abdominal Pain	37.5% 9/24 • Number of events 12 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	25.0% 16/64 • Number of events 27 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	19.0% 12/63 • Number of events 20 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Constipation	33.3% 8/24 • Number of events 19 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	14.1% 9/64 • Number of events 9 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	14.3% 9/63 • Number of events 9 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Stomatitis	25.0% 6/24 • Number of events 9 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	10.9% 7/64 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	12.7% 8/63 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Dyspepsia	20.8% 5/24 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	10.9% 7/64 • Number of events 9 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Ascites	16.7% 4/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Abdominal Distension	29.2% 7/24 • Number of events 13 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Abdominal Pain Upper	12.5% 3/24 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Fatigue	58.3% 14/24 • Number of events 35 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	25.0% 16/64 • Number of events 33 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	19.0% 12/63 • Number of events 17 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Pyrexia	41.7% 10/24 • Number of events 18 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	23.4% 15/64 • Number of events 23 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	17.5% 11/63 • Number of events 13 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Asthenia	20.8% 5/24 • Number of events 9 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	17.2% 11/64 • Number of events 20 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	11.1% 7/63 • Number of events 9 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Malaise	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	12.5% 8/64 • Number of events 14 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Chills	20.8% 5/24 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	9.4% 6/64 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Mucosal Inflammation	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Oedema Peripheral	29.2% 7/24 • Number of events 12 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.8% 3/63 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Blood Bilirubin Increased	33.3% 8/24 • Number of events 17 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	43.8% 28/64 • Number of events 71 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	22.2% 14/63 • Number of events 30 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Blood Creatinine Increased	12.5% 3/24 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	23.4% 15/64 • Number of events 26 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.8% 3/63 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Aspartate Aminotransferase Increased	20.8% 5/24 • Number of events 10 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	14.1% 9/64 • Number of events 19 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	11.1% 7/63 • Number of events 11 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Platelet Count Decreased	16.7% 4/24 • Number of events 16 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	12.5% 8/64 • Number of events 13 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	12.7% 8/63 • Number of events 11 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Alanine Aminotransferase Increased	16.7% 4/24 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	15.6% 10/64 • Number of events 22 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.9% 5/63 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Neutrophil Count Decreased	8.3% 2/24 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.9% 5/63 • Number of events 21 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Weight Decreased	12.5% 3/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Skin and subcutaneous tissue disorders Palmar-plantar Erythrodysaethesia Syndrome	25.0% 6/24 • Number of events 18 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	31.2% 20/64 • Number of events 32 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	30.2% 19/63 • Number of events 37 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	17.2% 11/64 • Number of events 13 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.9% 5/63 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Skin and subcutaneous tissue disorders Rash	16.7% 4/24 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	12.5% 8/64 • Number of events 10 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Skin and subcutaneous tissue disorders Skin Hyperpigmentation	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Decreased Appetite	50.0% 12/24 • Number of events 33 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	39.1% 25/64 • Number of events 49 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	17.5% 11/63 • Number of events 15 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hypoalbuminaemia	12.5% 3/24 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	9.4% 6/64 • Number of events 11 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.9% 5/63 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hypokalaemia	41.7% 10/24 • Number of events 20 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Number of events 6 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hyponatraemia	29.2% 7/24 • Number of events 10 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hypoglycemia	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Dehydration	25.0% 6/24 • Number of events 11 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Blood and lymphatic system disorders Anaemia	25.0% 6/24 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	20.3% 13/64 • Number of events 30 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	22.2% 14/63 • Number of events 27 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Pneumonia	0.00% 0/24 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Peripheral Sensory Neuropathy	4.2% 1/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Dizziness	29.2% 7/24 • Number of events 11 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Dysgeusia	8.3% 2/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 6 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Dyspnoea	20.8% 5/24 • Number of events 16 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Cough	12.5% 3/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.8% 3/63 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Cholangitis	8.3% 2/24 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 10 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.9% 5/63 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Hyperbilirubinaemia	12.5% 3/24 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	10.9% 7/64 • Number of events 16 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Musculoskeletal and connective tissue disorders Back Pain	29.2% 7/24 • Number of events 7 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Number of events 6 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Musculoskeletal and connective tissue disorders Myalgia	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Psychiatric disorders Insomnia	8.3% 2/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.8% 3/63 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Renal and urinary disorders Acute Kidney Injury	8.3% 2/24 • Number of events 9 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	7.8% 5/64 • Number of events 6 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Renal and urinary disorders Proteinuria	20.8% 5/24 • Number of events 6 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.7% 3/64 • Number of events 6 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Vascular disorders Hypotension	25.0% 6/24 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.2% 4/64 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Dry mouth	12.5% 3/24 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Enterocolitis	8.3% 2/24 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Faeces discolored	8.3% 2/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Hematemesis	8.3% 2/24 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Gastrointestinal disorders Oral pain	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Early satiety	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
General disorders Influenza like illness	8.3% 2/24 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hypomagnesaemia	12.5% 3/24 • Number of events 5 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hyperkalaemia	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Metabolism and nutrition disorders Hypocalcaemia	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Blood alkaline phosphatase increased	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	4.8% 3/63 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations Gamma-glutamyltransferase increased	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	6.3% 4/63 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Investigations International normalised ratio increased	8.3% 2/24 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Hypoaesthesia	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Nervous system disorders Paraesthesia	8.3% 2/24 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	12.5% 3/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Dysphonia	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Epistaxis	8.3% 2/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Musculoskeletal and connective tissue disorders Muscular weakness	12.5% 3/24 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Musculoskeletal and connective tissue disorders Bursitis	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Hepatobiliary disorders Bile duct obstruction	8.3% 2/24 • Number of events 8 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.1% 2/64 • Number of events 4 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Infections and infestations Urinary tract infection	12.5% 3/24 • Number of events 3 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/63 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Psychiatric disorders Anxiety	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	1.6% 1/64 • Number of events 1 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	3.2% 2/63 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.
Psychiatric disorders Depression	8.3% 2/24 • Number of events 2 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/64 • Subject screening visit to 28 days post last study drug administration, up to 2 years.	0.00% 0/63 • Subject screening visit to 28 days post last study drug administration, up to 2 years.

Additional Information

Study Director

ASLAN Pharmaceuticals

Phone: +65 6222 4235

Email: contact@aslanpharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place