Varlitinib in Combination With Capecitabine for Advanced... | NCT03093870

Name	Class
bioRASI, LLC	INDUSTRY
CMIC Co, Ltd. Japan	INDUSTRY
Syneos Health	OTHER

Label	Type	Description	Intervention Names
Varlitinib and Capecitabine	Experimental		Drug: Varlitinib Drug: Capecitabine
Placebo and Capecitabine	Placebo Comparator		Drug: Capecitabine Drug: Placebo (for Varlitinib)

Name	Type	Description	Arm Group Labels	Other Names
Varlitinib	Drug	Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.	Varlitinib and Capecitabine

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Objective Response Rate (ORR) - Part 1	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).	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.
Progression-free Survival (PFS) - Part 1	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.	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.

Secondary Outcomes

Measure	Description	Time Frame
Object Response Rates (ORR) - Safety Lead-In	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).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects will be eligible for the study if they:

Are of or older than the legal age in the respective countries at the time when written informed consent is obtained
Have histologically or cytologically confirmed advanced (unresectable) or metastatic biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma (CCA), gallbladder cancer and carcinoma of Ampulla of Vater. This includes clinical diagnosis of biliary tract cancer with histological confirmation of adenocarcinoma.
Have received and failed one and only one prior line of systemic treatment for advanced or metastatic disease with radiologic evidence of disease progression. This prior line of systemic treatment must also contain gemcitabine
Have received at least 6 doses of gemcitabine containing treatment in first line (Adjuvant therapy is not regarded as 1st line therapy)
Have radiographically measurable disease based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 as assessed by Independent Central Review (ICR) (For Part 1)
Have no evidence of biliary duct obstruction, unless obstruction is controlled by local treatment or, in whom the biliary tree can be decompressed by endoscopic or percutaneous stenting with subsequent reduction in bilirubin to below or equal to 1.5 × upper level of normal (ULN)
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Are able to understand and willing to sign the informed consent form
Have adequate organ and hematological function:
1. Hematological function, as follows:
  - Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
  - Platelet count ≥ 100 × 109/L
2. Renal functions, as follows:
  
  • Estimated glomerular filtration rate or creatinine clearance > 50 mL/min/1.73m2
3. Hepatic function, as follows:
  - Albumin ≥ 3 g/dL
  - Total bilirubin ≤ 1.5 × ULN
  - Aspartate aminotransferase and alanine aminotransferase ≤ 5 × ULN

Exclusion Criteria:

Subjects will be ineligible for the study if they:

Are currently on or have received anti-cancer therapy within the past 3 weeks before receiving the first dose of study medication
Are currently on or have received radiation or local treatment within the past 3 weeks for the target lesion(s) before receiving the first dose of study medication
Have evidence of multiple (≥ 2) peritoneal metastases or ascites at baseline as assessed by ICR (For Part 1). (Ascites which can be attributed by non-malignant causes is not excluded. Minimal ascites, which does not require paracentesis is permitted.)
Have had major surgical procedures within 14 days prior to first dose of study medication
Have a known metastatic brain lesion(s), including asymptomatic and well controlled lesion(s)
Have malabsorption syndrome, diseases significantly affecting gastrointestinal function, resection of the stomach or small bowel, or difficulty in swallowing and retaining oral medications which in the opinion of the Investigator could jeopardize the validity of the study results
Have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, diabetes, hypertension, or psychiatric illness/social situations that would limit compliance with study requirements
Have any history of other malignancy unless in remission for more than 1 year (non-melanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with curative intent is not exclusionary)
Are female patients who are pregnant or breast feeding
Have been previously treated with varlitinib or have been previously treated with capecitabine as first line therapy for advanced or metastatic disease. For patients who have previously received capecitabine as a radiosensitizer or as part of their adjuvant therapy and their disease has relapsed for more than 6 months after their last dose of capecitabine adjuvant therapy, their capecitabine therapy will not be considered as a line of systemic chemotherapy for metastatic/advanced disease, and thus they can participate in the study
Have received any investigational drug (or have used an investigational device) within the last 14 days before receiving the first dose of study medication
Have unresolved or unstable serious toxicity (≥ common terminology criteria for adverse events [CTCAE] 4.03 Grade 2), with the exception of anemia, asthenia, and alopecia, from prior administration of another investigational drug and/or prior cancer treatment
Have a known positive test for human immunodeficiency virus, hepatitis C (treatment naïve or after treatment without sustained virologic response), or hepatitis B infection with hepatitis B virus deoxyribonucleic acid exceeding 2000 IU/mL
Have a known history of drug addiction within last 1 year which, in the opinion of the Investigator, could increase the risk of non-compliance to investigational product
Need continuous treatment with proton pump inhibitors during the study period
Have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis, or have a history of interstitial lung disease or current interstitial lung disease
Have any history or presence of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic or psychiatric disease or any other condition which in the opinion of the Investigator could jeopardize the safety of the patient or the validity of the study results
Have a baseline corrected QT interval (Fridericia's formula) (QTcF) > 450 ms or patients with known long QT syndrome; torsade de pointes; symptomatic ventricular tachycardia; an unstable cardiac syndrome in the past 3 months before screening visit; > class 2 New York Heart Association heart failure; or > class 2 angina pectoris; or receiving quinidine, procainamide, disopyramide, amiodarone, dronedarone, arsenic, dofetilide, sotalol, or methadone. Please also see prohibited medication/therapy (Section 5.4.10.1)

Facility	Status	City	State	ZIP	Country	Contacts
Banner MD Anderson Cancer Center		Gilbert	Arizona	85234	United States
Karmanos Cancer Institute/Wayne State University

ID	Title	Description
FG000	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Aug 13, 2019	Jun 10, 2021

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Objective Response Rate (ORR) - Part 1

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).

Posted

Count of Participants

Participants

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.

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	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.

Units	Counts
Participants	OG00064 OG00163

Title

Denominators

Categories

Title	Measurements
Responders - CR	OG0000 OG0010
Responders - PR	OG000

Primary

Progression-free Survival (PFS) - Part 1

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.

Posted

Median

Inter-Quartile Range

Months

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.

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	Placebo and Capecitabine

Secondary

Object Response Rates (ORR) - Safety Lead-In

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).

Posted

Count of Participants

Participants

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.

ID	Title	Description
OG000	Varlitinib + Capecitabine	This part of the study was a single arm, open-label design to assess the safety of varlitinib (300 mg administered BID every day) plus capecitabine (1000 mg/m2 administered BID every day for 14 days, followed by a 7-day rest period) in a small set of subjects (12 to 20 subjects) with 12 subjects completing the PK and ECG evaluations. Treatment was continued until disease progression, development of unacceptable toxicity, withdrawal of consent, or death.

Units	Counts
Participants

Secondary

Overall Survival (OS) - Part 1

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.

Posted

Median

Inter-Quartile Range

Months

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

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	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.

Units

Secondary

Overall Survival (OS) - Safety Lead-In

Posted

Count of Participants

Participants

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

ID	Title	Description
OG000	Varlitinib + Capecitabine	This part of the study was a single arm, open-label design to assess the safety of varlitinib (300 mg administered BID every day) plus capecitabine (1000 mg/m2 administered BID every day for 14 days, followed by a 7-day rest period) in a small set of subjects (12 to 20 subjects) with 12 subjects completing the PK and ECG evaluations. Treatment was continued until disease progression, development of unacceptable toxicity, withdrawal of consent, or death.

Units	Counts
Participants	OG000

Secondary

Duration of Response (DoR) - Part 1

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.

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.

Posted

Median

Full Range

Days

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

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	Placebo and Capecitabine

Secondary

Disease Control Rate DCR - Part 1

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

Posted

Count of Participants

Participants

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

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	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.

Secondary

Tumor Size - Part 1

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

Posted

Mean

Standard Deviation

Percentage change from Baseline

Week 12

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	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.

Units	Counts
Participants

Secondary

Number of Participants With Clinically Significant Laboratory Tests- Safety Lead-in

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

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

Posted

Count of Participants

Participants

Subject screening visit to 28 days post last study drug administration

ID	Title	Description
OG000	Varlitinib + Capecitabine	This part of the study was a single arm, open-label design to assess the safety of varlitinib (300 mg administered BID every day) plus capecitabine (1000 mg/m2 administered BID every day for 14 days, followed by a 7-day rest period) in a small set of subjects (12 to 20 subjects) with 12 subjects completing the PK and ECG evaluations. Treatment was continued until disease progression, development of unacceptable toxicity, withdrawal of consent, or death.

Units	Counts
Participants	OG000

Secondary

Number of Participants With Clinically Significant Laboratory Tests - Part 1

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

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

Posted

Count of Participants

Participants

Subject screening visit to 28 days post last study drug administration

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	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.

Secondary

Number of Participants With Clinically Significant Change in Vital Signs and Physical Examinations - Safety Lead-In

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

Posted

Count of Participants

Participants

Subject screening visit to 28 days post last study drug administration

ID	Title	Description
OG000	Varlitinib + Capecitabine	This part of the study was a single arm, open-label design to assess the safety of varlitinib (300 mg administered BID every day) plus capecitabine (1000 mg/m2 administered BID every day for 14 days, followed by a 7-day rest period) in a small set of subjects (12 to 20 subjects) with 12 subjects completing the PK and ECG evaluations. Treatment was continued until disease progression, development of unacceptable toxicity, withdrawal of consent, or death.

Units	Counts
Participants	OG000

Secondary

Number of Participants With Clinically Significant Change in Vital Signs and Physical Examinations - Part 1

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

Posted

Count of Participants

Participants

Subject screening visit to 28 days post last study drug administration

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	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.

Units

Secondary

Number of Participants With ECG Parameters of Interest - Safety Lead-In

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.

Posted

Number

participants

Subject screening visit to 28 days post last study drug administration

ID	Title	Description
OG000	Varlitinib + Capecitabine	This part of the study was a single arm, open-label design to assess the safety of varlitinib (300 mg administered BID every day) plus capecitabine (1000 mg/m2 administered BID every day for 14 days, followed by a 7-day rest period) in a small set of subjects (12 to 20 subjects) with 12 subjects completing the PK and ECG evaluations. Treatment was continued until disease progression, development of unacceptable toxicity, withdrawal of consent, or death.

Units	Counts
Participants	OG000

Secondary

Number of Participants With ECG Parameters of Interest - Part 1

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.

Posted

Number

Participants

Subject screening visit to 28 days post last study drug administration

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.
OG001	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.

Secondary

ECOG Performance Status - Part 1

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

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.

Posted

Count of Participants

Participants

Subject screening visit to 28 days post last study drug administration

ID	Title	Description
OG000	Varlitinib and Capecitabine	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.

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Acute kidney injury	Renal and urinary disorders	Systematic Assessment	EG0002 affected24 at risk EG0012 affected64 at risk EG0021 affected63 at risk
Bile duct obstruction	Hepatobiliary disorders	Systematic Assessment	EG0002 affected24 at risk EG0012 affected64 at risk EG0020 affected63 at risk
Enterocolitis	Gastrointestinal disorders	Systematic Assessment	EG0002 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Abdominal Pain	Gastrointestinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0011 affected64 at risk EG0022 affected63 at risk
Aspiration	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Asthenia	General disorders	Systematic Assessment	EG0001 affected24 at risk EG0011 affected64 at risk EG0022 affected63 at risk
Cardiac arrest	Cardiac disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Cholangitis	Hepatobiliary disorders	Systematic Assessment	EG0001 affected24 at risk EG0014 affected64 at risk EG0024 affected63 at risk
Constipation	Gastrointestinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Dehydration	Metabolism and nutrition disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Diarrhoea	Gastrointestinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Haematemesis	Gastrointestinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Hyperbilirubinaemia	Hepatobiliary disorders	Systematic Assessment	EG0001 affected24 at risk EG0014 affected64 at risk EG0020 affected63 at risk
Hypercalcaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Hyponatremia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Hypoxic-ischaemic encephalopathy	Nervous system disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Ischaemic stroke	Nervous system disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Lung Infection	Infections and infestations	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Metabolic acidosis	Metabolism and nutrition disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Nausea	Gastrointestinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Pyrexia	General disorders	Systematic Assessment	EG0001 affected24 at risk EG0013 affected64 at risk EG0020 affected63 at risk
Rash generalized	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Respiratory Failure	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Septic shock	Infections and infestations	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Small intestinal obstruction	Gastrointestinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Spinal cord compression	Nervous system disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Toxic leukoencephalopathy	Nervous system disorders	Systematic Assessment	EG0001 affected24 at risk EG0010 affected64 at risk EG0020 affected63 at risk
Vomiting	Gastrointestinal disorders	Systematic Assessment	EG0001 affected24 at risk EG0014 affected64 at risk EG0022 affected63 at risk
Blood bilirubin increased	Investigations	Systematic Assessment	EG0000 affected24 at risk EG0015 affected64 at risk EG0025 affected63 at risk
Disease progression	General disorders	Systematic Assessment	EG0000 affected24 at risk EG0012 affected64 at risk EG0022 affected63 at risk
Pneumonia	Infections and infestations	Systematic Assessment	EG0000 affected24 at risk EG0012 affected64 at risk EG0021 affected63 at risk
Decreased appetite	Metabolism and nutrition disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0021 affected63 at risk
Hepatobiliary infection	Infections and infestations	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0021 affected63 at risk
Blood creatinine increased	Investigations	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Oedema peripheral	General disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Anemia	Blood and lymphatic system disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Biliary tract infection	Infections and infestations	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Erythema multiforme	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Hemobilia	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Hematuria	Renal and urinary disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Embolism	Blood and lymphatic system disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Bile duct stenosis	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Biliary dilatation	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Biliary sepsis	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Blood culture positive	Blood and lymphatic system disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Cerebrovascular accident	Nervous system disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Dyspnoea	Nervous system disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Haemorrhoidal haemorrhage	Gastrointestinal disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Hernia	Renal and urinary disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Intestinal obstruction	Gastrointestinal disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Jaundice	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Liver abscess	Infections and infestations	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Peritonitis bacterial	Infections and infestations	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Procedural complication	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Small intestinal haemorrhage	Gastrointestinal disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Abdominal pain upper	Gastrointestinal disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Biloma	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Cholangiolitis	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Cholecystitis	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
General physical health deterioration	General disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Inguinal hernia	Gastrointestinal disorders	Systematic Assessment	EG0000 affected24 at risk EG0010 affected64 at risk EG0021 affected63 at risk
Jaundice cholestatic	Hepatobiliary disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk
Pain	General disorders	Systematic Assessment	EG0000 affected24 at risk EG0011 affected64 at risk EG0020 affected63 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	Systematic Assessment	EG00029 events15 affected24 at risk EG00158 events33 affected64 at risk EG00219 events14 affected63 at risk
Diarrhoea	Gastrointestinal disorders	Systematic Assessment	EG00031 events13 affected24 at risk EG00143 events26 affected64 at risk EG00219 events16 affected63 at risk
Vomiting	Gastrointestinal disorders	Systematic Assessment	EG00027 events11 affected24 at risk EG00130 events22 affected64 at risk EG00218 events11 affected63 at risk
Abdominal Pain	Gastrointestinal disorders	Systematic Assessment	EG00012 events9 affected24 at risk EG00127 events16 affected64 at risk EG00220 events12 affected63 at risk
Constipation	Gastrointestinal disorders	Systematic Assessment	EG00019 events8 affected24 at risk EG0019 events9 affected64 at risk EG0029 events9 affected63 at risk
Stomatitis	Gastrointestinal disorders	Systematic Assessment	EG0009 events6 affected24 at risk EG0018 events7 affected64 at risk EG0028 events8 affected63 at risk
Dyspepsia	Gastrointestinal disorders	Systematic Assessment	EG0008 events5 affected24 at risk EG0019 events7 affected64 at risk EG0024 events4 affected63 at risk
Ascites	Gastrointestinal disorders	Systematic Assessment	EG0004 events4 affected24 at risk EG0013 events3 affected64 at risk EG0024 events4 affected63 at risk
Abdominal Distension	Gastrointestinal disorders	Systematic Assessment	EG00013 events7 affected24 at risk EG0015 events4 affected64 at risk EG0022 events2 affected63 at risk
Abdominal Pain Upper	Gastrointestinal disorders	Systematic Assessment	EG0003 events3 affected24 at risk EG0013 events3 affected64 at risk EG0022 events2 affected63 at risk
Gastrooesophageal Reflux Disease	Gastrointestinal disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0014 events3 affected64 at risk EG0022 events2 affected63 at risk
Fatigue	General disorders	Systematic Assessment	EG00035 events14 affected24 at risk EG00133 events16 affected64 at risk EG00217 events12 affected63 at risk
Pyrexia	General disorders	Systematic Assessment	EG00018 events10 affected24 at risk EG00123 events15 affected64 at risk EG00213 events11 affected63 at risk
Asthenia	General disorders	Systematic Assessment	EG0009 events5 affected24 at risk EG00120 events11 affected64 at risk EG0029 events7 affected63 at risk
Malaise	General disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG00114 events8 affected64 at risk EG0024 events4 affected63 at risk
Chills	General disorders	Systematic Assessment	EG0007 events5 affected24 at risk EG0017 events6 affected64 at risk EG0022 events2 affected63 at risk
Mucosal Inflammation	General disorders	Systematic Assessment	EG0000 events0 affected24 at risk EG0018 events5 affected64 at risk EG0022 events2 affected63 at risk
Oedema Peripheral	General disorders	Systematic Assessment	EG00012 events7 affected24 at risk EG0015 events4 affected64 at risk EG0023 events3 affected63 at risk
Blood Bilirubin Increased	Investigations	Systematic Assessment	EG00017 events8 affected24 at risk EG00171 events28 affected64 at risk EG00230 events14 affected63 at risk
Blood Creatinine Increased	Investigations	Systematic Assessment	EG0005 events3 affected24 at risk EG00126 events15 affected64 at risk EG0023 events3 affected63 at risk
Aspartate Aminotransferase Increased	Investigations	Systematic Assessment	EG00010 events5 affected24 at risk EG00119 events9 affected64 at risk EG00211 events7 affected63 at risk
Platelet Count Decreased	Investigations	Systematic Assessment	EG00016 events4 affected24 at risk EG00113 events8 affected64 at risk EG00211 events8 affected63 at risk
Alanine Aminotransferase Increased	Investigations	Systematic Assessment	EG0007 events4 affected24 at risk EG00122 events10 affected64 at risk EG0028 events5 affected63 at risk
Neutrophil Count Decreased	Investigations	Systematic Assessment	EG0005 events2 affected24 at risk EG0017 events3 affected64 at risk EG00221 events5 affected63 at risk
Weight Decreased	Investigations	Systematic Assessment	EG0004 events3 affected24 at risk EG0013 events3 affected64 at risk EG0021 events1 affected63 at risk
Palmar-plantar Erythrodysaethesia Syndrome	Skin and subcutaneous tissue disorders	Systematic Assessment	EG00018 events6 affected24 at risk EG00132 events20 affected64 at risk EG00237 events19 affected63 at risk
Pruritus	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected24 at risk EG00113 events11 affected64 at risk EG0025 events5 affected63 at risk
Rash	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0007 events4 affected24 at risk EG00110 events8 affected64 at risk EG0027 events4 affected63 at risk
Skin Hyperpigmentation	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0000 events0 affected24 at risk EG0015 events5 affected64 at risk EG0021 events1 affected63 at risk
Decreased Appetite	Metabolism and nutrition disorders	Systematic Assessment	EG00033 events12 affected24 at risk EG00149 events25 affected64 at risk EG00215 events11 affected63 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0003 events3 affected24 at risk EG00111 events6 affected64 at risk EG0027 events5 affected63 at risk
Hypokalaemia	Metabolism and nutrition disorders	Systematic Assessment	EG00020 events10 affected24 at risk EG0016 events2 affected64 at risk EG0022 events2 affected63 at risk
Hyponatraemia	Metabolism and nutrition disorders	Systematic Assessment	EG00010 events7 affected24 at risk EG0015 events4 affected64 at risk EG0020 events0 affected63 at risk
Hypoglycemia	Metabolism and nutrition disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0014 events3 affected64 at risk EG0020 events0 affected63 at risk
Dehydration	Metabolism and nutrition disorders	Systematic Assessment	EG00011 events6 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Anaemia	Blood and lymphatic system disorders	Systematic Assessment	EG0007 events6 affected24 at risk EG00130 events13 affected64 at risk EG00227 events14 affected63 at risk
Pneumonia	Infections and infestations	Systematic Assessment	EG0000 events0 affected24 at risk EG0015 events5 affected64 at risk EG0021 events1 affected63 at risk
Peripheral Sensory Neuropathy	Nervous system disorders	Systematic Assessment	EG0002 events1 affected24 at risk EG0018 events5 affected64 at risk EG0022 events2 affected63 at risk
Dizziness	Nervous system disorders	Systematic Assessment	EG00011 events7 affected24 at risk EG0015 events4 affected64 at risk EG0022 events2 affected63 at risk
Dysgeusia	Nervous system disorders	Systematic Assessment	EG0004 events2 affected24 at risk EG0016 events5 affected64 at risk EG0021 events1 affected63 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG00016 events5 affected24 at risk EG0015 events5 affected64 at risk EG0024 events4 affected63 at risk
Cough	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0004 events3 affected24 at risk EG0014 events4 affected64 at risk EG0023 events3 affected63 at risk
Cholangitis	Hepatobiliary disorders	Systematic Assessment	EG0005 events2 affected24 at risk EG00110 events5 affected64 at risk EG0028 events5 affected63 at risk
Hyperbilirubinaemia	Hepatobiliary disorders	Systematic Assessment	EG0008 events3 affected24 at risk EG00116 events7 affected64 at risk EG0027 events1 affected63 at risk
Back Pain	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0007 events7 affected24 at risk EG0015 events4 affected64 at risk EG0026 events4 affected63 at risk
Myalgia	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0013 events3 affected64 at risk EG0020 events0 affected63 at risk
Insomnia	Psychiatric disorders	Systematic Assessment	EG0004 events2 affected24 at risk EG0014 events3 affected64 at risk EG0023 events3 affected63 at risk
Acute Kidney Injury	Renal and urinary disorders	Systematic Assessment	EG0009 events2 affected24 at risk EG0016 events5 affected64 at risk EG0021 events1 affected63 at risk
Proteinuria	Renal and urinary disorders	Systematic Assessment	EG0006 events5 affected24 at risk EG0016 events3 affected64 at risk EG0022 events2 affected63 at risk
Hypotension	Vascular disorders	Systematic Assessment	EG0008 events6 affected24 at risk EG0014 events4 affected64 at risk EG0020 events0 affected63 at risk
Dry mouth	Gastrointestinal disorders	Systematic Assessment	EG0003 events3 affected24 at risk EG0011 events1 affected64 at risk EG0020 events0 affected63 at risk
Enterocolitis	Gastrointestinal disorders	Systematic Assessment	EG0008 events2 affected24 at risk EG0010 events0 affected64 at risk EG0021 events1 affected63 at risk
Faeces discolored	Gastrointestinal disorders	Systematic Assessment	EG0004 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Hematemesis	Gastrointestinal disorders	Systematic Assessment	EG0005 events2 affected24 at risk EG0010 events0 affected64 at risk EG0022 events2 affected63 at risk
Oral pain	Gastrointestinal disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0011 events1 affected64 at risk EG0020 events0 affected63 at risk
Early satiety	General disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Influenza like illness	General disorders	Systematic Assessment	EG0003 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0005 events3 affected24 at risk EG0011 events1 affected64 at risk EG0020 events0 affected63 at risk
Hyperkalaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0012 events2 affected64 at risk EG0022 events1 affected63 at risk
Hypocalcaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0012 events2 affected64 at risk EG0021 events1 affected63 at risk
Blood alkaline phosphatase increased	Investigations	Systematic Assessment	EG0002 events2 affected24 at risk EG0013 events2 affected64 at risk EG0023 events3 affected63 at risk
Gamma-glutamyltransferase increased	Investigations	Systematic Assessment	EG0002 events2 affected24 at risk EG0012 events1 affected64 at risk EG0024 events4 affected63 at risk
International normalised ratio increased	Investigations	Systematic Assessment	EG0003 events2 affected24 at risk EG0013 events1 affected64 at risk EG0020 events0 affected63 at risk
Hypoaesthesia	Nervous system disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Paraesthesia	Nervous system disorders	Systematic Assessment	EG0003 events2 affected24 at risk EG0011 events1 affected64 at risk EG0020 events0 affected63 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0004 events3 affected24 at risk EG0011 events1 affected64 at risk EG0020 events0 affected63 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0004 events2 affected24 at risk EG0012 events2 affected64 at risk EG0020 events0 affected63 at risk
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0004 events3 affected24 at risk EG0012 events1 affected64 at risk EG0020 events0 affected63 at risk
Bursitis	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0012 events2 affected64 at risk EG0021 events1 affected63 at risk
Bile duct obstruction	Hepatobiliary disorders	Systematic Assessment	EG0008 events2 affected24 at risk EG0014 events2 affected64 at risk EG0020 events0 affected63 at risk
Urinary tract infection	Infections and infestations	Systematic Assessment	EG0003 events3 affected24 at risk EG0011 events1 affected64 at risk EG0021 events1 affected63 at risk
Anxiety	Psychiatric disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0011 events1 affected64 at risk EG0022 events2 affected63 at risk
Depression	Psychiatric disorders	Systematic Assessment	EG0002 events2 affected24 at risk EG0010 events0 affected64 at risk EG0020 events0 affected63 at risk

ID	Term
D001661	Biliary Tract Neoplasms
D009369	Neoplasms
D001650	Bile Duct Neoplasms
D005706	Gallbladder Neoplasms

ID	Term
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D001660	Biliary Tract Diseases
D004066	Digestive System Diseases
D001649	Bile Duct Diseases
D005705	Gallbladder Diseases

ID	Term
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D011743	Pyrimidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D005472	Fluorouracil
D014498	Uracil
D011744	Pyrimidinones
D003853	Deoxyribonucleosides
D009705	Nucleosides
D009706	Nucleic Acids, Nucleotides, and Nucleosides

ID	Title	Description
BG000	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.
BG001	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.
BG002	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.
BG003	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.	2	24	13	24	24	24
EG001	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.	35	64	25	64	64	64
EG002	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.	35	63	27	63	59	63