Conditions: Biliary Tract Cancer
Keywords: Neoplasms Biliary Tract Neoplasms Bile Duct Neoplasms Gallbladder Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 151
Healthy volunteers: no

Brief summary:
This protocol for Varlitinib is developed for the treatment of Biliary Tract Cancer. Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate competitive inhibitor of the tyrosine kinases - epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, and HER4. Varlitinib may be beneficial to subjects with cancer by simultaneous inhibition of these receptors. The purpose of this study is to determine the safety and efficacy of Varlitinib in combination with capecitabine for the treatment of Biliary Tract Cancer. Treatment groups are Varlitinib+capecitabine and Placebo + capecitabine

Detailed description:
Part 1 of study(Phase 2) is planned to have 120 patients and anticipated completion on July 2019. Recruitment completed.

Part 2 of study(Phase 3) is planned to have 350 patients and anticipated completion on Dec 2022. Not yet recruiting.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Varlitinib intervention 2: Capecitabine intervention 3: Placebo (for Varlitinib)
Intervention descriptions: intervention 1: Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. intervention 2: 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. intervention 3: oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death

Protocol document:
Prot_002.pdf: 
 
Confidential © 2018 ASLAN Pharmaceuticals Pte. Ltd., all rights reserved 
                            
 
CLINICAL STUDY PROTOCOL 
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY OF VARLITINIB PLUS CAPECITABINE 
VERSUS PLACEBO PLUS CAPECITABINE IN PATIENTS WITH ADVANCED 
OR METASTATIC BILIARY TRACT CANCER AS SECOND-LINE SYSTEMIC 
THERAPY 
Abbreviated Protocol Title: 
Treatment Opportunity with Varlitinib in Biliary Tract 
Cancer (TreeTopp) 
Protocol Number: 
ASLAN001-009 
EudraCT Number: 
2017-000114-30 
Investigational Product: 
Varlitinib 
Phase: 
Phase 2/3 
Sponsor: 
ASLAN Pharmaceuticals Pte. Ltd. 
83 Clemenceau Avenue 
#12-03 UE Square 
Singapore 239920 
Protocol Date: 
13 Aug 2019 
Protocol Version: 
Version 6.0 
CONFIDENTIAL AND PROPRIETARY 
This document contains proprietary and confidential information of ASLAN Pharmaceuticals Pte. Ltd. 
(ASLAN). Acceptance of this document constitutes agreement by the recipient that no previously 
unpublished information contained herein will be published or disclosed without the prior written approval 
of ASLAN with the exception that this document may be disclosed to study personnel under your 
supervision who need to know the contents for conducting the study and appropriate Institutional Review 
Boards (IRBs)/Independent Ethics Committees (IECs) under the condition that the personnel have agreed 
to keep this information confidential. The foregoing shall not apply to disclosure required by governmental 
regulations or laws; however, ASLAN shall be promptly notified of any such disclosure. Nothing herein 
constitutes an invitation or offer to invest in or deal in the securities of ASLAN. Anyone considering 
investment in ASLAN should refer to the information officially published the Taiwan Stock Exchange 
Market Observation System, and/or filed with the U.S. Securities and Exchange Commission. 


 
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1 
SYNOPSIS 
Protocol 
Number: 
ASLAN001-009 
Abbreviated 
Protocol Title: 
Treatment Opportunity with Varlitinib in Biliary Tract Cancer (TreeTopp) 
Protocol Title 
A multicenter, double-blind, randomized, placebo-controlled study of varlitinib plus 
capecitabine versus placebo plus capecitabine in patients with advanced or metastatic 
biliary tract cancer as second-line systemic therapy 
Investigational 
Product: 
Varlitinib 
Study Centers: 
Multicenter–United States, Japan, South Korea, Singapore, Taiwan, China, multiple 
countries in Europe, and the rest of world (ROW) 
Phase: 
Phase 2/3 
Objectives: 
Primary objectives: 
Safety lead-in 
To assess the safety and tolerability of varlitinib 300 mg twice daily (BID) (every 
day), in combination with capecitabine 1000 mg/m2 (BID for 14 days followed by a 
7-day rest) as measured by the incidence of adverse events (AEs), and changes from 
baseline in safety parameters. 
 
Part 1 
To assess the efficacy of varlitinib in combination with capecitabine as measured by 
co-primary endpoints of objective response rate (ORR) and progression-free survival 
(PFS), both assessed by an Independent Central Review (ICR). 
 
Part 2 
To assess the efficacy of varlitinib in combination with capecitabine as measured by 
overall survival (OS). 
 
Secondary objectives: 
Safety lead-in 
1. To evaluate the pharmacokinetics (PK) of varlitinib (and any relevant circulating 
metabolites) and capecitabine (and its active metabolite 5-FU) when given in 
combination  
2. To evaluate the effect of varlitinib on QT/QTc 
3. To evaluate the efficacy of varlitinib in combination with capecitabine as 
measured by ORR, duration of response (DoR) and disease control rate (DCR), 
all based on site assessment 
 
Part 1 
1. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by DoR, and DCR as assessed by ICR, and OS and ORR as assessed 
by the site 
2. To assess the safety and tolerability of varlitinib when combined with 
capecitabine 
3. To explore exposure-response relationships for varlitinib (and any relevant 
circulating metabolites) for measures of efficacy, safety, and pharmacological 
responses  


 
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4. To examine the effects of varlitinib, when added to capecitabine on ECG 
parameters including QTcF, QTcB, HR (heart or ventricular rate), PR and QRS 
 
Part 2 
1. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by ORR, DoR, DCR and PFS, all based on site assessment 
2. To assess the safety and tolerability of varlitinib when combined with 
capecitabine 
3. To explore exposure-response relationships for varlitinib (and any relevant 
circulating metabolites) for measures of efficacy, safety, and pharmacological 
responses via sparse PK sampling and population PK analyses 
 
Exploratory objectives: 
Part 1 
1. To explore the role of human epidermal growth factor family of receptors (HER) 
status as a predictor of benefit to varlitinib 
2. To explore possible relationships between HER family and downstream 
signaling protein and phospho-protein expression levels and clinical outcomes 
3. To explore possible relationships between gene mutational status and clinical 
outcomes 
 
Part 2 
If a relationship is found between biomarker(s) expression and clinical outcomes in 
Part 1 of the study, the biomarker(s) could be prospectively evaluated in Part 2 of the 
study. 


 
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Study Design: 
 
 
This study will commence initially with a Safety lead-in group. This part of the study 
is a single arm, open label design to assess the safety of varlitinib (300 mg 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 patients (12 to 20 patients) with 12 
patients completing the PK and ECG evaluation. Treatment will continue until disease 
progression or development of unacceptable toxicity or consent withdrawal or death. 
 
 
Part 1 of the study is designed as a double-blind, randomized, placebo controlled 
study to assess the efficacy and safety of varlitinib (300 mg BID) plus capecitabine 
(1000 mg/m2 BID for 14 days out of 21 days) in comparison with placebo plus 
capecitabine in approximately 120 patients. Eligible patients will be randomized to 
varlitinib or placebo in a 1:1 ratio. Treatment will continue until disease progression 
or development of unacceptable toxicity or consent withdrawal or death. 


 
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Part 2 of the study is designed as double-blind, randomized, placebo controlled study 
to confirm the efficacy of varlitinib plus capecitabine compared to capecitabine in 
approximately 350 patients. Part 2 will follow the same design and treatment schedule 
as Part 1. This part of the study will commence following review of the Part 1 results.  
Number of 
Patients: 
Safety lead-in 
A total of 12 to 20 eligible patients will be enrolled to receive varlitinib plus 
capecitabine. 
United States:  6 to 12 eligible patients are expected to be enrolled from the United 
States. 
Rest of the World: An additional 6 to 8 eligible patients will be enrolled from the rest 
of the world. 
Patients in this group will be replaced if varlitinib compliance is <85% in the first 14 
days. Pharmacokinetic sampling will be performed in approximately 12 patients. 
 
Part 1 
Approximately 120 eligible patients will be enrolled and randomized in a 1:1 ratio to 
receive varlitinib and capecitabine (n=60) or placebo and capecitabine (n=60). 
 
Part 2 
Approximately 350 eligible patients will be enrolled and randomized in a 1:1 ratio to 
receive varlitinib and capecitabine (n=175) or placebo and capecitabine (n=175) 
 
In both Part 1 and Part 2 of the study, patients will be stratified by: 
• 
region - US and the ROW and;  
• 
primary tumor location - gallbladder vs non-gallbladder 


 
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Treatment: 
Safety lead-in 
Per oral (PO) varlitinib 300 mg BID, every day. 
PO capecitabine 1000 mg/m2 BID from Day 1 to Day 14 followed by 7-day of rest 
period, every 21 days. 
Treatment will continue for a minimum of 14 days, during which dose adjustment is 
not allowed. Dose adjustment and interruption is allowed from day 15 onwards. 
Treatment will continue in 21-day cycles until disease progression, development of 
unacceptable toxicity, withdrawal of consent, or death. 
 
Part 1 and Part 2 
PO varlitinib 300 mg (if assessed as safe in Safety lead-in) or matching placebo, both 
BID, every day 
PO capecitabine 1000 mg/m2 BID from Day 1 to Day 14 followed by a 7-day of rest 
period, every 21 days 
Treatment will continue until unacceptable toxicity, disease progression, withdrawal 
of consent or death. 
Dose modification will be permitted where required according to protocol. 
Study 
Duration: 
Screening Period: 
Up to 14 days. It may be extended up to 21 days subjected to a case by case review 
and approval by the Sponsor. 
 
Treatment Period:  
Safety lead-in 
Study treatment will be given in 21-day cycles. Patients will receive study medication 
until disease progression, unacceptable toxicity, withdrawal of consent or death. 
Patients will be followed for disease status every 6 weeks.  
 
Part 1 and Part 2 
Study treatment will be given in 21-day cycles. Patients will receive study medication 
until disease progression, development of unacceptable toxicity, withdrawal of 
consent or death. Patients will be followed for disease status every 6 weeks during 
treatment period and follow-up period until disease progression. Patients who 
discontinue treatment for reasons other than disease progression will be followed for 
disease status every 6 weeks until disease progression. 
 
Follow-up Period: 
Patients will complete a safety follow-up visit 28 days after the last dose of varlitinib 
therapy. All patients will be followed for survival and status of further anti-cancer 
treatment every 12 weeks until death or until the data cut-off (DCO) for the final 
overall survival analysis. 
 
Part 1 
After the DCO for the primary analysis of ORR and PFS, patients who are ongoing 
on the trial will continue to be followed for survival every 12 weeks. The OS follow-
up analysis is planned when approximately 95 OS events have occurred. Note, 
survival calls may be made in the week following the date of Data Cut Off (DCO) for 
the analyses, and if subjects are confirmed to be alive or if the death date is after the 
DCO, these subjects will be censored at the date of DCO. 


 
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Study 
Population: 
Inclusion Criteria: 
Patients will be eligible for the study if they: 
1. 
Are of or older than the legal age in the respective countries at the time when 
written informed consent is obtained 
2. 
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.  
3. 
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 
4. 
Have received at least 6 doses of gemcitabine containing treatment in first line 
(Adjuvant therapy is not regarded as 1st line therapy) 
5. 
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) 
6. 
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) 
7. 
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1 
8. 
Are able to understand and willing to sign the informed consent form 
9. 
Have adequate organ and hematological function: 
a. 
Hematological function, as follows: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
• 
Platelet count ≥ 100 × 109/L 
b. 
Renal functions, as follows: 
• 
Estimated glomerular filtration rate or creatinine clearance 
> 50 mL/min/1.73m2 
c. 
Hepatic function, as follows: 
• 
Albumin ≥ 3 g/dL 
• 
Total bilirubin ≤ 1.5 × ULN 
• 
Aspartate aminotransferase and alanine aminotransferase ≤ 5 × ULN 
 
Exclusion Criteria: 
Patients will be ineligible for the study if they: 
1. 
Are currently on or have received anti-cancer therapy within the past 3 weeks 
before receiving the first dose of study medication 
2. 
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  
3. 
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.) 
4. 
Have had major surgical procedures within 14 days prior to  first dose of study 
medication 
5. 
Have a known metastatic brain lesion(s), including asymptomatic and well 
controlled lesion(s) 
6. 
Have malabsorption syndrome, diseases significantly affecting gastrointestinal 
function, resection of the stomach or small bowel, or difficulty in swallowing 


 
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and retaining oral medications which in the opinion of the Investigator could 
jeopardize the validity of the study results 
7. 
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 
8. 
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) 
9. 
Are female patients who are pregnant or breast feeding 
10. 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 
11. Have received any investigational drug (or have used an investigational device) 
within the last 14 days before receiving the first dose of study medication 
12. 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 
13. 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 
14. 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 
15. Need continuous treatment with proton pump inhibitors during the study period 
16. 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 
17. 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 
18. 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) 
 
Study 
Endpoints: 
Primary Endpoints:  
Safety lead-in 
• Incidence of AEs, categorized in accordance to CTCAE 4.03 and changes from 
baseline in safety parameters (including vital signs, ECG parameters, clinical 
laboratory tests) 
 
Part 1 


 
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• ORR: Defined as the proportion of patients with a best objective response of 
complete response (CR) or partial response (PR), as assessed by ICR defined by 
the RECIST v1.1 criteria. 
• PFS: Defined as the time from randomization until the date of objective disease 
progression or death (by any cause in the absence of disease progression). 
Progression is defined in accordance with the RECIST v1.1 criteria will derived 
programmatically based on data from the ICR of radiological data. 
 
 
Part 2 
• OS: Defined as the time from randomization until death by any cause. Any 
patient not known to have died at the time of DCO will be censored based on 
the last recorded date on which the patient was known to be alive. 
 
Secondary Endpoints: 
Safety lead-in 
• Pharmacokinetics endpoints: The PK of varlitinib (and any relevant circulating 
metabolites) and capecitabine and 5-FU (active metabolite of capecitabine) will 
be determined at selected time points (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 
12 hours post-dose). Other relevant circulating metabolites of capecitabine (5’-
DFCR, 5’-DFUR, and FBAL) will only be determined if this is considered 
necessary based on the pharmacokinetic and safety findings). The following PK 
parameters will be evaluated where possible: 
Cycle 1 Day 1, Day 8 and Day 14: 
- 
maximum plasma concentration (Cmax) 
- 
time to Cmax(tmax) 
- 
plasma concentration before next dose (Ctrough) 
- 
area under the plasma concentration-time curve from 0 to 12 hours 
(AUC0- τ) 
- 
half-life (t1/2) 
- 
apparent clearance (Cl/F) 
- 
apparent volume of distribution (Vz/F) 
- 
apparent volume of distribution at the steady state (Vss/F) 
- 
where τ = 12 hours (dosing interval) 
Cycle 1 Day 8 
- 
accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 8/Day 1) 
- 
accumulation ratio of Cmax RacCmax (Day 8/Day 1) 
Cycle 1 Day 14 
- 
accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 14/Day 1) 
- 
accumulation ratio of Cmax RacCmax (Day 14/Day 1) 
• Exploratory electrocardiogram endpoints: QTcF, QTcB, PR, QRS, HR 
• Efficacy endpoints 
- 
ORR: as determined by site review of radiological data. 
- 
DoR: Defined as the time, in days, from the first recorded achievement of 
a response (PR or above) until time of objective disease progression in the 
subset of patients classified as responders in the assessment of ORR 
- 
DCR: Defined as the proportion of patients with a best response of stable 
disease maintained for at least 12 weeks (-5 days) from randomization, 
PR or CR as defined by RECIST v1.1 criteria. 
 
Part 1 
• Efficacy Endpoints 
- 
OS 


 
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- 
DoR 
- 
DCR 
- 
ORR as based on site review of radiological data 
- 
Tumor size: Defined as the percentage change from baseline in the sum 
of target lesions at Week 12 ((%ΔTSWk12) 
• Safety Endpoints 
- 
Incidence of AEs, categorized in accordance to CTCAE 4.03 and changes 
from baseline in safety parameters (including vital signs, ECG 
parameters, clinical laboratory tests) 
• Electrocardiogram Endpoints 
- 
QTcF, QTcB, PR, QRS, HR 
• PK Endpoints 
PK samples will be obtained for the PK evaluation of varlitinib (and any relevant 
circulating metabolites). PK samples will be collected at the following time 
points for all patients: 
- 
Cycle 1 Day 1: 5 minutes pre-dose, 1.5 hours, 3 hours, 5 hours, and 8 
hours post-dose 
- 
Cycle 1 Day 8: 20 minutes pre-dose, 1.5 hours, 3 hours, 5 hours, and 8 
hours post-dose 
- 
End of study after full drug washout: 28 days after last dose at the patient’s 
safety follow-up visit 
 
Part 2 
• Efficacy Endpoints (all based on site review of radiological data) 
- 
ORR  
- 
DoR 
- 
DCR 
- 
PFS 
• Safety Endpoints 
- 
Incidence of AEs, categorized in accordance to CTCAE 4.03 and changes 
from baseline in safety parameters (including vital signs, clinical 
laboratory tests) 
• PK Endpoints 
- 
A population PK study with sparse sampling will be included in the Part 
2 of the study to explore exposure-response relationships for varlitinib 
(and any relevant circulating metabolites) for measures of efficacy, safety, 
and pharmacological responses via sparse PK sampling and population 
PK analyses. 
 
Exploratory Endpoints: 
Part 1 only 
Possible relationships between protein and phospho-protein expression levels and 
clinical outcome, and gene mutational status and clinical outcome will be explored 
using proteins and genes including, but not limited to: 
• Via IHC: 
- 
epidermal growth factor receptor (EGFR), pEGFR  
- 
HER2, pHER2  
- 
HER3, pHER3 
- 
HER4, pHER4 
• Via PCR/Sequencing 
- 
Mutational status of genes, such as KRAS, NRAS, BRAF, EGFR, HER2 and 
other genetic factors that may affect response to therapy. 


 
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The protein and gene studies will be conducted using archival material (and if not 
available, biopsy tissue samples). 
If a relationship is found between biomarker(s) expression and clinical outcomes in 
Part 1 of the study, the biomarker(s) could be prospectively evaluated in Part 2 of the 
study. 
Study 
Assessments: 
Safety Evaluations: 
Patient safety will be evaluated based on the incidence of AEs and serious AEs 
(SAEs), physical examination, vital signs (blood pressure [systolic and diastolic], 
heart rate, respiratory rate, weight, and body temperature), electrocardiogram (ECG) 
parameters (Safety lead-in and Part 1), and clinical laboratory tests (hematology, 
clinical chemistry, coagulation and urinalysis).  
All AEs will be evaluated according to NCI-CTCAE 4.03 and will be captured from 
the time of informed consent and continue until the safety follow-up assessment 
(28 days after last administration of study treatment). For the purpose of this study, 
fluctuations of pre-existing conditions that do not represent a clinically significant 
exacerbation or worsening need not be considered AEs. In addition, progression of 
the cancer of target disease under study is generally not considered an AE.  
 
Safety lead-in: 
In the Safety lead-in, triplicate 12-lead ECG will be performed on Cycle 1 Day 1 and 
Cycle 1 Day 8 at the following time points and will be analyzed by a Core ECG 
Laboratory: 
• 
Cycle 1 Day 1: 45 minutes pre-dose, 5 minutes pre-dose, 1, 2, 3, 4, 5, 6, 8.5, 
and 12 hours post-dose 
• 
Cycle 1 Day 8: 45 minutes pre-dose, 5 minutes pre-dose, 1, 2, 3, 4, 5, 6, 8.5, 
and 12 hours post-dose 
Triplicate ECGs will also be collected 3 hours post-dose Day 22 (Cycle 2 Day 1) and 
onwards every cycle while the subject remains in the study. The 12-lead ECGs will 
be taken in the supine position, after the patient has been lying down for at least 10 
minutes in a quiet environment. Detailed instructions will be described in the ECG 
manual. The ECG machines supplied by the Core ECG Laboratory will be used for 
all ECG collection, and the digital files of each tracing will be archived. 
 
Part 1: 
The primary electrocardiographic analysis of the protocol will be from the time-based 
ECG analysis performed in Part 1 at baseline, Cycle 1 Day 1, Cycle 1 Day 8, and the 
safety follow-up visit. Triplicate ECGs will be collected with a PK sample collected 
immediately following ECG acquisition.  ECGs will be analyzed by a Core ECG 
Laboratory. 
Collection time points: 
• 
Cycle 1 Day 1: 45 minutes pre-dose, 5 minutes pre-dose, 1.5, 3, 5 and 8 
hours post-dose.  Concomitant PK samples will be collected immediately 
after the ECG collections, except for the 45 minutes pre-dose time points 
where no PK sample will be collected. 
• 
Cycle 1 Day 8: 45 minutes pre-dose, 5 minutes pre-dose, 1.5, 3, 5, and 8 
hours post-dose.  Concomitant PK samples will be collected immediately 
after the ECG collections, except for the 45 minutes and 5 minutes pre-dose 
time points. One pre-dose PK sample will be collected at the 20 minutes pre-
dose time point. 
• 
End of Study after full drug washout (28 days after the last dose) a set of 
triplicate ECGs will be collected 3 hours after a light snack. 


 
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In addition, triplicate safety ECGs will be collected 3 hours post-dose on Day 22 
(Cycle 2 Day 1), Day 64 (Cycle 4 Day 1) and every 2 cycles while the subject remains 
in the study. This data will not be analyzed by the Core ECG Laboratory but will be 
assessed by the investigator. The digital ECGs will be archived. 
 
Part 2: 
ECGs will be collected in Part 2 of the study as part of standard safety monitoring at 
screening, baseline (before a snack), and 3 hours post-dose on Day 22 (Cycle 2 Day 
1), Day 64 (Cycle 4 Day 1) and every 2 cycles while the subject remains in the study.  
These data will not be analyzed by the Core ECG Laboratory but assessed by 
investigators. 
 
A data safety monitoring board (DSMB) will meet on 2 specified occasions to review 
safety data; the first DSMB will occur after the first 12 patients in the Safety lead-in 
have completed the 21 days of follow-up and the second DSMB will be at a selected 
time point to be confirmed during Part 1 of the study. Additional DSMB meetings 
may occur if needed. Details will be specified in the DSMB Charter. 
 
Efficacy Evaluations: 
Tumor evaluations will be performed to evaluate the efficacy of treatment according 
to RECIST v1.1. Tumor response will be assessed by means of computed tomography 
(CT) or magnetic resonance imaging (MRI) at baseline and every 6 weeks until EOT 
(Safety Lead-in) or disease progression (Part 1 and Part 2). All tumor responses 
should be assessed at every assessment time point using the same methods (contrast-
enhanced CT or MRI) used to characterize lesions identified at baseline.  
 
Safety Lead-in 
Radiological images collected in the Safety lead-in will be assessed by the site.  
 
Part 1 
Radiological images collected in the Part 1 of the study will be assessed by an ICR. 
Patients cannot be randomized into Part 1 of the study until the ICR has confirmed 
eligibility. Central radiological reading will not interfere with the Investigator’s 
judgment on disease progression.  
The co-primary endpoints of ORR and PFS will be programmatically derived using 
the ICR’s assessment of the radiological data in Part 1. Objective response rate as 
determined by the site review will also be reported as a secondary endpoint. 
 
Part 2 
All efficacy endpoints based on radiological data in Part 2 will be programmatically 
derived based on data provided by the site review of the Part 2 radiological data.  
 
Part 1 and 2 only 
Blood to be collected for analysis of cancer antigen 19.9 (CA19.9) and 
carcinoembryonic antigen (CEA) every 6 weeks starting from Week 6.  
Archival paraffin-embedded tumor tissues will be collected during screening for 
future analysis if the patient has provided the optional tumor tissue consent.  


 
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Biopsies will be performed during screening for those patients who did not have 
enough archival tumor tissue if the patient has provided the optional tumor tissue 
consent. 
 
Pharmacokinetic Evaluations: 
Safety Lead-in 
Blood samples for PK analysis of varlitinib (and any relevant circulating metabolites), 
capecitabine, and 5-FU (metabolite of capecitabine) will be collected at the following 
time points in the Safety lead-in part only: 
• 
Cycle 1 Day 1: 5 minutes pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours 
post-dose 
• 
Cycle 1 Day 8: 20 minutes pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours 
post-dose 
• 
Cycle 1 Day 14: 5 minutes pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours 
post-dose 
When ECGs and PK samples are collected at the same time point, the PK samples are 
always collected after the ECGs. 
In addition, unscheduled PK samples collected 7 days following dose reduction of 
varlitinib at any cycle of treatment will include: up to 5 minutes pre-dose, 0.5, 1, 2, 3, 
4, 5, 6, 8.5, 10, and 12 hours post-dose, if required.  
 
Part 1 and Part 2 
PK samples will be obtained for the PK evaluation of varlitinib (and any relevant 
circulating metabolites). PK samples will be collected at the following time points: 
 
Part 1 (All patients) 
• 
Cycle 1 Day 1: 5 minutes pre-dose, 1.5, 3, 5, and 8 hours post-dose 
• 
Cycle 1 Day 8: 20 minutes pre-dose, 1.5, 3, 5, and 8 hours post-dose 
• 
End of study after full drug washout:  28 days after last dose at the patient’s 
safety follow-up visit 
When ECGs and PK samples are collected at the same time point, the PK samples are 
always collected after the ECGs. 
 
Part 2 (Sparse Sampling) 
• 
Cycle 1 Day 1: 5 minutes pre-dose, 1-3 hours post-dose, 3-5 hours post-dose, 
and 5-8 hours post-dose 
• 
Cycle 2 Day 1: 20 minutes pre-dose, 1-3 hours post-dose, 3-5 hours post 
dose, and 5-8 hours post-dose 
 
In order to maintain the double-blind design of the study, blood samples will be 
collected from patients in both groups for plasma measurements of varlitinib and its 
potential relevant metabolites. 
In addition, unscheduled PK samples will be collected at least 7 days following dose 
reduction of varlitinib at any cycle of treatment: up to 5 minutes pre-dose and 3-5 
hours post-dose. 
 
Biomarker Evaluations: 
Blood samples for potential retrospective analysis of potential biomarkers will be 
collected at baseline and post Week 6 treatment tumor assessment. 
Prohibited 
Please see Appendix 14.3 for a complete list 


 
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Medications 
Any other antitumor treatment, proton pump inhibitors, warfarin, strong CYP3A4 
inhibitors, investigational products, and herbal preparations are prohibited throughout 
this study. H2 blocker can be given 3 hours after each dose of varlitinib. 
 
 
Safety lead-in and Part 1  (2 weeks prior to first dose up to and including Cycle 2 Day 
1) 
Use with caution: Non-excluded drugs that are associated with torsade de pointes and 
QTc prolongation (Appendix 14.4) or QT prolongation without torsade de pointes 
(Appendix 14.5) should be at steady-state dosing for at least 2 weeks before 
enrollment. The dose of such drugs should not be increased, and new drugs in either 
group should not be initiated without the medical monitor’s approval. 
 
Safety lead-in and Part 1 (from Cycle 2 Day 2 onwards) 
Use with caution: Non-excluded drugs that are associated with torsade de pointes and 
QTc prolongation (Appendix 14.4) or QT prolongation without torsade de pointes 
(Appendix 14.5) should be at steady-state dosing for at least 2 weeks before 
enrollment. From Cycle 2 Day 2 onwards, the dose of drugs associated with torsade 
de pointes and QTc prolongation (Appendix 14.4) or QT prolongation without torsade 
de pointes (Appendix 14.5) ideally should not be increased. Every attempt should be 
made to minimize the initiation of such drugs (Appendix 14.4 or Appendix 14.5). The 
initiation of any such drugs (Appendix 14.4 or Appendix 14.5) requires the medical 
monitor’s approval. 
 
Varlitinib may cause a drug-drug interaction with other medications that are 
cytochrome P450 (CYP) 3A4, CYP2C8, or CYP2C9 inducers, inhibitors, or 
substrates. CYP3A4 is the major metabolic enzyme of varlitinib, and CYP2C8 only 
a minor enzyme. Due to the potential for drug interactions based on in vitro screens, 
concomitant use of moderate CYP3A4, CYP2C8, CYP2C9, and P-gp inducers or 
inhibitors will be recorded during the entire clinical study. 
Statistical 
Analysis: 
Safety lead-in 
All safety data will be listed and summarized using appropriate descriptive statistics. 
Full details will be provided in the statistical analysis plan (SAP). 
The pharmacokinetic endpoints of varlitinib, capecitabine and 5-FU will be plotted 
and summarized using descriptive statistics. 
QTcF exposure response modeling, along with time-based central tendency effects 
and categorical QTc analyses will be evaluated. Both the Bazett and Fridericia 
correction (primary correction method) formulae will be used to estimate QTc. 
 
Parts 1 and 2 
For Part 1 and 2, all primary and key secondary efficacy endpoints will be analyzed 
based on the Full Analysis Set (FAS) using an intention-to-treat principle. Patients 
who were randomized but did not subsequently go on to receive study treatment will 
be included in the FAS. Analyses performed in the protocol-defined “Evaluable for 
Response set (EFR)” will be supportive. 
Objective response rate will be analyzed using a stratified exact binomial test (Mehta 
et al, Emerson) which extends Fisher’s Exact test to more than one stratum. The 
analysis will be stratified by primary tumor location (GB/non-GB). The 2-sided 
p-value will be obtained by doubling the 1-sided p-values. 


 
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To test for heterogeneity across strata, the exact test of Zelen will be performed testing 
whether the treatment effect differs between the 2 strata included in the primary 
analysis. 
Progression-free survival will be analyzed using a stratified log-rank test using the 
Breslow method to handle ties (Breslow, 1974). The analysis will be stratified by 
primary tumor location (GB/Non-GB).  
Overall survival will be analyzed using the methods outlined above for PFS. For Part 
1, OS will be analyzed twice. A preliminary analysis of OS will be performed at the 
time of the primary analysis of ORR and PFS. It is anticipated that the OS data at this 
time will be immature, thus a second analysis of OS is planned for when 
approximately 95 patients (approx. 79%) have an OS event. The second analysis of 
OS will be considered the primary analysis of OS for Part 1 of the trial. For Part 2, 
the primary analysis of OS will be performed when 247 patients have experienced an 
OS event. Further details will be provided in the study SAP. 
Duration of response will be listed and summarized descriptively for the duration of 
response in responding patients, including the associated Kaplan-Meier curves.  
Disease control rate will be analyzed using the methods described above for ORR. 
Tumor size is a secondary endpoint in Part 1 and will be used to assess the exploratory 
objective of evaluating the role of HER family expression levels as predictors of 
benefit to varlitinib. Tumor size will be analyzed by analysis of covariance 
(ANCOVA). 
Plasma sampling will be conducted for population PK evaluation in Parts 1 and 2 of 
the study and will use an NLME. PK sampling of all patients is planned for Part 1 of 
the study while sparse PK sampling is planned for Part 2.  For the sparse PK sampling 
in Part 2, the double-blind design will be maintained and blood samples will be 
collected from a selected number of patients without limiting the sampling to 
varlitinib patients only. 
All PK data will be analyzed according to treatment received. Deviations that have 
the potential to significantly affect the PK will be reviewed. The population, and 
decisions regarding which profiles are usable, will be defined by the Study Team 
Physician, Pharmacokineticist, and Statistician prior to unblinding or any analyses 
being performed. 
 
ECG/QT Analysis (Safety Lead-in and Part 1) 
General Principles 
Baseline will be defined as the mean of the triplicate ECG readings performed pre-
dose on Day 1. On Day 1, pre-dose is defined as 2 sets of triplicate ECGs taken 
45 minutes and 5 minutes prior to dosing. The ECG values from these 2 sets of ECGs 
will be averaged to create the baseline value. Similarly, for all other time points, for 
each ECG parameter, each patient’s mean will be calculated from the triplicate 
readings and the mean value will be used. 
 
The final ECG assessments (including interval measurements) will be made by the 
Core ECG laboratory. The Part 1 electrocardiographic Core ECG Laboratory 
assessments constitute the study’s primary assessment of ECG/QTc. Any analysis of 
ECG data from the Safety lead-in is considered exploratory. 
 
Due to the non-randomized, open label design of the Safety lead-in, data from the 
Safety lead-in will be presented separately from data from Part 1 of the study. 
Furthermore, ECG/QT outputs will be made available to the DSMB for consideration 
when determining whether the study should progress to Part 1. 


 
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Methods of Analysis 
For the Safety lead-in, exploratory descriptive and categorical analyzes, including 
change from baseline will be performed to investigate the impact of varlitinib and 
capecitabine treatments on the changes from baseline in ECG parameters. 
 
The ECG parameters of interest include: QT including QTcF and QTcB, HR, PR, 
QRS intervals. 
 
For Part 1, a multi-step approach will be applied to evaluate the effect of capecitabine 
alone and varlitinib in combination with capecitabine on the ECG parameters at 
different time points post-dose. The comparisons will be done between ECG values 
at each time point post-dose and baseline and between treatment arms with and 
without varlitinib for each time point individually. The evaluation of the 
cardiodynamic effects of capecitabine and varlitinib may be explored using exposure-
response modeling if there appears to be a meaningful effect of varlitinib when added 
to capecitabine on the ECG parameters including QTcF.  This will be further 
described in the SAP. 
 
Central Tendency Analysis 
For both the Safety lead-in and Part 1, the change from baseline in QTcF, PR, QRS, 
QTcB, and heart rate, will be summarized by time point (and treatment arm for Part 
1) using descriptive statistics (n, mean, SD, min, median, max, 90% confidence 
intervals).  
 
Categorical Analyses 
For both the Safety lead-in and Part 1, the following will be summarized: 
• 
The proportion of patients obtaining treatment-emergent absolute QTcF values > 
450 msec and ≤ 480 msec; > 480 msec and ≤ 500 msec; and > 500 msec 
• 
The proportion of patients obtaining a QTcF increase from baseline values ≥ 30 
and <60 msec and ≥ 60 msec 
• 
The proportion of patients obtaining a QRS change from baseline > 25% 
resulting in QRS > 120 msec 
• 
The proportion of patients obtaining a PR interval change from baseline >25% 
reaching a value >220 msec 
• 
The proportion of patients obtaining a > 25% decrease from baseline in heart rate 
resulting in a heart rate < 50 beats per minute (bpm) or a > 25% increase from 
baseline in heart rate resulting in a heart rate > 100 bpm 
For Part 1, the above categorical data summaries will be presented by treatment arm. 
 
Morphological T-wave Analysis 
T-wave morphology will also be analyzed, focusing on change from baseline, i.e., 
treatment emergent changes. 
 
Following Part 1, a formal statistical analysis will be performed to assess the potential 
impact of varlitinib and capecitabine on changes in ECG parameters.  


 
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The statistical stepwise approach will be used to separate the cardiodynamic effect of 
varlitinib from normal circadian fluctuation in the ECG values and from the effect of 
capecitabine: 
1. ANOVA mixed effects comparison of the absolute values of ECG parameters at 
each time point vs baseline using treatment as a fixed effect in order to evaluate 
the contribution of circadian fluctuation and to determine how treatment 
differences contribute to the changes. The ECG parameter values will be log-
transformed and the resulting output will include the geometric mean ratio for 
test vs reference with the corresponding confidence interval and p-value. 
Interaction term, time point x treatment, will be also evaluated if the data allow. 
2. ANOVA comparison of the absolute values of ECG parameters as well as change 
from baseline (ΔECG) between treatments for each post-dose time point assessed 
separately in order to separate the varlitinib effect from that of capecitabine. The 
ECG parameter values will be log-transformed and the resulting output will 
include the geometric mean ratio for test vs reference with the corresponding 
confidence interval and p-value.  ΔECG will be tested as untransformed and log-
transformed parameters to avoid bias from discarding 0 ΔECG values from the 
comparisons. 
3. Exposure-Response Analysis:  Linear mixed effect model between ΔQTcF and 
time matched concentrations of varlitinib and other potential metabolites if 
measured and as appropriate.  Other ECG variable may be similarly analyzed and 
other models used, if appropriate. 
3.1. ΔQTcF will be calculated as the difference between each time point value 
and the average baseline value for each arm with the combination 
varlitinib/capecitabine treatment.  
3.2. ΔΔQTcF will be calculated for each patient in the combination arm 
individually as the difference between the ΔQTcF value for the arm with 
combination varlitinib/capecitabine treatment and the average value of all 
patients in the capecitabine alone arm matching time point. Other ECG 
parameters may also be used in the analysis including QTcB, heart rate, etc 
to provide supporting information. 
3.3. Base linear mixed effect model will include patients as a random effect. 
3.4. The total dose of capecitabine may be included as a fixed effect in the model 
to account for differences in total doses received by subjects with different 
body surface area. 
4. Linear mixed effect model between ΔQTcF parameters and time matched 
concentrations of capecitabine and 5-FU (metabolite of capecitabine) and other 
potential metabolites if measured and as appropriate 
4.1. ΔQTcF will be calculated for all patients in both arms as the difference 
between each time point value and the average baseline value. 
4.2. Base linear mixed effect model will include patients as a random effect and 
treatment (capecitabine alone or in combination with varlitinib) as a fixed 
effect; the total capecitabine dose may also be used as a fixed effect. 
5. Different covariates may be included in the complex models in addition to the 
base model as fixed effects such as time point in order to ensure the model 
feasibility and to evaluate covariates influential to ECG parameters. 
The results of the fitted models will be presented using statistical parameters such as 
the geometric mean ratios and corresponding confidence intervals (for ANOVA) and 
estimates of the slope, and associated confidence interval for the linear mixed effect 
models. 
In addition, graphic exploration of the exposure-ECG relationship may be performed: 


 
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• 
Residual plots to predict results 
• 
Double Y plots with time on the X axis and time matched values of PK 
concentrations for varlitinib and capecitabine on the Y1 axis, ΔECG on the 
Y2 axis to determine the possibility of hysteresis between drug concentration 
and cardiodynamic effects 
• 
Regression/scatter plots with time matched concentrations of varlitinib and 
capecitabine on the X axis and ΔECG on the Y axis 
• 
Regression/scatter plots with varlitinib or capecitabine non-compartmental 
PK parameters of Cmax,  Ctrough,  AUCtau and others on the X axis and 
maximum ΔECG on the Y axis 
• 
Forest plots for different categories in ECG changes vs mean (SD) non-
compartmental PK parameters for varlitinib or capecitabine on the X axis 
Further details of the statistical methods will be provided in the SAP. 
Sample Size: 
Part 1:  
The study is designed with co-primary endpoints, ORR, and PFS. In order to maintain 
an overall 1-sided 10% type I error rate for the study, a Hochberg procedure will be 
used, such that the trial will be deemed to have met its primary objective if either 
endpoint is significant at the 1-sided 5% level or if both endpoints are significant at 
the 1-sided 10% significance level. 
To ensure that adequate data are available to evaluate the effects of varlitinib on both 
co-primary endpoints, the DCO for the primary analysis will be the later of 3 months 
after the last patient in or when 70% of the patients (84 patients) have experienced a 
PFS event. Based on a minimum of 84 PFS events at the time of the primary analysis, 
the study would have a minimum of 80% power to detect a true Hazard Ratio (HR) of 
0.58 for PFS, based on a 1-sided 5% significance level. 
Furthermore, if the primary objective of the study is met, the following approach to 
type I error control will be applied in order to support marketing approval: 
• 
The overall type I error rate for marketing approval will be controlled at the 
two-sided 5% level, using a Hochberg procedure 
• 
Using this approach, statistical significance may be claimed if either ORR or 
PFS is significant at the two-sided 2.5% significance level or if both ORR 
and PFS are significant at the two-sided 5% significance level.  
One hundred and twenty patients will provide approximately 80% power to detect a 
true difference of 20% in response rate, based on a 2-sided 5% significance level and 
assuming a 10% response rate for the placebo/capecitabine group and a 30% response 
rate for the varlitinib/capecitabine group. 
A total of 84 PFS events provides 80% power to detect a true HR of 0.54, based on a 
two-sided 5% significance level. Assuming an 8-month non-linear recruitment period, 
a 2.67-month median PFS for capecitabine alone, and a true HR of 0.54, it is estimated 
that the DCO for the primary analysis of Part 1 will occur approximately 12 months 
after the first patient is randomized into the study (first patient in). 
 
Part 2: 
Part 2 is designed with a primary endpoint of OS. Approximately 350 patients will be 
randomized (1:1) to obtain 247 OS events. If the true OS HR for the comparison of 
varlitinib + capecitabine vs. placebo + capecitabine is 0.7, the study will have 
approximately 80% power to demonstrate a statistically significant difference for 
varlitinib, based on a 2-sided 5% significance level. 
Assuming a 24-month non-linear recruitment period whereby the proportion of 
patients recruited by the end of the month i is (i/24)^2, a median OS of 6 months for 


 
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placebo + capecitabine and a true HR of 0.7, it is estimated that 247 OS events will 
occur approximately 31 months after the first patients is randomized into Part 2. 


 
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Table 1: 
Schedule of Assessments – Safety Lead-in 
Assessments 
Screening 
Study Treatment Period 
EOTm 
Safety Follow 
upn 
Cycle 1 
Subsequent Cycles 
Day -14 
to 0 
Day 1 
(±0 day) 
Day 8 
(±0 day) 
Day 14 
(±0 day) 
Cycle 2 Day 1, 
Cycle 3 Day 1, etc.   
(±5 days) 
EOT 
(+7 days) 
28 days post 
last study 
medication 
administration 
(+7 days) 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
Vital Signs a 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG  
X 
X b 
X b 
 
X b 
 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
AE review c 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medication and Therapy 
X 
X 
X 
X 
X 
X 
X 
Varlitinib Administration d 
 
X d 
X d 
X d 
X 
 
 
Capecitabine Administration e 
 
X 
X 
 
X 
 
 
Urine or Serum β-HCG f 
X 
 
 
 
 
X 
 
Hematology g 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry g 
X 
X 
X 
X 
X 
X 
X 
Urinalysis g 
X 
X 
X 
X 
X 
X 
 
Coagulation g,h 
X 
 
 
 
 
X 
 
Serology i 
X 
 
 
 
 
 
 
Pharmacokinetics j 
 
X 
X 
X 
 
 
 
CT/ MRI  
X l 
 
 
 
X k 
 
 


 
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Abbreviations: AE = adverse event, β-HCG = beta human chorionic gonadotropin, BID = twice daily, CT = computed tomography, ECG = electrocardiogram, 
ECOG = Eastern Cooperative Oncology Group, EOT = End of Treatment, MRI = magnetic resonance imaging, PK = pharmacokinetics, SAE = serious 
adverse event. 
Footnotes: 
a. Vitals (blood pressure, heart rate, respiratory rate, temperature) are to be collected in a standardized manner in a sitting position after the patient has 
rested comfortably for 5 minutes. 
b. For patients participating in the ECG collection, triplicate 12-Lead ECG using the Central Laboratory-supplied ECG machines will be performed as 
close as possible and within 25 minutes prior to PK sampling at selected time points as follows: Day 1 and Day 8: 45 minutes pre-dose, 5 minutes pre-
dose, 1, 2, 3, 4, 5, 6, 8.5, and 12 hours post-dose. Select time points in this ECG assessments can be waived by the sponsor on a case by case basis. 
Patients should be rested for at least 10 minutes in a supine position and be resting quietly before the triplicate 12-lead ECG assessment. There should 
be no significant external stimulation (TV, radio, interaction with other subjects). On Days 1 and 8, concomitant PK samples will be collected 
immediately after ECG collection at all post-dose time points. At pre-dose time points, PK samples will be collected at 5 minutes and 20 minutes prior 
to dosing on Cycle 1 Day 1 and Cycle 1 Day 8, respectively.  
Triplicate ECGs will be collected 3 hours post-dose on Day 22 (Cycle 2 Day 1) and onwards every cycle until disease progression. The timing of the 
ECG acquisition needs to be recorded in the CRF. Refer to the ECG Manual.  
c. Adverse event recording will commence from the time of consent and continues until the safety follow-up assessment with the patient. 
d. Varlitinib tablets 300 mg administered orally, BID, every day with food. Patients should avoid a high-fat meal. Note: Day 1, Day 8, and Day 14 morning 
dose can only be administered under supervision of the Investigator (or designee), following collection of pre-dose PK sample and ECG.  
e. Capecitabine tablets 1000 mg/m2 administered orally, BID with food for 14 days from Day 1 to Day 14, followed by 1 week of rest. 
f. Serum pregnancy test to be performed at the screening visit for all females except those surgically sterile or 2 years postmenopausal. Serum or urine 
pregnancy tests will be performed at EOT. Unscheduled serum or urine pregnancy tests may be performed at the Investigator’s discretion. 
g. Screening clinical laboratory tests (hematology, clinical chemistry, urinalysis and coagulation) must be completed ≤ 21 days prior to Day 1. Screening 
clinical laboratory tests may be used in lieu of pre-treatment Day 1 tests, if performed within 1 week prior to the first administration of study medications. 
The clinical laboratory tests obtained as per site standard clinical practice prior to consent is acceptable for screening laboratory tests if it meets the 
protocol required time window. 
h. Coagulation laboratory test will be performed at screening and EOT visit, however investigator may perform coagulation tests at other visits if required 
based on clinical judgment. 
i. Screening viral serology test for HBV and HCV is only needed if there are no existing results within the year prior to screening. Screening viral serology 
test must be completed ≤ 21 days prior to Day 1. Serology tests include Hepatitis B surface antigen, Hepatitis C Virus antibody and human 
immunodeficiency virus antibody tests. 
j. For patients participating in the PK sampling, blood samples for PK analysis of varlitinib , any relevant varlitinib circulating metabolites, capecitabine 
and 5-FU (active metabolite of capecitabine) will be collected as follows: Day 1, Day 8 and Day 14: post-dose: 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours 
post-dose. Pre-dose PK samples will be collected on Day 1 at 5 minutes pre-dose, Day 8 at 20 minutes pre-dose, and Day 14 at 5 minutes pre-dose. In 
addition, unscheduled PK will be collected 7 days following dose reduction of varlitinib at any cycle of treatment: up to 5 minutes pre-dose, 0.5, 1, 2, 3, 
4, 5, 6, 8.5, 10, and 12 hours post-dose if required. Select time points in this PK assessments can be waived by the sponsor on a case by case basis. 
k. During study treatment period, CT/MRI imaging of the chest, abdomen, and pelvis images to be performed every 6 weeks (±5 days) from Cycle 1 Day 
1. Brain and/or bone lesions may be scanned if applicable. Radiological assessments should continue until EOT visit of the patient is conducted. 


 
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l. 
Baseline CT/MRI of the chest, abdomen, and pelvis images must be performed within 21 days prior to Cycle 1 Day 1, brain and/or bone lesions may be 
scanned if applicable. The CT/MRI image obtained as per site standard clinical practice prior to consent is acceptable for baseline image if it meets the 
protocol required CT/MRI image acquisition guidelines and time window. 
m. EOT assessments should be performed before the start of a new anti-tumor treatment. 
n. If the patient needs to start a new anti-tumor treatment within 28 days post last study medication administration, the safety follow-up assessments should 
be performed within 1 day before the start of the new anti-tumor treatment. 
 
 


 
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Table 2: 
Schedule of Assessments – Part 1 and Part 2 
Assessments 
Screening 
Study Treatment Period 
EOTu 
Safety Follow 
up r 
Disease 
Status FU s 
Survival 
FU t 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles  
Day -14 
to 0 
Day 1  
(±0 day) 
Day 8 – 
Part 1 
(±1 day) 
Day 8 – 
Part 2  
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(± 5 days) 
Day 1 
(± 5 days) 
Cycle 4 Day 1, 
Cycle 5 Day 1, 
etc. (± 5 days) 
EOT 
(+7 days) 
28 days post 
last study 
medication 
administration 
(+7 days) 
Every 6 
weeks (from 
Cycle 1 Day 
1) post EOT 
until disease 
progression 
(± 5 days) 
Every 12 
Weeks post 
disease 
progression 
(± 7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Body Weight 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Vital Signs a 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG  
X 
X b 
X b 
 
 
X b 
 
X b 
 
Xb 
 
 
ECOG 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
AE review c 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
Prior and 
Concomitant 
Medication and 
Therapy 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
Varlitinib 
Administration d 
 
X d 
X d 
X 
X 
X d 
X 
X 
 
 
 
 
Capecitabine 
Administration e 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Urine or Serum β-
HCG f 
X 
 
 
 
 
 
 
 
X 
 
 
 
Hematology g 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 


 
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Abbreviations: AE = adverse event, β-HCG = beta human chorionic gonadotropin, CA19.9 = cancer antigen 19.9, CEA = carcinoembryonic antigen, 
CT = computed tomography, ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, EOT = End of Treatment, MRI = magnetic resonance 
imaging, SAE = serious adverse event. 
 
 
Assessments 
Screening 
Study Treatment Period 
EOTu 
Safety Follow 
up r 
Disease 
Status FU s 
Survival 
FU t 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
Day -14 
to 0 
Day 1  
(±0 day) 
Day 8 – 
Part 1 
(±1 day) 
Day 8 – 
Part 2  
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(± 5 days) 
Day 1 
(± 5 days) 
Cycle 4 Day 1, 
Cycle 5 Day 1, 
etc. (± 5 days) 
EOT 
(+7 days) 
28 days post 
last study 
medication 
administration 
(+7 days) 
Every 6 
weeks (from 
Cycle 1 Day 
1) post EOT 
until disease 
progression 
(± 5 days) 
Every 12 
Weeks post 
disease 
progression 
(± 7 days) 
Clinical Chemistry g 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
Liver Function Test 
q 
 
 
 
X 
X 
 
 
 
 
 
 
 
Urinalysis g 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
Coagulation g,h 
X 
 
 
 
 
 
 
 
X 
 
 
 
Serology i 
X 
 
 
 
 
 
 
 
 
 
 
 
CA19.9 and CEA j 
X 
 
 
 
 
 
X 
Xj 
Xj 
 
 
 
Collection of tumor 
tissue k 
X 
 
 
 
 
 
 
 
 
 
 
 
Biopsy l 
X 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics m 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
Biomarker 
Sampling n 
X 
 
 
 
 
 
X 
 
 
 
 
 
CT/ MRI o 
X p 
 
 
 
 
 
X 
Xo 
 
 
X 
 
Survival status 
contact 
 
 
 
 
 
 
 
 
 
 
 
X 


 
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Footnotes: 
a. 
Vitals (blood pressure, heart rate, respiratory rate, temperature) to be collected in a standardized manner in a sitting position after the patient has rested 
comfortably for 5 minutes. 
b. Part 1: Triplicate 12-Lead ECG using the Core Laboratory-supplied ECG machines will be performed as close as possible and within 25 minutes prior 
to PK sampling at selected time points on 
• 
Cycle 1 Day 1: 45 minutes pre-dose, 5 minute pre-dose, 1.5, 3, 5, and 8 hours post-dose. Concomitant PK samples will be collected 
immediately after the ECG collections, except for 45 minutes pre-dose time point where no PK sample will be collected. 
• 
Cycle 1 Day 8: 45 minutes pre-dose, 5 minutes pre-dose, 1.5, 3, 5, and 8 hours post-dose.  Concomitant PK samples will be collected 
immediately after the ECG collections, except for the 45 minutes and 5 minutes pre-dose time points.  One pre-dose PK sample will be 
collected on Cycle 1 Day 8 at the 20 minutes pre-dose time point.  
• 
End of Study after full drug washout (at 28 days after the last dose) a set of triplicate ECGs will be collected 3 hours after a light snack. A 
concomitant PK sample will be collected immediately after the ECG collection. 
• 
In addition, triplicate safety ECGs will be collected 3 hours post-dose on Day 22 (Cycle 2 Day 1), Day 64 (Cycle 4 Day 1) and every 2 cycles 
until disease progression.  These ECGs will not be analyzed by the Core ECG Laboratory. 
Patients should be rested for at least 10 minutes in a supine position and be resting quietly before the triplicate 12-Lead ECG assessment. There should 
be no significant external stimulation (TV, radio, interaction with other subjects). 
 
Part 2: Triplicate safety ECGs will be collected at screening, baseline (before a snack), and 3 hours post-dose on Day 22 (Cycle 2 Day 1) and Day 64 
(Cycle 4 Day 1) and every 2 cycles while the subject remains in the study.  These ECGs will not be analyzed by the Core ECG Laboratory but assessed 
by the investigators. 
c. 
Adverse event recording will commence from the time of consent and continues until the safety follow-up assessment with the patient. 
d. Varlitinib tablets 300 mg administered orally, BID, every day with food. Patients should avoid a high-fat meal. Note: Cycle 1 Day 1, Cycle 1 Day 8 
(Part 1 only), and Cycle 2 Day 1 morning dose can only be administered under supervision of the Investigator (or designee), following collection of 
pre-dose PK sample and ECG. 
e. 
Capecitabine tablets 1000 mg/m2 administered orally, BID with food for 14 days from Day 1 to Day 14, followed by 1 week of rest. 
f. 
Serum pregnancy test to be performed at the screening visit for all females except those surgically sterile or 2 years postmenopausal. Serum or urine 
pregnancy tests will be performed at EOT. Unscheduled serum or urine pregnancy tests will be performed at the Investigator’s discretion. 
g. Screening clinical laboratory tests (hematology, clinical chemistry, urinalysis and coagulation) must be completed ≤ 21 days prior to Day 1. Screening 
clinical laboratory tests may be used in lieu of pre-treatment Day 1 tests, if performed within 1 week prior to the first administration of study medications. 
The clinical laboratory tests obtained as per site standard clinical practice prior to consent is acceptable for screening laboratory tests if it meets the 
protocol required time window. Liver function testing is included in the Clinical Chemistry testing.  
h. Coagulation laboratory test will be performed at screening and EOT visit, however investigator may perform coagulation tests at other visits if required 
based on clinical judgment. 
i. 
Screening viral serology test for HBV and HCV is only needed if there are no existing results within the year prior to screening. Screening viral serology 
test must be completed ≤ 21 days prior to Day 1. Serology tests include Hepatitis B surface antigen, Hepatitis C Virus antibody and human 
immunodeficiency virus antibody tests. 


 
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j. 
During the study treatment period, blood is to be collected for the analysis of CA19.9 and CEA at every 6 weeks (±5 days) from Cycle 1 Day 1 together 
with CT/MRI. The final collection of blood for these analyses should occur at EOT. If the reason for EOT is due to radiological disease progressions 
and CA19.9/CEA have already been assessed with the most recent scans, then CA19.9/CEA at EOT can be omitted. 
k. Archival paraffin-embedded tumor tissues will be collected during screening for future analysis (the minimum archival tumor tissue to be collected is 
19 unstained slides of 5 microns). 
l. 
Biopsy will be performed during screening for those patients who did not have enough archival tumor tissue if the patient has provided the optional 
tumor tissue consent. 
m. Blood samples for PK analysis of varlitinib and any relevant circulating metabolites will be collected as follows: 
Part 1 (All Patients):  
• 
Cycle 1 Day 1: 5 minutes pre-dose, 1.5, 3, 5, and 8 hours post-dose. PK samples will be collected immediately after the ECG collections.  
• 
Cycle 1 Day 8: 20 minutes pre-dose, 1.5, 3, 5, and 8 hours post-dose.  PK samples will be collected immediately after the ECG collections. 
• 
End of study after full drug washout:  28 days after last dose at the patient’s safety follow-up visit. PK samples will be collected within 25 
minutes after ECG evaluation. 
Part 2:  
Sparse plasma sampling will be conducted for the population PK evaluation by using nonlinear mixed effects models on: 
• 
Cycle 1 Day 1: 5 minutes pre-dose, 1-3 hours post-dose, 3-5 hours post-dose, and 5-8 hours post-dose 
• 
Cycle 2 Day 1: 20 minutes pre-dose, 1-3 hours post-dose, 3-5 hours post-dose, and 5-8 hours post-dose.  
Part 1 & Part 2: In addition, unscheduled PK samples will be collected at least 7 days following dose reduction of varlitinib at any cycle of treatment: 
up to 5 minutes pre-dose and 3-5 hours post-dose. 
n. Blood samples for potential retrospective analysis of potential biomarkers will be collected at baseline and Cycle 3 Day 1 
o. CT/MRI imaging of the chest, abdomen, and pelvis images to be performed every 6 weeks (±5 days) from Cycle 1 Day 1. Brain and/or bone lesions 
may be scanned if applicable. Radiological assessments should continue until the patient experiences disease progression, regardless of whether the 
patient discontinues randomized therapy or starts a subsequent anti-cancer therapy. 
p. Baseline CT/MRI of the chest, abdomen, and pelvis images must be performed within 21 days prior to Cycle 1 Day 1, brain and/or bone lesions may 
be scanned if applicable. The CT/MRI image obtained as per site standard clinical practice prior to consent is acceptable for baseline image if it meets 
the protocol required CT/MRI image acquisition guidelines and time window. 
q. Additional weekly liver function test (AST, ALT, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, direct bilirubin) will also be 
performed for all patients on Cycle 1 Day 8 and Cycle 1 Day 15. 
r. 
No other additional study-related activities or assessments are mandated during follow-up visit; however, patient data available from the assessments 
done as part of their routine follow-up visits will be collected by the sponsor. If the patient needs to start a new anti-tumor treatment within 28 days 
post last study medication administration, the safety follow-up assessments should be performed within 1 day before the start of a new anti-tumor 
treatment. 
s. 
Disease status follow-up will be performed post EOT every 6 weeks from Cycle 1 Day 1, regardless of timing of EOT.  
t. 
Survival follow-up by either telephone or clinic visit will be performed every 12 weeks post EOT and PD until death to find out the survival status, 
new chemotherapy or biological treatments and the outcome of any ongoing adverse events. 
u. EOT assessments should be performed before the start of new anti-tumor treatment. 
 


 
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2 
TABLE OF CONTENTS 
1 
Synopsis ............................................................................................................. 2 
2 
Table of Contents ............................................................................................ 27 
2.1 
List of In-text Tables ...................................................................................... 32 
2.2 
List of In-text Figures ..................................................................................... 32 
List of Abbreviations and Definition of Terms .......................................................... 33 
3 
Introduction .................................................................................................... 36 
3.1 
Background ..................................................................................................... 36 
3.2 
Varlitinib ......................................................................................................... 37 
3.2.1 
Nonclinical Studies.......................................................................... 37 
3.2.2 
Clinical Studies................................................................................ 38 
3.2.3 
Known or Potential Risks of Varlitinib ........................................... 39 
3.2.4 
Known or Potential Risks of Capecitabine...................................... 40 
3.3 
Rationale for the Study .................................................................................. 40 
4 
Study Objectives ............................................................................................. 42 
4.1 
Primary Objective .......................................................................................... 42 
4.2 
Secondary Objective(s) .................................................................................. 42 
4.3 
Exploratory Objectives .................................................................................. 43 
5 
Investigational Plan ........................................................................................ 44 
5.1 
Overall Study Design and Plan: Description ............................................... 44 
5.1.1 
Study Design ................................................................................... 44 
5.2 
Discussion of Study Design ............................................................................ 46 
5.3 
Selection of Study Population ........................................................................ 48 
5.3.1 
Number of Planned Patients ............................................................ 48 
5.3.2 
Inclusion Criteria ............................................................................. 48 
5.3.3 
Exclusion Criteria ............................................................................ 49 
5.3.4 
Removal of Patients from Therapy or Assessments ........................ 50 
5.3.5 
Pregnancy ........................................................................................ 52 
5.3.5.1 
Acceptable Forms of Contraception ................................................ 53 
5.3.5.2 
Time Period for the Collection of Pregnancy Information .............. 53 
5.3.5.3 
Follow-up in the Event of a Pregnancy ........................................... 53 
5.4 
Investigational Products ................................................................................ 54 
5.4.1 
Study Medication Administered ...................................................... 54 


 
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5.4.2 
Identity of Investigational Products and Background 
Therapy ............................................................................................ 55 
5.4.3 
Storage Condition of Study Medications ........................................ 55 
5.4.4 
Packaging and Labeling .................................................................. 56 
5.4.5 
Method of Assigning Patients to Treatment Groups ....................... 56 
5.4.6 
Procedures for Randomization ........................................................ 57 
5.4.7 
Selection of Doses in the Study ....................................................... 58 
5.4.8 
Selection and Timing of Dose for Each Patient .............................. 60 
5.4.8.1 
Dose Modification ........................................................................... 62 
5.4.8.2 
Management of Toxicities ............................................................... 64 
5.4.9 
Blinding ........................................................................................... 68 
5.4.10 
Prior and Concomitant Therapy ...................................................... 69 
5.4.10.1 Prohibited Medication/Therapy ....................................................... 70 
5.4.11 
Treatment Compliance .................................................................... 71 
6 
Timing of Study Procedures .......................................................................... 71 
6.1 
Study Visits – Safety Lead-in ........................................................................ 71 
6.1.1 
Screening Visit – Safety Lead-in..................................................... 71 
6.1.2 
Treatment Visits – Safety Lead-in................................................... 72 
6.1.3 
End of Treatment Visit (+ 7 Days) – Safety Lead-in ...................... 73 
6.1.4 
Safety Follow up Visit 28 Days Post Last Study Medication 
Administration (+ 7 Days) – Safety Lead-in ................................... 73 
6.2 
Study Visits – Part 1 ....................................................................................... 74 
6.2.1 
Screening Visit – Part 1 ................................................................... 74 
6.2.2 
Treatment Visits – Part 1 ................................................................. 74 
6.2.3 
Safety Follow-up Visit 28 Days Post Last Study Medication 
Administration (+ 7 Days) – Part 1 ................................................. 77 
6.2.4 
Disease Status Follow-up Visit Every 6 Weeks (± 5 Days) 
Post End of Treatment until Disease Progression – Part 1 .............. 77 
6.2.5 
Survival Follow-up Visit, Every 12 Weeks (± 7 Days) Post 
Disease Progression – Part 1 ........................................................... 78 
6.3 
Study Visits – Part 2 ....................................................................................... 78 
6.3.1 
Screening Visit – Part 2 ................................................................... 78 
6.3.2 
Treatment Visits – Part 2 ................................................................. 79 
6.3.3 
Safety Follow-up Visit 28 Days Post Last Study Medication 
Administration (+ 7 Days) – Part 2 ................................................. 81 
6.3.4 
Disease Status Follow-up Visit Every 6 Weeks (± 5 Days) 
Post End of Treatment until Disease Progression – Part 2 .............. 81 
6.3.5 
Survival Follow-up Visit, Every 12 Weeks (± 7 Days) Post 
Disease Progression – Part 2 ........................................................... 81 
6.4 
Duration of Treatment ................................................................................... 82 
7 
SAFETY, EFFICACY, PHARMACOKINETIC AND BIOMARKER 
VARIABLES ................................................................................................... 82 


 
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7.1 
Safety, Efficacy Pharmacokinetic and Pharmacodynamic 
Measurements Assessed ................................................................................. 83 
7.1.1 
Safety Assessments ......................................................................... 83 
7.1.1.1 
Adverse Events ................................................................................ 83 
7.1.1.2 
Reporting of Serious Adverse Events ............................................. 87 
7.1.1.3 
Unexpected Adverse Reactions ....................................................... 88 
7.1.1.4 
Clinical Laboratory Evaluation ....................................................... 89 
7.1.1.5 
Vital Signs ....................................................................................... 90 
7.1.1.6 
Physical Examination ...................................................................... 90 
7.1.1.7 
12-lead ECG .................................................................................... 90 
7.1.1.8 
ECOG Performance Status .............................................................. 92 
7.1.2 
Efficacy Variables ........................................................................... 92 
7.1.2.1 
Tumor Evaluation ............................................................................ 92 
7.1.2.2 
Cancer Antigen Evaluation ............................................................. 93 
7.1.3 
Pharmacokinetic Variables .............................................................. 93 
7.1.3.1 
Determination of Drug Concentrations in Biological 
Samples ........................................................................................... 93 
7.1.3.2 
Pharmacokinetic Sampling .............................................................. 93 
7.1.3.3 
Pharmacokinetic Analysis ............................................................... 95 
7.1.4 
Biomarker Variables........................................................................ 96 
7.2 
Data Safety Monitoring Board and Independent Central Review ............ 97 
8 
STATISTICAL ANALYSIS .......................................................................... 98 
8.1 
General Statistical Considerations ................................................................ 98 
8.2 
Sample Size Derivation .................................................................................. 99 
8.2.1 
Safety Lead-in Sample Size ............................................................ 99 
8.2.2 
Part 1 Sample Size ........................................................................... 99 
8.2.3 
Part 2 Sample Size ......................................................................... 100 
8.3 
Analysis Populations .................................................................................... 100 
8.3.1 
Safety Population .......................................................................... 100 
8.3.2 
Full Analysis Set ........................................................................... 101 
8.3.3 
Evaluable for Response Set (Part 1 only) ...................................... 101 
8.3.4 
Per Protocol Analysis Population .................................................. 101 
8.3.5 
PK Analysis Set ............................................................................. 102 
8.4 
Study Endpoints ........................................................................................... 103 
8.4.1 
Objective Response Rate ............................................................... 103 
8.4.2 
Progression-Free Survival ............................................................. 104 
8.4.3 
Overall Survival ............................................................................ 104 
8.4.4 
Duration of Response .................................................................... 105 
8.4.5 
Disease Control Rate ..................................................................... 105 
8.4.6 
Tumor Size .................................................................................... 106 
8.4.7 
Safety Endpoints............................................................................ 106 
8.4.8 
ECG Parameters ............................................................................ 106 


 
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8.5 
Methods of Statistical Analysis ................................................................... 106 
8.5.1 
Primary Endpoints ......................................................................... 106 
8.5.1.1 
Part 1 - Objective Response Rate .................................................. 106 
8.5.1.2 
Part 1 – Progression-Free Survival ................................................ 107 
8.5.1.3 
Part 2 – Overall Survival ............................................................... 110 
8.5.2 
Secondary Endpoints ..................................................................... 110 
8.5.2.1 
Efficacy Endpoints ........................................................................ 110 
8.5.2.2 
Safety Data Analysis ..................................................................... 113 
8.5.2.3 
ECG/QT Analysis.......................................................................... 115 
9 
Quality Assurance and Quality Control ..................................................... 118 
9.1 
Audit and Inspection .................................................................................... 118 
9.2 
Monitoring .................................................................................................... 118 
9.3 
Data Management and Coding ................................................................... 119 
10 
Records and Supplies ................................................................................... 120 
10.1 Drug Accountability ..................................................................................... 120 
10.2 Financing and Insurance ............................................................................. 120 
11 
Ethics ............................................................................................................. 120 
11.1 Independent Ethics Committee or Institutional Review Board ............... 120 
11.2 Regulatory Authorities................................................................................. 120 
11.3 Ethical Conduct of the Study ...................................................................... 121 
11.4 Informed Consent ......................................................................................... 121 
11.5 Patient Confidentiality ................................................................................. 122 
12 
Reporting and Publication, Including Archiving ...................................... 123 
13 
References ..................................................................................................... 124 
14 
Appendices .................................................................................................... 126 
14.1 RECIST Criteria .......................................................................................... 126 
14.2 ECOG Performance Scale ........................................................................... 127 
14.3 Prohibited Concomitant Medication/Therapy .......................................... 128 
14.4 Use with Caution: Drugs Associated with Torsade de Pointes and 
QT Prolongation ........................................................................................... 129 
14.5 Drugs that Prolong the QTc and are Not Clearly Associated with 
Torsade de Pointes........................................................................................ 134 
14.6 Protocol Approval Signatures ..................................................................... 137 


 
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14.7 Investigator Signature Page ........................................................................ 138 
14.8 Study Personnel ............................................................................................ 139 
14.8.1 
Sponsor Personnel ......................................................................... 139 
14.8.2 
Clinical Research Organization Personnel .................................... 140 
 
 


 
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2.1 
List of In-text Tables 
Table 1: 
Schedule of Assessments – Safety Lead-in .................................................. 20 
Table 2: 
Schedule of Assessments – Part 1 and Part 2 ............................................... 23 
Table 3: 
Investigational Product ................................................................................. 54 
Table 4: 
Background Therapy .................................................................................... 54 
Table 5: 
Dose Calculations for Starting Dose of Capecitabine of 1000 mg/m2 ......... 60 
Table 6: 
Recommended Dose Adjustments for Varlitinib/Placebo ............................ 63 
Table 7: 
Recommended Dose Adjustment for Capecitabine ...................................... 63 
Table 8: 
Recommended Management of Diarrhea Attributable to Varlitinib ............ 65 
Table 9: 
Recommended Management of Nausea/Vomiting attributable to Varlitinib 66 
Table 10: Recommended Dose Adjustment for Management of Hyperbilirubinemia 
with Increased Transaminases ...................................................................... 67 
Table 11: Recommended Dose Adjustment for Management of Hyperbilirubinemia 
due to Indirect Bilirubin ............................................................................... 67 
Table 12: Recommended Dose Adjustment for Management of Increase Serum 
Creatinine ..................................................................................................... 68 
Table 13: Clinical Laboratory Parameters .................................................................... 89 
Table 14: Summary of Outcome Variables and Analysis Populations ....................... 103 
 
2.2 
 List of In-text Figures 
Figure 1: Safety Lead-in Study Design ........................................................................ 44 
Figure 2: Part 1 Study Design ...................................................................................... 45 
Figure 3: Part 2 Study Design ...................................................................................... 46 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
adverse event 
AKT 
protein kinase B 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUCτ 
area under the plasma concentration-time curve during a dosage 
interval (τ) 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BTC 
biliary tract cancer 
CCA 
cholangiocarcinoma 
CI 
confidence interval 
CL 
observed systemic plasma clearance 
Cmax 
maximum concentration 
CTCAE 
common terminology criteria for adverse events 
Ctrough 
Trough plasma concentration  
CRF 
case report form 
CRO 
contract research organization 
DCO 
data cut-off 
DCR 
disease control rate 
DoR 
duration of response 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EFR 
evaluable for response 
EGFR 
epidermal growth factor receptor 
5’-DFCR 
5’-deoxy-5-fluorocytidine 
5’-DFUR 
5’-deoxy-5-fluorouridine 
EOT 
end of treatment 


 
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5-FU 
5-fluorouracil 
FAS 
full analysis set 
FBAL 
α-fluoro-β-alanine 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HER 
human epidermal growth factor receptor 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICR 
independent central review 
IEC 
independent ethics committee 
IRB 
institutional review board 
KM 
LLN 
Kaplan Meier 
Lower Limit of Normal 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NLME 
nonlinear mixed effects model 
ORR 
objective response rate 
OS 
overall survival 
PFS 
Progression-free survival 
PK 
pharmacokinetic  
PP 
Per protocol 
PR 
partial response 
QTc 
corrected QT interval 
QTcF 
corrected QT interval (Fridericia’s formula) 
Rac AUC 
Accumulation ratio calculated from AUCτ,ss and AUCτ after single 
dosing 
Rac Cmax 
Accumulation ratio calculated from Cmax,ss and Cmax after single dosing 
RECIST 
Response Evaluation Criteria in Solid Tumours 
ROW 
rest of world 


 
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RTSM 
Randomization and Trial Supply Management 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SLI 
Safety lead-in 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
TID 
three times a day 
Tmax 
time of maximum concentration 
ULN 
upper limit of normal 
US 
United States 
Vz 
apparent volume of distribution during terminal phase 
Vss 
steady-state volume of distribution 


 
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3 
INTRODUCTION 
Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate 
competitive inhibitor of the tyrosine kinases-epidermal growth factor receptor (EGFR), 
human epidermal growth factor receptor (HER)2, and HER4, developed by Array 
BioPharma.  
ASLAN Pharmaceuticals Pte. Ltd. (ASLAN) has in-licensed varlitinib (ASLAN001) as 
of July 2011, and is responsible for future clinical development of the molecule. In August 
2015, varlitinib was granted orphan-drug designation status for the treatment of 
cholangiocarcinoma by the United States (US) Food and Drug Administration (FDA), 
Office of Orphan Products Development. 
3.1 
Background 
Biliary tract cancers (BTCs) are heterogeneous and highly lethal malignancies including 
a spectrum of invasive carcinomas arising in the gallbladder and bile ducts (intrahepatic 
and extrahepatic), and variably, ampullary carcinoma. These tumors are very uncommon, 
representing less than 1% of all cancers in the developed countries. Approximately 1200 
new cases in the United Kingdom and 9000 new cases in the US are diagnosed per year, 
although the incidence is increasing, perhaps related to gallstone disease. Despite this 
relative rarity, these tumors present a significant therapeutic challenge as most patients 
are often diagnosed at an advanced stage when surgical resection is not feasible and 
treatment options are limited. The 5-year overall survival rates are 5% to 10% for 
gallbladder cancers and 10% to 40% for cholangiocarcinomas.1,2,3 
Surgical resection with negative margins or liver transplantation remains the potential 
therapy for cure, but only for the minority of patients whose tumors appear resectable on 
staging assessments. However, recurrence occurs frequently for this resectable subset, 
with more local than distant relapse. Orthotopic liver transplantation is also a potential 
avenue for cure in patients with unresectable perihilar or intrahepatic cholangiocarcinoma. 
The benefit of neoadjuvant chemoradiation in quality of resection as well as survival is 
limited. Thus, systemic therapy, largely relied on cytotoxic chemotherapy, remains a 
necessary component of treatment both for recurrent disease or for tumors advanced at 
diagnosis.2 Currently, the FDA approved agents that are used to treat cholangiocarcinoma 
include gemcitabine, capecitabine, cisplatin, oxaliplatin, fluoropyrimidines (including 5-
Fluorouracil [5-FU]), or a combination of these. However, it is important to note that none 
of these agents is FDA approved primarily for use in biliary tract cancers.4 
Historically, there has been no standard treatment for advanced or metastatic BTC. A 
randomized Phase 2 study was conducted in 410 patients with locally advanced or 
metastatic cholangiocarcinoma, gallbladder cancer and ampullary cancer to receive 
cisplatin (25 mg/m2) followed by gemcitabine (1000 mg/m2) on Days 1 and 8 every 
21 days or gemcitabine (1000 mg/m2) on Days 1, 8, and 15 every 28 days. A significant 
benefit in both response rate and progression free survival (PFS) was seen favoring the 
gemcitabine/cisplatin arm. Furthermore, median overall survival (OS) was 11.7 months 
in the gemcitabine/cisplatin group compared with 8.1 months in the gemcitabine-only 


 
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group (hazard ratio 0.64; 95% CI, 0.52–0.80, p < 0.001), with no increase in adverse 
events (AEs) for the combination arm when compared with the single-agent. 
While cytotoxic chemotherapeutic agents are useful in the treatment of biliary tract 
cancers, the magnitude of their beneficial effects is less than desired. Targeted therapies 
based on the understanding of the molecular basis of tumors are being investigated in 
biliary tract cancers with some promising results. Targeted therapies, perhaps in 
combination with cytotoxic agents, may be the most promising advancement in this tumor 
type.2 
The human EGFR family consists of four members: HER1 (EGFR), HER2 (c-erbB-2), 
HER3 (c-erbB-3) and HER4 (c-erbB-4). Epidermal growth factor receptor, HER2, and 
HER4 are single-pass transmembrane glycoprotein receptors, members of the type I 
receptor tyrosine kinase family. Upon ligand binding, their activation induces the homo- 
or hetero-dimerization and subsequent phosphorylation of intracellular tyrosines, which 
lead to both cell proliferation and survival and therefore cancer development and 
progression. Aberrations in EGFR family members play a role in the development and 
progression of many human cancers.5,6,7,8 
Epidermal growth factor receptor is variably expressed in the majority of biliary tract 
cancers, 
with 
expression 
occurring 
nearly 
ubiquitously 
in 
intrahepatic 
cholangiocarcinomas, and to a slightly lesser extent in the other tumor types. Human 
epidermal growth factor 2 is overexpressed in only a minority of biliary tract cancers, but 
preclinical experiments have shown that simultaneous blockade of EGFR and HER2 by 
lapatinib leads to growth inhibition of an orthotopic rat model of intrahepatic 
cholangiocarcinoma if administered early.2,9 Both EGFR and HER2 inhibitors have 
demonstrated clinical efficacy in cancer treatment. Thus, a simultaneous inhibition of 
EGFR, HER2, and HER4 represents a new therapeutic approach for broadly targeting 
different tumor types that may be more effective than selective inhibition of each receptor. 
3.2 
Varlitinib  
Varlitinib is a potent, small-molecule, adenosine triphosphate-competitive inhibitor of the 
receptor tyrosine kinases EGFR, HER2, and HER4. ASLAN believes that varlitinib is a 
compound that may be beneficial to patients with cancer by simultaneous inhibition of 
these receptors.  
Full details of nonclinical and clinical studies conducted to date are provided in the 
Investigator’s Brochure (IB).10 The following sections provide a summary of varlitinib 
studies conducted. 
3.2.1 Nonclinical Studies 
Nonclinical studies including in vivo pharmacology studies, pharmacokinetic studies, 
toxicokinetic studies, absorption, distribution, metabolism and excretion studies, and 
toxicology studies have been conducted with varlitinib. 


 
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Numerous pharmacology studies have demonstrated the activity of varlitinib in tumor-
bearing animal models of breast cancer, non-small cell lung cancer, gastric cancer, 
ovarian cancer, and epidermoid cancer. Significant inhibition of tumor growth (> 70%) 
was seen with twice daily (BID) doses of 100 mg/kg and once daily doses of 200 mg/kg 
in the EGFR-driven A431 tumor xenograft model of epidermoid carcinoma.  
Toxicity studies have been conducted in Sprague-Dawley rats (acute and repeat dose) and 
cynomolgus monkeys (repeat dose). The main observed adverse effects in both species 
were gastrointestinal disturbances, soft stools, weight loss, mild clinical chemistry, and 
hematology changes and partially reversible histopathological alterations. 
The administration of varlitinib at doses up to 60 mg/kg was tolerated in most animals in 
an extensive panel of safety studies. The overall conclusion from safety studies is that 
varlitinib has an acceptable safety profile for administration in human cancer patients at 
the proposed doses. 
Details of the full varlitinib nonclinical program are presented in the IB.10 
3.2.2 Clinical Studies 
Varlitinib has been administered as a single agent and in combination with other agents 
in 5 completed Phase 1 studies and 1 completed Phase 2A study and is currently being 
administered in 7 on-going studies. Patients with metastatic gastric cancer, gastro-
esophageal tumors, breast cancer, and biliary tract cancer have been being evaluated. As 
of 31 December 2016, a total of 345 patients with solid tumors had been administered 
varlitinib at total daily doses ranging from 50 mg to 1200 mg.  
Completed single-agent studies of varlitinib include a Phase 1 dose-escalation and 
expansion study of the ditosylate salt capsule (Clinical Study ARRY-0501), a Phase 1 
dose-escalation study of the free base tablet (Clinical Study ARRAY-543-103), and a 
Phase 2a study of the tolerability and biological activity of the free base tablet (Clinical 
Study ASLAN001-001). Completed combination studies of varlitinib as a free base tablet 
include a Phase 1 dose-escalation combination study with docetaxel (Clinical Study 
ARRAY-543-104), a Phase 1 dose-escalation combination study with capecitabine 
(Clinical Study ARRAY-543-204), and a Phase 1 dose-escalation combination study with 
gemcitabine (Clinical Study ARRAY-543-206). The maximum tolerated dose (MTD) has 
been determined for varlitinib as a single agent and in combination with 3 separate 
standard chemotherapies (docetaxel, capecitabine, and gemcitabine) in patients with 
advanced solid tumors. Ongoing Phase 2 studies are being conducted in patients with 
BTC, metastatic breast cancer, and gastric cancer. 
Evaluation of the efficacy of varlitinib in the clinical studies conducted to date has 
demonstrated that partial response (PR) or stable disease (SD), as defined by the Response 
Evaluation Criteria in Solid Tumours (RECIST) has been observed with varlitinib in each 
clinical study to date. In one study (ARRAY-543-103), the incidence of stable disease 
was higher in the varlitinib 500 mg BID cohort than the varlitinib 300 mg or 400 mg BID 
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There was a trend for patients with HER2-positive tumors to have an increased rate of 
stable disease compared to patients with HER2-negative tumors. Conversely, there was a 
trend for patients with EGFR-positive tumors to have a decreased rate of stable disease 
compared with to patients with EGFR-negative tumors (ARRAY-543-0501). 
Adverse events of diarrhea, nausea, and vomiting have been reported frequently across 
all studies conducted with varlitinib. The time of onset of these AEs has been variable 
with the majority of episodes being managed with standard anti-emetic and anti-diarrheal 
medications. Dermatological AEs have been reported during varlitinib therapy including 
rash, erythematous rash, papular rash, macular rash, maculopapular rash, exfoliative rash, 
skin exfoliation, dermatitis acneiform, and acne. If symptoms are not adequately 
controlled with symptomatic treatment, a dose holiday (either with or without subsequent 
dose reduction) may be required.  
Elevation in serum liver transaminases (alanine aminotransferase [ALT] and/or aspartate 
aminotransferase [AST]) and cases of hyperbilirubinemia have been observed in some 
patients receiving varlitinib. Levels of ALT, AST, conjugated and total blood bilirubin as 
well as signs and symptoms of liver toxicity should be monitored during varlitinib 
treatment. Cases of increased serum creatinine have been observed particularly when 
varlitinib is administered with platinum-based chemotherapies. Appropriate monitoring 
of renal function is recommended. 
Prolongation of the corrected QT interval (QTc) by > 60 milliseconds (msec) from 
baseline has been observed in 2 patients. Two patients in Study ARRAY-543-204 
experienced clinically significant QT prolongations with one of the patients having 
multiple cardiopulmonary complications at baseline and remaining on treatment with 
verapamil and digoxin, both of which could have interfered with QTc measurements 
during the study. The QTc prolongation in the second patient was assessed as not related 
to study treatment and the patient was withdrawn from the study due to a major protocol 
violation. In vitro studies have shown that therapeutically active concentrations of 
varlitinib are 1200- to 1625-fold lower than those likely to produce any change in cardiac 
conduction. Therefore, it is unclear if the existing data implicate varlitinib in any way in 
the observed QTc prolongation events. 
Details of the full varlitinib clinical program are presented in the IB.10  
3.2.3 Known or Potential Risks of Varlitinib 
Varlitinib has demonstrated an acceptable safety profile in nonclinical toxicology studies 
and in the completed Phase 1 and Phase 2A studies in humans. However, as with any new 
investigational drug, unexpected AEs may occur with the use of varlitinib. The following 
is a summary of potential risks; additional details are presented in the IB10: 
• Varlitinib must not be administered to pregnant or nursing women 
• Varlitinib exposure is negatively influenced by co-administration of proton pump 
inhibitors, H2 antagonists, and co-medications that increase gastric pH 
• Varlitinib may cause a drug-drug interaction with other medications that are 
CYP3A4, CYP2C8, or CYP2C9 inducers, inhibitors, or substrates. Due to the 
potential for drug interactions based on in vitro screens, concomitant use of 


 
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moderate CYP3A4, CYP2C8, CYP2C9, and P-gp inducers or inhibitors will be 
recorded during the entire clinical study 
• Signs of gastrointestinal side effects (diarrhea, nausea, and vomiting) should be 
monitored in patients receiving varlitinib. However, prophylactic anti-emetics are 
usually not required with varlitinib administration 
• ALT, AST, and bilirubin along with signs or symptoms of liver toxicity should be 
monitored during varlitinib treatment 
3.2.4 Known or Potential Risks of Capecitabine 
In this study, varlitinib will be co-administered with capecitabine. Refer to the XELODA® 
(capecitabine) prescribing information leaflet12 for known and potential risks following 
administration of capecitabine. 
3.3 
Rationale for the Study 
Biliary tract cancer (BTC) is a therapy-refractory cancer with very limited treatment 
alternatives. First-line therapy is often a combination of gemcitabine and cisplatin, as 
recommended in the National Comprehensive Cancer Network (NCCN) guidelines. A 
standard second-line therapy for BTC has not been established and no drug is currently 
approved in the US for this indication. In the ABC-02 study, approximately 15% of the 
patients were treated with 5-FU-based chemo¬therapy as second-line treatment after 
progression from the gemcitabine/cisplatin (GC) regimen, with a median OS of 
11.2 months (Valle et al. 2010). There is data suggesting that the 5-FU principle may be 
useful in BTC, such as the S-1 data from Japan and small studies with capecitabine in 
BTC. 
However, although the efficacy was demonstrated in phase II studies in a small number 
of patients and the second-line chemotherapies are considered for patients who can 
receive chemotherapies, sufficient evidence has not been established. In addition, no 
clinical studies have been conducted to directly compare the second-line chemotherapies 
with no treatment (supportive therapy) and it is necessary to investigate whether the 
second-line chemotherapies contribute to the extension of survival. The NCCN 
recommends monotherapy or combination of the following agents indicated for 
unresectable biliary cancer: gemcitabine, capecitabine, cisplatin, oxaliplatin, and 
fluoropyrimidine (including 5-FU). These agents, however, are not prioritized agents for 
biliary cancer approved by the FDA. 
The second-line agents for biliary cancer differ in each country, but capecitabine is one 
of the common options at the present. Capecitabine is an oral fluorouracil prodrug that 
undergoes enzyme conversion to 5-FU in the body and is used for advanced biliary cancer 
off-label in accordance with the NCCN guideline, because of the limited therapies for 
advanced biliary cancer. From the above, ASLAN considers that varlitinib in combination 
with capecitabine can provide even more benefits to patients with biliary tract cancer. 
Varlitinib has demonstrated tumor shrinkage responses and durable disease stabilization 
in BTC in ongoing Phase IB safety and tolerability studies in Singapore (ASLAN001-
002SG) and Taiwan (ASLAN001-002). 


 
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The potential efficacy of varlitinib in BTC is also supported by nonclinical studies which 
have demonstrated dysregulated HER1 and HER2 activity in this tumor type and support 
the hypothesis that HER receptors are driving BTC tumor proliferation and survival. In 
terms of drug metabolism, varlitinib is cleared via the biliary tract and therefore drug 
concentrations should be high at the primary tumor site. 
Furthermore, results from an ongoing study in trastuzumab-failed metastatic breast cancer 
(ASLAN001-003) where 400 mg BID varlitinib in combination with capecitabine 
demonstrate that the combination of varlitinib and capecitabine has anti-tumor activity, 
is well-tolerated and would be a rational combination in multiple malignancies, including 
BTC. 
Second-line BTC remains an area of high unmet medical need. To date, no randomized 
clinical studies have demonstrated statistically significant improvements in any efficacy 
parameters. Most of the studies used small, single arm designs. Thus a study with a 
double-blind, placebo-controlled, randomized design has the potential to provide robust, 
evidence of efficacy in second-line BTC. Primary efficacy endpoints that will be used to 
evaluate efficacy in the study include Objective Response Rate (ORR) and PFS for Part 
1 of the study and OS for Part 2 of the study. These are well known endpoints for oncology 
studies and have been used to support health authority decisions on drug approvability. 
See Section 5.2 for a further discussion of the study design. 
 
 


 
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4 
STUDY OBJECTIVES 
4.1 
Primary Objective 
The primary objectives of the study are: 
Safety lead-in: 
• 
To assess the safety and tolerability of varlitinib 300 mg BID (every day), in 
combination with capecitabine 1000 mg/m2 (BID for 14 days followed by a 7-day 
rest) as measured by incidence of AEs, and changes from baseline in safety 
parameters. 
Part 1: 
• 
To assess the efficacy of varlitinib in combination with capecitabine as measured 
by co-primary endpoints of ORR and PFS, both assessed by an Independent 
Central Review (ICR). 
Part 2: 
• 
To assess the efficacy of varlitinib in combination with capecitabine as measured 
by OS. 
4.2 
Secondary Objective(s) 
The secondary objectives of the study are: 
Safety lead-in: 
1. To evaluate the pharmacokinetics (PK) of varlitinib (and any relevant circulating 
metabolites) and capecitabine (and its active metabolite 5-FU) when given in 
combination 
2. To evaluate the effect of varlitinib on QT/QTc 
3. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by ORR, duration of response (DoR), and disease control rate (DCR), 
all based on site assessment 
Part 1: 
1. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by DoR, and DCR as assessed by ICR, and OS and ORR as assessed by 
the site 
2. To assess the safety and tolerability of varlitinib when combined with capecitabine 
3. To explore exposure-response relationships for varlitinib (and any relevant 
circulating metabolites) for measures of efficacy, safety, and pharmacological 
responses 
4. To examine the effects of varlitinib, when added to capecitabine on 
electrocardiogram (ECG) parameters including QTcF, QTcB, HR, PR and QRS 
 
 


 
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Part 2: 
1. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by ORR, DoR, DCR and PFS, all based on site assessment 
2. To assess the safety and tolerability of varlitinib when combined with capecitabine 
3. To explore exposure-response relationships for varlitinib (and any relevant 
circulating metabolites) for measures of efficacy, safety, and pharmacological 
responses via sparse PK sampling and population PK analyses 
4.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
Part 1: 
1. To explore the role of HER family of receptor status as a predictor of benefit to 
varlitinib 
2. To explore possible relationships between HER family and downstream signaling 
protein and phospho-protein expression levels and clinical outcomes 
3. To explore possible relationships between gene mutational status and clinical 
outcomes 
Part 2: 
If a relationship is found between biomarker(s) expression and clinical outcomes in Part 1 
of the study, the biomarker(s) could be prospectively evaluated in Part 2 of the study. 
 
 
 
 


 
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5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design and Plan: Description 
5.1.1 
Study Design 
This study is designed as a multicenter, double-blind, randomized, placebo-controlled 
study of varlitinib plus capecitabine versus placebo plus capecitabine in patients with 
advanced or metastatic BTC as second-line systemic therapy. 
Safety Lead-in: 
This study will commence initially with a Safety lead-in group (Figure 1). This part of 
the study is 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 patients (12 to 20 patients) 
with 12 patients completing the PK and ECG evaluations. Treatment will continue until 
disease progression, development of unacceptable toxicity, withdrawal of consent, or 
death. 
A data safety monitoring board (DSMB) meeting will occur after the first 12 patients in 
the Safety lead-in who have completed 21 days of follow-up in order to review the safety 
and tolerability data prior to commencement of Part 1 of the study. 
Figure 1: 
Safety Lead-in Study Design 
 
Abbreviations: AE = adverse event, DCR = disease control rate, DoR = duration of response, DSMB = data safety 
monitoring 
board, 
ECG = electrocardiogram, 
N = number 
of 
patients, 
ORR = objective 
response 
rate, 
PK = pharmacokinetics, QT/QTc = QT interval / corrected QT interval, USA = United States of America. 
 
 


 
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Part 1: 
Part 1 of the study is designed as a double-blind, randomized, placebo-controlled study 
to assess the efficacy and safety of varlitinib plus capecitabine in comparison with placebo 
plus capecitabine in approximately 120 patients (Figure 2). Eligible patients will be 
randomized to varlitinib or placebo (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). Treatment will continue until disease progression, development of 
unacceptable toxicity, withdrawal of consent, or death. A DSMB will meet at a selected 
time point (to be confirmed) during Part 1 for review of safety data. 
Figure 2: 
Part 1 Study Design 
 
 
Abbreviations: N = number of patients, DCR = disease control rate, DoR = duration of response, DSMB = data safety 
monitoring board, ECG = Electrocardiogram, OS = overall survival, PD = progressive disease, PFS = progression-free 
survival, PK = pharmacokinetics. 
 
 


 
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Part 2: 
Part 2 of the study is designed as double-blind, randomized, placebo-controlled study to 
confirm the efficacy of varlitinib (300 mg administered BID) plus capecitabine 
(1000 mg/m2 administered BID for 14 days out of 21 days) compared to capecitabine in 
approximately 350 patients (Figure 3). Part 2 will follow the same design and treatment 
schedule as Part 1. This part of the study will commence following review of Part 1 
results. 
Figure 3: 
Part 2 Study Design 
 
Abbreviations: N = number of patients, DCR = disease control rate, DoR = duration of response, OS = overall survival, 
PD = progressive disease, PFS = progression-free survival, PK = pharmacokinetics. 
 
5.2 
Discussion of Study Design 
To date, no randomized clinical studies in second-line BTC have demonstrated 
statistically significant improvements in any efficacy parameters. Historically, clinical 
studies in second-line BTC have been conducted using small, single arm designs. 
Consequently, the results of these studies can be difficult to interpret and compare, due 
to the intrinsic bias known to afflict single arm designs. 
The proposed study has been designed to provide robust, unequivocal evidence of 
efficacy in second-line BTC. For that reason, a randomized, double-blind, placebo-
controlled design has been selected to definitively quantify the contribution of varlitinib, 
above and beyond the background chemotherapy agent, capecitabine. 
ASLAN001-009 is designed to provide sufficient data on the efficacy and safety of 
varlitinib in combination with capecitabine in patients with advanced or metastatic BTC 


 
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who have progressed after one line of systemic therapy in order to support a decision on 
its approvability for marketing. The control will be capecitabine plus placebo. 
The proposed dose of varlitinib is 300 mg BID. The MTD of varlitinib in combination 
with capecitabine 1000 mg/m2 BID was determined to be 400 mg BID based on previous 
studies of the combination therapy (ARRAY-543-204). Considering that patients with 
BTC who have failed one line of systemic therapy are usually frail with multiple co-
morbidities, the dose of varlitinib selected for this study is 300 mg BID in combination 
with capecitabine. 
The dosing schedule of capecitabine selected for this study will be capecitabine at 
1000 mg/m2 BID for 2 weeks followed by a 1-week rest period in 3-week cycles. The 
dosage, PK, and safety of capecitabine (1000 mg/m2 BID, Day 1 to Day 14, followed by 
a 7-day rest period) have been established in the ARRAY-543-204 study. This dose of 
capecitabine has been successfully used with varlitinib in patients with advanced 
metastatic breast cancer (ASLAN001-003) and in a study (NCT00078572) where 
capecitabine was used in combination with lapatinib in metastatic breast cancer.11,13 
Study ASLAN001-009 is anticipated to be conducted worldwide with approximately 20% 
of the patients from US sites. 
This study will commence initially with a Safety lead-in group designed as a single arm, 
open label study to assess the safety of varlitinib plus capecitabine in a small set of 
patients (12 to 20) prior to commencing Part 1 in a larger study population (n=120). A 
DSMB will review safety data on 2 occasions (refer to Section 7.2) to monitor the safety 
of patients. Part 2 (n=350) of the study will not commence until the results of Part 1 have 
been evaluated. 
Part 1 of the study includes co-primary endpoints of ORR and PFS determined via central 
review. Overall survival is the primary endpoint in Part 2 of the study. These are well 
known endpoints for oncology studies and have been used to support health authority 
decisions on drug approvability. 
In Part 1 of the study, for the purpose of marketing approval, a Hochberg procedure will 
be used to control the overall type I error rate associated with the co-primary endpoints, 
ORR and PFS, at the two-sided 5% level. Using this approach, statistical significance can 
be declared if either ORR or PFS is significant at the two-sided 2.5% level, or if both 
endpoints are significant at the two-sided 5% significance level. For significance at the 
2-sided 5% level, the study has approximately 80% power to detect a 20% difference in 
ORR, assuming a 10% response rate for the control arm. Similarly, for significance at the 
two-sided 5% level, 84 PFS events would provide approximately 80% power to detect a 
true HR of 0.54 (approximately an 84% prolongation in PFS). If statistical significance is 
demonstrated, ASLAN believes that these effect sizes represent a clinically meaningful 
improvement in efficacy relative to the current care options. This improvement would 
represent a step-change in the treatment options for patients with second line BTC. To 
enable a further illustration of the clinical benefit realized through the improvement in 
ORR, DoR will be included as a secondary endpoint in the study and will help 
characterize the durability of the observed responses. All radiological data collected in 


 
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the Part 1 of the study will be assessed via an ICR of the imaging data thus eliminating 
the potential bias that can arise from site evaluations. 
Data from the Safety lead-in, Part 1 and Part 2 will be evaluated separately for safety and 
efficacy. Patients whose data contributed to the Part 1 analysis will not be included in the 
Part 2 analysis. 
5.3 
Selection of Study Population 
5.3.1 Number of Planned Patients 
Safety lead-in: 
A total of 12 to 20 eligible patients will be enrolled to receive varlitinib plus capecitabine.  
United States:  6 to 12 eligible patients are expected to be enrolled from the United States. 
Rest of the World: An additional 6 to 8 eligible patients will be enrolled from the rest of 
the world. 
Patients in this group will be replaced if investigational product compliance is < 85% in 
the first 14 days. Pharmacokinetic sampling will be performed in approximately 12 
patients. 
Part 1: 
Approximately 120 eligible patients will be enrolled and randomized in a 1:1 ratio to 
receive varlitinib and capecitabine (n=60) or placebo and capecitabine (n=60). 
Part 2: 
Approximately 350 eligible patients will be enrolled and randomized in a 1:1 ratio to 
receive varlitinib and capecitabine (n=175) or placebo and capecitabine (n=175). 
In both Part 1 and Part 2 of the study, patients will be will be stratified by: 
• region - US and the rest of world (ROW) and;  
• primary tumor location - gallbladder vs non-gallbladder. 
5.3.2 Inclusion Criteria 
To be eligible for study entry patients must satisfy all of the following criteria: 
1. Are of or older than the legal age in the respective countries at the time when 
written informed consent is obtained 
2. 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.  
3. Have received and failed one and only one prior line of systemic treatment for 
advanced or metastatic disease with radiologic evidence of disease progression. 
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4. Have received at least 6 doses of gemcitabine containing treatment in first line 
(Adjuvant therapy is not regarded as 1st line therapy) 
5. Have radiographically measurable disease based on RECIST v1.1 as assessed by 
Independent Central Review (ICR) (For Part 1). 
6. 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) 
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1 
8. Are able to understand and willing to sign the informed consent form (ICF) 
9. Have adequate organ and hematological function: 
a. 
Hematological function, as follows: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
• 
Platelet count ≥ 100 × 109/L 
b. Renal functions, as follows: 
• 
Estimated 
glomerular 
filtration 
rate 
or 
creatinine 
clearance 
> 50 mL/min/1.73m2 
c. 
Hepatic function, as follows: 
• 
Albumin ≥ 3g/dL 
• 
Total bilirubin ≤ 1.5 × ULN 
• 
ALT and AST ≤ 5 × ULN 
5.3.3 Exclusion Criteria 
Patients will be excluded from the study if one or more of the following criterion is 
applicable: 
1. Are currently on or have received anti-cancer therapy within the past 3 weeks 
before receiving the first dose of study medication  
2. 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 
3. 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.) 
4. Have had major surgical procedures within 14 days prior to first dose of study 
medication 
5. Have a known metastatic brain lesion(s), including asymptomatic and well 
controlled lesion(s) 
6. 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 
7. 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 
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8. 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) 
9. Are female patients who are pregnant or breast feeding 
10. 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 
11. Have received any investigational drug (or have used an investigational device) 
within the last 14 days before receiving the first dose of study medication 
12. 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 
13. 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 
14. 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 
15. Need continuous treatment with proton pump inhibitors during the study period 
16. 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 
17. 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 
18. 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_Prohibited_Medication/Therapy) 
5.3.4 Removal of Patients from Therapy or Assessments 
A patient may withdraw from the study for any reason without prejudice to further 
treatment. A patient can be withdrawn from the study for any of the following reasons: 
• Patient voluntarily withdraws from participation* 
• Radiographic disease progression* 


 
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• Clinical disease progression 
• Unacceptable toxicity* 
• Patient’s withdrawal of consent* 
• Death 
• Pregnancy 
• Significant protocol deviation 
• Lost to follow-up* 
• If deemed by the Investigator that it is not in patient’s interest to continue in the 
study 
* Further details provided below. 
Patients who do not comply with the protocol or who withdraw consent will be replaced 
in the Safety lead-in part only. Patients who stop study drug for any other reasons will not 
be replaced. Withdrawn patients will not be replaced in Part 1 and Part 2. The reason(s) 
for withdrawal will be documented in the case report form (CRF). 
The sponsor also has the right to terminate the study at any time in case of serious adverse 
events (SAEs) or if special circumstances concerning the study medication or the 
company itself occur, making further treatment of patients impossible. In this event, the 
Investigators will be informed of the reason for study termination. All patients receiving 
active treatment and who, in the opinion of the investigator, may benefit from continued 
varlitinib treatment, will be offered participation in an open-label extension study where 
only varlitinib will be provided by the sponsor or be managed under a compassionate use 
program governed by the regulatory authorities in the respective countries. 
Withdraws from participation (follow-up permitted): Patients withdrawing from the 
study treatment will be encouraged where possible to return to the site for a study follow-
up visit, particularly for safety evaluations, tumor assessments, and survival follow-up. 
In Part 1 and Part 2 of the study, patients will be followed up for survival when they 
withdraw from the study treatment every 12 weeks after the end of treatment (EOT) visit 
until death or up to data cut-off (DCO) of the study, whichever occurs first. 
In this instance, it is important to note that the patient is ceasing participation, NOT 
withdrawing consent. 
Radiographic disease progression: Sites should continue to perform radiological 
assessments until disease progression (or death in the absence of progression) in 
accordance with RECIST v1.1. Patients will be withdrawn from the treatment if there is 
radiological evidence of disease progression as defined by RECIST v1.1. Additional 
radiological assessments of disease will not be undertaken unless there is a clinical 
indication (such as additional symptoms or signs). If radiological progression is equivocal, 
for example within the bounds of measurement error, it is recommended to continue 
randomized study treatment until the next scheduled assessment and reassess. Once 
permanently discontinued, randomized study medication cannot be re-started. 
Unacceptable toxicity: If the symptoms are not controlled with standard treatments and 
are considered to be clinically significant, study therapy will be stopped and the patient 


 
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will be withdrawn from the study treatment. Refer to Section 5.4.8.1 for more details of 
dose interruption/resumption/modification. Patients removed from study treatment for 
unacceptable toxicity will be followed until resolution or stabilization of the AE. 
Patients who are withdrawn from treatment prior to radiographic disease progression 
should continue to be followed until progression in accordance with the study plan. 
Consent Withdrawal: Patients may withdraw from the study at any time at their own 
request. The withdrawal of consent should be explained in detail in the medical records 
by the Investigator and entered on the appropriate CRF page. Details of withdrawal 
should indicate whether the withdrawal is from further treatment with study medication 
only or also from study procedures and/or post treatment study follow-up. Patients who 
request to withdraw from further treatment and study procedures may be followed up for 
OS (if consented by patients). 
The Investigator should inquire about the reason for withdrawal and request that the 
patient return all unused study medication. The Investigator should also ask the patient to 
return for a final visit, if applicable, and follow-up with the patient regarding any 
unresolved AEs. 
Lost to follow-up: If a patient does not return for a scheduled visit, every effort should 
be made at least once every month to contact the patient to reschedule the visit, including 
mandatory telephone contact and written letter; as well as on a case-by-case basis patient 
visit. All efforts should be documented in the patient’s medical source record. Patient is 
considered lost to follow-up if patient cannot be reached after 3 months from the 
scheduled visit or before date of DCO, whichever is earlier. 
All patients who are withdrawn or discontinued from the study are required to complete 
a safety follow-up visit within 28 days after the last administration of study medication, 
where possible. If the Investigator is unable to complete the safety follow-up visit 
assessments, the reason(s) must be recorded in the eCRF. All AEs/SAEs will be collected 
until 28 days after the last administration of study medication. 
If a patient discontinues study treatment and is withdrawn from the study for any reason, 
the study center must immediately notify the medical monitor. The Investigator should 
also ensure the return of unused study medication. 
5.3.5 Pregnancy 
There is no information regarding the effects varlitinib could have on the development of 
a human fetus. Capecitabine may cause fetal harm if given to a pregnant woman. 
Capecitabine causes embryolethality and teratogenicity in mice and embryolethality in 
monkeys when administered during organogenesis12. Therefore, it is important that 
females and the partners of male patients do not become pregnant during the study and 
for at least 3 months after the patient has taken their last dose of varlitinib. 
Female patients of child bearing potential and men enrolled in this study, in addition to 
partners of male patients must agree to use adequate contraception (as listed in 
Section 5.3.5.1) prior to study entry, for the duration of study participation, and for 3 
months following completion of varlitinib/placebo or capecitabine therapy.  


 
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A female of child-bearing potential is any woman (regardless of sexual orientation, 
having undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria: 
• Has not undergone a hysterectomy or bilateral oophorectomy; or  
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., 
has had menses at any time in the preceding 12 consecutive months). 
5.3.5.1 
Acceptable Forms of Contraception 
A highly effective method of birth control is defined as those which result in a low failure 
rate (i.e., less than 1% per year) when used consistently and correctly.  
Individually hormonal, barrier or intrauterine device methods alone are not acceptable. 
Examples of acceptable forms of highly effective contraception for women include:  
• Established use of oral, injected or implanted hormonal methods of contraception 
in combination with a barrier method* 
• Placement of an intrauterine device or intrauterine system in combination with a 
barrier method 
• Sterilized male partner (with the appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate) in combination with a barrier method 
• True abstinence: When this is in line with your preferred and usual lifestyle 
Examples of non-acceptable methods of contraception include:  
• Barrier method alone 
• Periodic abstinence (e.g., calendar, ovulation, sympthothermal, post ovulation)  
• Withdrawal  
• Spermicide 
*Barrier methods include: diaphragm, cervical cap, and condom. 
For men, it is recommended that a condom be worn for all sexual intercourse (in addition 
to another effective means of contraception) as it is not known if study drug may affect 
sperm risking the potential for congenital abnormalities. 
5.3.5.2 
Time Period for the Collection of Pregnancy Information 
All pregnancies in female patients and in female partners of male patients receiving study 
drug will be recorded from enrolment until 3 months after last dose of varlitinib/placebo 
or capecitabine. 
5.3.5.3 
Follow-up in the Event of a Pregnancy 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, or should a male patient’s partner become pregnant or suspect she is pregnant while 
the male is participating in this study, the treating Investigator should be informed 
immediately. Female patients will be withdrawn from study treatment, and all 
pregnancies will be reported along the same timelines as a SAE. 


 
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If a female patient or the female partner of a male patient who has received study drug 
becomes pregnant the pregnancy will be recorded. The independent ethics committee 
(IEC) and the Sponsor will be informed. In all cases of pregnancy, the patient will be 
asked to provide information on the outcome of the pregnancy, including premature 
termination should the case arise.  
Spontaneous miscarriage and congenital abnormalities will be reported as a SAE. 
The follow-up period will be deemed to have ended when the health status of the child 
has been determined on its birth and followed up for eight weeks following the birth for 
any potential abnormalities. 
5.4 
Investigational Products 
5.4.1 Study Medication Administered 
In the Safety lead-in, eligible patients will receive varlitinib plus capecitabine (n=12 to 
20). 
In Part 1 and Part 2 of the study, eligible patients will be randomized into 2 arms; 
experimental arm will receive varlitinib plus capecitabine (part 1: n=60; part 2: n=175) 
or control arm will receive placebo plus capecitabine (part 1: n=60; part 2: n=175). 
Study medications are presented in Table 3 and Table 4. 
Table 3: 
Investigational Product 
Investigational 
Products 
Dose form 
Route  
Dose (mg) 
Dose 
frequency 
Duration* 
Varlitinib 
Tablet 
Oral 
300 mg 
BID 
Every day in a 21-day cycle 
Placebo 
Tablet 
Oral 
Not 
Applicable 
BID 
Every day in a 21-day cycle 
Abbreviation: BID = twice daily. 
*Treatment will continue until disease progression assessed by the Investigator as per RECIST version 1.1, 
unacceptable toxicity, withdrawal of consent, or death. 
Table 4: 
Background Therapy 
Background 
Therapy 
Dose form 
Route  
Dose (mg) 
Dose 
frequency 
Duration* 
Capecitabine 
Tablet 
Oral 
1000 mg/m2 
BID 
14 days (Day 1-14) 
followed by 7 days rest in a 
21-day cycle 
Abbreviation: BID = twice daily. 
*Treatment will continue until disease progression assessed by the Investigator as per RECIST version 1.1, 
unacceptable toxicity, withdrawal of consent, or death. 


 
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5.4.2 Identity of Investigational Products and Background Therapy 
Varlitinib 
ASLAN will supply the varlitinib tablets.  
Varlitinib tablets consist of varlitinib (ASLAN001) (as free base), lactose monohydrate, 
hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, and Opadry II 
yellow film-coat. The tablets are yellow, round, standard convex, film-coated tablets, 5/16 
inch in diameter.  
Placebo 
ASLAN will supply the matching placebo tablets.  
Placebo tablets will be identical in appearance to varlitinib tablets; yellow, round, standard 
convex, film-coated tablets, 5/16 inch in diameter.  
Capecitabine 
Capecitabine (XELODA®) will be sourced centrally and be supplied to the study by 
ASLAN for Safety lead-in Part 1 and Part 2. For the study lead-in and after the Part 1 
DCO, capecitabine (does not have to be XELODA® if other commercial brands are more 
readily available at the site) can also be supplied by the study site, if needed. 
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally 
administered systemic prodrug of 5’-deoxy-5-fluorouridine, which is converted to 5-
fluorouracil. 
Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 26 
mg/mL at 20ºC. Capecitabine is supplied as biconvex, oblong film-coated tablets for 
oral administration. Tablets are supplied as either 150 mg or 500 mg strength 
capecitabine.  
The inactive ingredients in capecitabine include: anhydrous lactose, croscarmellose 
sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium 
stearate and purified water. The peach or light peach film coating contains 
hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red 
iron oxides. 
Refer to the XELODA® (capecitabine) prescribing information leaflet for additional 
details12. 
5.4.3 Storage Condition of Study Medications 
Varlitinib/Placebo 
It is recommended that varlitinib/placebo is stored up to 25ºC (77 ºF) protected from 
light. 


 
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No special procedures for the safe handling of varlitinib are required. 
Capecitabine 
It is recommended that capecitabine is stored, as per the instruction on the package 
insert, at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F). 
The storage area of the study center has to be a secure, temperature controlled, locked 
room with restricted access. Study centers will be required to keep a temperature log 
to establish a record of compliance with these storage conditions.  
Accurate records must be kept regarding dispensing and return of study medication for 
each individual patient in the study. Reasons for inconsistency from the expected 
dispensing or return of study medication must be recorded. The Sponsor will be 
permitted upon request to audit the supplies, storage, dispensing procedures and 
records. 
5.4.4 Packaging and Labeling 
All packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products and the relevant regulatory requirements. 
Varlitinib, matching placebo and capecitabine tablets (Part 1 and 2 only*) are packaged 
in DosePak wallet with Child-Resistant ATSM Index class XIIIA re-closable semi rigid 
blister packaging. 
*Since each site’s pharmacy will be supplying their own capecitabine in the Safety lead-in 
part of the study and after the Part 1 DCO, the packaging and labeling will be dependent on 
their selected brand.  
5.4.5 Method of Assigning Patients to Treatment Groups 
Safety Lead-in: 
The Safety Lead-in part of the study has a non-randomized single arm design. All eligible 
patients will receive varlitinib 300 mg BID, every day plus capecitabine 1000 mg/m2 BID, 
Day 1 to 14, followed by a 7-day rest period (21-day cycle). 
Each patient’s eligibility will be reviewed by the medical monitor during the screening 
period. Patients will be sequentially enrolled after being screened for eligibility and 
providing consent. 
At screening, potential patients will be assigned a unique screening number that starts 
with “S” and 4 digits (i.e., S1001) manually or by electronic data capture system.  
In the case of discontinuation of chemotherapy due to toxic effects, varlitinib or placebo 
therapy will be continued until disease progression, the development of unacceptable 
toxicities, or withdrawal of consent or death. 


 
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After the DCO in Part 1, all patients receiving treatment including those from the Safety 
Lead-in and who, in the opinion of the investigator, may benefit from continued varlitinib 
treatment, will be offered participation in an open-label extension study where only 
varlitinib will be provided by the sponsor; or be managed under a compassionate use 
program governed by the regulatory authorities in the respective countries. 
Parts 1 and 2: 
At the initial screening visit, the Investigator or suitably trained delegate will: 
1. Obtain signed ICF (main study) from the potential patient before any study 
specific procedures are performed. 
2. Potential patients will be assigned a unique screening number that starts with “S” 
and 4 digits (i.e., S1001) by electronic data capture system. This screening number 
will be sequential from Safety lead-in, and will not be repeated. 
3. Determine patient eligibility. See Section 5.3.2 and Section 5.3.3.  
4. Once the patient is confirmed to be eligible, the Investigator or suitably trained 
delegate will assign eligible patient a unique randomization number via 
Randomization and Trial Supply Management (RTSM) system. Randomization 
numbers will start with “R” followed by 4 digits (i.e., R1001 for part 1, R2001 for 
part 2) and will be assigned strictly sequentially by RTMS (starting at R1001, 
R2001 in part 1 and 2, respectively), as patients are eligible for randomization. 
This number is the patient’s unique identifier and is used to identify the patient 
with the assigned treatment. This randomization number will be available to the 
Investigator in the electronic data capture system. 
5.4.6 Procedures for Randomization 
Patients must not be randomized unless all eligibility criteria have been met. For Part 1 
only, this includes receiving eligibility confirmation from the ICR. 
Patients who satisfy all the entry criteria will be centrally assigned to study treatment by 
the RTSM, according to the randomization scheme generated by the designated CRO. 
Patients will be randomized in a 1:1 ratio to either varlitinib or placebo, both on a 
background of capecitabine (n=120 for Part 1 and n=350 for Part 2). The randomization 
scheme will be stratified by the following 2 covariates: 
• Geographical region - US or ROW 
• Primary tumor location – gallbladder (GB) or non-GB 
The actual treatment given to patients will be determined by the randomization scheme 
in RTSM. The randomization scheme will be produced using SAS® version 9.4, which 
incorporates a standard procedure for generating randomization numbers. One 
randomization list will be produced containing sufficient random numbers for each of the 
4 randomization strata. A blocked randomization will be generated and all centers will 
use the same list in order to minimize any imbalance in the number of patients assigned 
to each treatment group. 
The dose and regimen of randomized therapy to be administered is as follows: 


 
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• Varlitinib 300 mg BID, every day 
• Placebo BID, every day 
Patients in both arms will receive background chemotherapy with capecitabine 
1000 mg/m2 BID, Day 1 to 14, followed by a 7-day rest period (21-day cycle). 
Patients will be identified to the Centralized Randomization Center using site number, 
screening number, randomization number, gender, and date of birth. Patients will be 
randomized strictly sequentially within each stratum, as patients are eligible for 
randomization. The RTSM will inform the Investigator of the Kit ID number to be 
allocated to the patient at each dispensing visit via electronic data capture (EDC). 
Study medication should only be dispensed to each randomized patient at the Cycle 1 
Day 1 visit. It is allowed to randomize patient up to 24 hours prior to first dose. The first 
dose of study medication must only be administered in the morning of Cycle 1 Day 1 after 
pre-dose assessment (e.g., safety laboratory sampling, electrocardiogram [ECG], PK 
sampling) are completed. The day on which a patient takes the first dose of study 
medication will be considered Cycle 1 Day 1.  
The Kit ID number dispensed at each visit will correspond to the treatment to which the 
patient was originally randomized. 
If a patient discontinues participation in the study, then their screening/randomization 
number cannot be reused. 
5.4.7 Selection of Doses in the Study 
Varlitinib 
The MTD of varlitinib in combination with capecitabine 1000 mg/m2 BID was 
determined to be 400 mg BID in a previous study of the varlitinib/capecitabine 
combination therapy (Study ARRAY-543-204). Considering that patients with BTC who 
have failed one line of systemic therapy are usually frail with multiple co-morbidities, the 
dose of varlitinib selected for this study is 300 mg BID in combination with capecitabine. 
This dose combination of varlitinib and capecitabine will be assessed for safety and 
tolerability in the first 12 patients in the Safety lead-in, prior to randomization of patients 
in Parts 1 and 2 of the study.  
Capecitabine 
In this study capecitabine will be administered as 1000 mg/m2 BID for 14 days followed 
by 1-week rest. Refer to Table 5 for the dose calculation. Capecitabine tablets are 
available in 2 dosage strengths, 500mg and 150mg. In order to allow improved patient 
compliance and to be in line with routine clinical practice, it is allowed for patient to be 
dosed with ± 5% deviation from the Dose per administration (mg) listed in Table 5 to 
reduce number of capecitabine tablets used. 


 
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The dosage, PK, and safety of capecitabine (1000 mg/m2 BID, Day 1 to Day 14, followed 
by a 7-day rest period) have been established in the ARRAY-543-204 Phase I study. This 
dose of capecitabine has been successfully used with varlitinib in patients with advanced 
metastatic breast cancer (ASLAN001-003) and in a study (NCT00078572) conducted by 
Geyer, et al. where capecitabine was used in combination with lapatinib in metastatic 
breast cancer.11 This dose of capecitabine is also supported by an article by Patt et al. 
2004.13 
 


 
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Table 5: 
Dose Calculations for Starting Dose of Capecitabine of 1000 mg/m2 
Full dose 
1000 mg/m2 
Number of 150 mg tablets and/or 500 mg 
tablets per administration  
(each administration to be given morning 
and evening)  
Reduced dose 
(75%)  
750 mg/m2 
Reduced dose 
(50%)  
500 mg/m2 
Body Surface 
Area (m2) 
Dose per 
administration 
(mg)  
150 mg  
500 mg  
Dose per 
administration 
(mg)  
Dose per 
administration 
(mg)  
≤1.26 
1150  
1  
2  
800  
600  
1.27 - 1.38 
1300  
2  
2  
1000  
600  
1.39 - 1.52 
1450  
3  
2  
1100  
750  
1.53 - 1.66 
1600  
4  
2  
1200  
800  
1.67 - 1.78 
1750  
5  
2  
1300  
800  
1.79 - 1.92 
1800  
2  
3  
1400  
900  
1.93 - 2.06 
2000  
-  
4  
1500  
1000  
2.07 - 2.18 
2150  
1  
4  
1600  
1050  
≥ 2.19 
2300  
2  
4  
1750  
1100  
 
5.4.8 Selection and Timing of Dose for Each Patient 
Safety Lead-in 
Varlitinib will be administered BID with a meal or within 30 minutes after food intake, 
approximately at the same time (±2 hours), in the morning and evening each day, using 
the appropriate number of 100 mg tablets. High fat meal should be avoided and varlitinib 
tablets should not be chewed, crushed, or broken. 
On Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 1 Day 14, varlitinib tablets (morning dose) 
can only be administered under the supervision of the Investigator (or designee).  
Capecitabine will be administered with food at the same time as varlitinib BID for 14 
days with 7 days rest in a 21-day cycle. 
A sample low fat meal is: 


 
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*Type of low fat meal to be given with varlitinib should be based on the investigator’s 
judgement 
During the Cycle 1 Day 1 and Day 8 visits, the morning meal will be a small snack to 
be taken approximately 30 minutes prior to morning dosing of varlitinib. Patients will 
remain fasted until after the 6-hour ECG/PK assessment when they will receive a 
snack/small meal. The next meal can be taken after the 8.5-hour ECG/PK assessment. 
Timing and type of meal will be recorded on the CRF. 
Part 1 and 2 
Varlitinib or placebo will be administered BID with a meal or within 30 minutes after 
food intake, approximately at the same time (±2 hours), in the morning and evening each 
day, using the appropriate number of 100 mg tablets. High fat meal should be avoided 
and varlitinib tablets should not be chewed, crushed or broken. 
Retake of one dose of varlitinib or placebo is allowed if patient vomits within 30 minutes 
after administration of varlitinib or placebo. Retaking of varlitinib is not allowed if patient 
vomits again upon first retake. 
On Cycle 1 Day 1 and Cycle 1 Day 8 (Part 1 only), Cycle 2 Day 1, varlitinib tablets 
(morning dose) can only be administered under the supervision of the Investigator (or 
designee).  
Capecitabine will be administered with food at the same time as varlitinib or placebo 
BID for 14 days with 7 days rest in a 21-day cycle. Dose modification details are 
provided in Section 5.4.8.1.  
Study medication will be dispensed to each patient to take at home after leaving the study 
center until the next scheduled visit. The study medication is to be taken until the patient 


 
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experiences an unacceptable toxicity, withdraws consent, disease progression (as 
assessed by the Investigator based on RECIST version 1.1 [Appendix 14.1]), or death. 
5.4.8.1 
Dose Modification 
If a patient experiences a clinically significant adverse event of CTCAE 4.03 Grade 3 and 
above, not attributable to the disease or disease-related processes under investigation, 
dosing of investigational product and/or background therapy will be interrupted or the 
dose reduced and supportive therapy administered as required*. Any change in study 
medication needs to be recorded in the CRFs along with the reason for the change. 
*Note: In the Safety lead-in, treatment will continue for a minimum of 14 days, during 
which time dose adjustment is not allowed. Dose adjustment and interruption is allowed 
from Day 15 onwards. 
The recommended dose adjustment schedule for the investigational product 
(varlitinib/placebo) and capecitabine are described in Table 6 and Table 7 below, 
respectively, with the exception of hyperbilirubinemia, as well as serum creatinine 
increase, which are described separately in Section 5.4.8.2. Clinical judgment of the 
treating investigator should guide the management plan for each patient based on 
individual benefit/risk assessments. 
 
 


 
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Table 6: 
Recommended Dose Adjustments for Varlitinib/Placebo 
Toxicity 
(NCI CTCAE 4.03 Grades) 
During a Course of Therapy 
Dose Adjustment for 
Next Treatment 
Grade 1 and 2 
Maintain dose level 
Maintain dose level 
Grade 3 and above 
1st appearance 
Interrupt until resolved to grade 0-2 
300 mg BID 
2nd appearance 
200 mg BID 
3rd appearance 
100 mg BID 
4th appearance 
Discontinue treatment permanently 
- 
Abbreviations: BID = twice daily, NCI CTCAE = The National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
Table 7: 
Recommended Dose Adjustment for Capecitabine 
Toxicity 
(NCI CTCAE 4.03 Grades) 
During a Course of Therapy 
Dose Adjustment for Next 
Treatment 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
1st appearance 
Interrupt until resolved to grade 0-1 
1000 mg/m2 
2nd appearance 
750 mg/m2 
3rd appearance 
500 mg/m2 
4th appearance 
Discontinue treatment permanently 
- 
Grade 3 
1st appearance 
Interrupt until resolved to grade 0-1 
750 mg/m2 
2nd appearance 
500 mg/m2 
3rd appearance 
Discontinue treatment permanently 
- 
Grade 4 
1st appearance 
Discontinue permanently 
OR 
If physician deems it to be in the 
patient’s best interest to continue, 
interrupt until resolved to Grade 0-1 
500 mg/m2 
Abbreviation: NCI CTCAE = The National Cancer Institute Common Terminology Criteria for Adverse Events. 
Any interruption in dose or reduction in dose of study medication and background therapy 
needs to be captured in the CRF. In the event that the administration of varlitinib/placebo 
or capecitabine is interrupted for longer than 6 consecutive weeks, varlitinib/placebo or 
capecitabine must be permanently withdrawn. If capecitabine is permanently withdrawn, 
patients are allowed to continue in the study on varlitinib/placebo until disease 
progression, unacceptable toxicity, withdrawal of consent, or death. Similarly, in the 
event that varlitinib/placebo is permanently withdrawn, patients are allowed to continue 


 
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in the study on capecitabine until disease progression, unacceptable toxicity, withdrawal 
of consent, or death.  
5.4.8.2 
Management of Toxicities 
Management of Gastrointestinal Toxicities attributable to Varlitinib 
Diarrhea: 
For the management of diarrhea for patients in this study, routine loperamide prophylaxis 
as a standby is recommended. The recommend dose of loperamide is 2 mg three times a 
day (TID). Buscopan or a similar antispasmodic agent is recommended for management 
of acute symptoms. The recommended initial dose of Buscopan is 20 mg TID and can be 
escalated to 20 mg QID. 
The pharmacologic interventions for treatment emergent diarrhea should include: 
First line therapy – loperamide 
• If receiving routine loperamide prophylaxis, increase dose to a maximum of 
16 mg/day. 
• If new-onset diarrhea, take loperamide 4 mg with first bout of diarrhea followed 
by 2 mg every 4 hours or after every unformed stool (maximum 16 mg/day). 
Continue until diarrhea-free for 12 hours. 
• With recovery to < Grade 1, take loperamide 2 mg TID. 
As a second line therapy for the treatment of diarrhea refer to Table 8. 
 
 


 
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Table 8: 
Recommended Management of Diarrhea Attributable to Varlitinib 
Toxicity 
(NCI CTCAE 4.03 
Grades) 
Treatment 
Dose Adjustment  
Grade 1 
If persistent diarrhea on loperamide, add 
diphenoxylate hydrochloride plus atropine 
sulfate (Lomotil®) 2.5 mg every 6 to 8 hours 
Maintain dose level 
Grade 2 
If persistent diarrhea on loperamide, add 
octreotide (short acting) 150 µg SC TID, or 
after the initial dose of short acting 
octreotide, if well tolerated, a single dose of 
octreotide LAR 20 mg intramuscularly 
Maintain dose level 
Grade 3 or Grade 4 
after intensive loperamide therapy, titrate 
loperamide to keep diarrhea controlled 
(< 4 stools/day) 
1st occurrence 
Maintain dose level 
Octreotide (100 to 150 µg SC BID or 25 to 
50 µg/hour IV if dehydration is severe, with 
dose escalation up to 500 µg SC TID 
2nd occurrence 
Reduce Varlitinib/placebo 
dose to 200 mg BID 
IV fluids as appropriate 
3rd or more occurrence 
Reduce Varlitinib/placebo 
dose to 100 mg BID 
consider prophylactic antibiotics, especially 
if diarrhea is persistent beyond 24 hours or if 
there is a fever or Grade 3 /4 neutropenia 
Abbreviations: BID = twice daily, IV = intravenous, NCI CTCAE = The National Cancer Institute Common 
Terminology Criteria for Adverse Events, SC = subcutaneous, TID = 3 times a day. 
Nausea/Vomiting: 
Both varlitinib and capecitabine are considered to have low to minimal emetic risk. 
Routine prophylaxis for nausea/vomiting is not recommended. Anti-emetic medications 
can be used on an as-needed basis (PRN). If nausea/vomiting recur in later cycles of 
treatment, prophylactic medications can be used on the discretion of Investigator. Several 
anti-emetic drugs have QT prolongation effects and therefore are not allowed in the Safety 
lead-in part of this study, which will assess the QTc prolongation effect of study 
medications. The recommended management of nausea/vomiting is listed in Table 9.  
*Metoclopramide, dolasetron, granisetron, and ondansetron are prohibited in the Safety 
lead-in (Cycle 1 Day 1 to Cycle 2 Day 1) and Part 1 (Cycle 1 Day 1 to Cycle 2 Day 1) of 
this study due to their QT prolonging effect. These medications can be used with caution 
in Part 2 of this study (Section 5.4.10). From Cycle 2 Day 2 in the Safety lead-in and Part 
1 of this study and in the event that symptoms cannot be controlled by panolosetron or 
patients are intolerant to panolosetron, then investigators are allowed to prescribe 
metoclopramide, dolasetron, granisetron, and ondansetron without prior approval. 
However for tracking purpose, Sponsor must be informed if the above medications have 
been used. 


 
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Table 9: 
Recommended Management of Nausea/Vomiting attributable to 
Varlitinib 
Study part 
Breakthrough treatment for 
acute symptom control 
Prophylaxis for recurrent 
nausea/vomiting (start 30 mins 
before study treatment) 
Safety lead-in 
Part1 (Cycle 1 Day 1 
to Cycle 2 Day 1) 
Olanzapine 5-10 mg PO QD 
PRN 
or 
Prochlorperazine: 5-10 mg every 
6 hours PRN (maximum 
40 mg/day)  
 
Prochlorperazine: 10 mg PO and 
then every 6 hours PRN 
(maximum 40 mg/day)  
or 
Palonsetron: 0.25 mg IV every 
5 days 
Part 1 (Cycle 2 
Day 2 and afterward) 
and 
Part 2 
Olanzapine 5-10 mg PO QD 
PRN 
or 
Prochlorperazine: 5-10 mg every 
6 hours PRN (maximum 
40mg/day)  
or 
Metoclopramide: 10-20 mg 
PO/IV every 4-6 hours PRN 
or 
Dexamethasone 12 mg PO/IV 
and QD PRN* 
or 
Haloperidol 0.5-2 mg PO/IV 
every 4-6 hours 
Or one of the following:  
Dolasetron: 100 mg PO QD PRN 
Granisetron: 1-2 mg (total dose) 
PO QD PRN or 1 mg PO BID 
PRN or 1 mg IV QD PRN or 3.1 
mg/24 hours transdermal patch 
every 7 days 
Ondansetron: 16-24 mg PO QD 
PRN or 8-16 mg IV QD PRN 
Metoclopramide: 10-20 mg PO 
and then every 6 h PRN 
or 
Prochlorperazine: 10 mg PO and 
then every 6 hours PRN 
(maximum 40 mg/day) 
or one of the following: 
Dolasetron: 100 mg PO QD 
PRN 
Granisetron: 1-2 mg PO QD 
PRN or 3.1 mg/24 hours 
transdermal patch every 7 days 
Ondansetron: 8-16 mg PO QD 
PRN 
Palonsetron: 0.25 mg IV every 
5 days 
Abbreviations: BID = twice daily, IV = intravenous, PO = per oral, PRN = as needed, QD = once daily. 
Taken from NCCN Guidelines version 1.2017: Antiemesis. 
*: moderate CYP3A4 inhibitor, use with caution. 
 
Management of hyperbilirubinemia and serum creatinine attributable to 
Varlitinib 
Hyperbilirubinemia 
The dose adjustment schedule for investigational product (varlitinib/placebo) when 
hyperbilirubinemia occurs in combination with an increase in transaminases (ALT, AST) 
of CTCAE 4.03 Grade 2 and above is described in Table 10. 
 
 


 
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Table 10: 
Recommended Dose Adjustment for Management of 
Hyperbilirubinemia with Increased Transaminases 
Toxicity  
(NCI CTCAE 4.03 
Grades) 
During a Course of Therapy 
Dose Adjustment for 
Next Treatment 
Grade 1  
Maintain dose level 
Maintain dose level 
Grade 2 and 3 
1st appearance 
Interrupt until resolved to grade 0-1 
300 mg BID 
2nd appearance 
200 mg BID 
3rd appearance 
100 mg BID 
4th appearance 
Discontinue treatment permanently 
- 
Grade 4 
1st appearance 
Interrupt until resolved to grade 0-1 
200 mg BID 
2nd appearance 
Interrupt until resolved to grade 0-1 
100 mg BID 
3rd appearance 
Discontinue treatment permanently 
- 
Abbreviations: BID = twice daily, NCI CTCAE = The National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
If hyperbilirubinemia is primarily due to an increase in indirect bilirubin (with indirect 
bilirubin > direct bilirubin and direct bilirubin ≤ 1.5 × ULN) with no increase in 
transaminases levels (ALT, AST) or an increase in transaminases of ≤ Grade 1, follow 
the dose adjustment schedule in Table 11. 
Table 11: 
Recommended Dose Adjustment for Management of 
Hyperbilirubinemia due to Indirect Bilirubin 
Toxicity (NCI 
CTCAE 4.03 Grades) 
During a Course of Therapy 
Dose Adjustment for 
Next Treatment 
Grade 1 and 2 
Maintain dose level 
Maintain dose level 
Grade 3 and above 
1st appearance 
Interrupt until resolved to grade 0-2 
300 mg BID 
2nd appearance 
200 mg BID 
3rd appearance 
100 mg BID 
4th appearance 
Discontinue treatment permanently 
- 
Abbreviations: BID = twice daily, NCI CTCAE = The National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
Increased Serum creatinine 
Dose adjustment schedule for investigational product (varlitinib/placebo) as a result of 
increased serum creatinine levels is described in the Table 12. 


 
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Table 12: 
Recommended Dose Adjustment for Management of Increase Serum 
Creatinine 
Toxicity (NCI 
CTCAE 4.03 Grades) 
During a Course of Therapy 
Dose Adjustment for 
Next Treatment 
Grade 1  
Maintain dose level 
Maintain dose level 
Grade 2 and 3 
1st appearance 
Interrupt until resolved to grade 0-1 
300 mg BID 
2nd appearance 
200 mg BID 
3rd appearance 
100 mg BID 
4th appearance 
Discontinue treatment permanently 
- 
Grade 4 
1st appearance 
Interrupt until resolved to grade 0-1 
200 mg BID 
2nd appearance 
Interrupt until resolved to grade 0-1 
100 mg BID 
3rd appearance 
Discontinue treatment permanently 
- 
Abbreviations: BID = twice daily, NCI CTCAE = The National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
5.4.9 Blinding 
Part 1 and Part 2 of the study is a double-blind study and thus the Investigator, site staff 
and patients are all blinded to treatment. No individual-patient information that can 
potentially un-blind the Investigator or patient will be reported until the end of the study. 
The presentation of the placebo will be identical in appearance to the study drug. 
A communication plan will describe the procedure for un-blinding the study. The 
Investigator at the site will have access to the details of the double-blind treatment for 
each patient. Access to these details will be via RTSM.  
Note!: The Investigator may only break the code if knowledge of the study medication 
is necessary to provide optimal treatment to the patient in an emergency situation. 
Whenever possible, the Investigator must consult with the sponsor before breaking the 
code. The unblinding procedure is described in RTSM User Guide. 
Emergency unblinding will not preclude patient’s data being included in the study 
analyses. The primary efficacy analyses are performed on an intention-to-treat basis 
(Section 8.3.2, Section 8.3.3), and unblinding will not result in a patient being excluded 
from any analysis sets. Similarly, safety will be assessed using the safety population 
(Section 8.3.1), which includes all patients who received at least one dose of study drug, 
regardless of any subsequent unblinding. However, a listing of all cases requiring 
unblinding will be provided, including details of the reason for unblinding. 
Unblinding of all study treatment assignment will be performed at the time of data cut-off 
(DCO) of Part 1 and Part 2 of the study respectively before primary analysis. 


 
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The data cut-off for the primary analysis of Part 1 will be the later of 3 months after Last 
Patient In (LPI) or when 70% of the patients (84 patients) have experienced PFS events, 
while the data cut-off for Part 2 will be when 247 OS events have occurred.  
After the treatment allocation is unblinded post DCO, all patients receiving active 
treatment and who, in the opinion of the investigator, may benefit from continued 
varlitinib treatment, will be offered participation in an open-label extension study where 
only varlitinib will be provided by the sponsor; or be managed under a compassionate use 
program governed by the regulatory authorities in the respective countries. 
5.4.10 Prior and Concomitant Therapy 
Concomitant medication may be given as medically indicated. All patients will be asked 
to provide a complete list of concomitant medication including prescription, over-the-
counter, complementary, and alternative medications that have been taken within 4 weeks 
before the first treatment visit. They must also inform the Investigator about any new 
medication started while on the study. 
Details (including indication, doses, frequency, and start/stop dates) of concomitant 
medication taken, as well as concomitant therapy (including indication, start and stop 
dates) administered within 4 weeks before the first treatment visit, during the study , until 
the completion of the safety follow-up visit, must be documented in the medical record 
and the appropriate CRF. 
Varlitinib 
Varlitinib may cause a drug-drug interaction with other medications that are cytochrome 
P450 (CYP) 3A4, CYP2C8, CYP2C9 or CYP2C19 inducers, inhibitors, or substrates. 
Human CYP3A4 is the major route of metabolism of varlitinib, whereas CYP2C8 and 
CYP2C19 are minor routes. Due to the potential for drug interactions based on in vitro 
screens, concomitant use of moderate CYP3A4, CYP2C8, CYP2C9, and P-gp inducers 
or inhibitors will be recorded during the entire clinical study. Refer to the FDA’s Drug 
Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.14 
Examples of CYP2C8 substrates are: 
• amodiaquine (antimalarial, anti-inflammatory) 
• serivastatin (statin) 
• paclitaxel (chemotherapeutic) 
• repaglinide (antidiabetic) 
• torasemide (loop diuretic) 
• sorafenib (tyrosine kinase inhibitor) 
• rosiglitazone (antidiabetic) - converted to active metabolites 
Examples of strong CYP2C8 inhibitors (one that causes a > 5-fold increase in the plasma 
area under the plasma concentration-time curve (AUC) values or more than 80% decrease 
in clearance) are: 
• gemfibrozil (hypolipidemic) 


 
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Examples of moderate CYP2C8 inhibitors (one that causes a > 2-fold increase in the 
plasma AUC values or 50% to 80% decrease in clearance): 
• trimethoprim (antibiotic) 
Examples of CYP2C8 inhibitors with unspecified potency: 
• thiazolidinediones (antidiabetic) 
• montelukast (leukotriene receptor antagonist) 
• quercetin (anti-inflammatory) Examples of CYP2C8 inducer: 
• rifampicin (antibiotic) 
Varlitinib is a weak inhibitor of CYP2C8 and CYP2C9 with an IC50 of 3.2 µM and 10.6 
µM, respectively. Its plasma protein binding is higher than 99% so the free fraction of 
varlitinib in the blood is not likely to reach that concentration. 
In the Safety Lead-in and Part 1 of the study, non-excluded drugs that are associated with 
torsade de pointes and QTc prolongation (Appendix 14.4) or QT Prolongation without 
torsade de pointes (_Drugs_that_ProlongAppendix 14.5) should be at steady-state dosing 
for at least 2 weeks before enrollment. During the study, from 2 weeks before the first 
dose to up to and including Cycle 2 Day 1, the dose of such drugs should not be increased, 
and new drugs in either group should not be initiated without approval from medical 
monitor. 
In addition to the above, in the Safety lead-in and Part 1 of the study, from Cycle 2 Day 
2 onwards, the dose of drugs associated with torsade de pointes and QTc prolongation 
(Appendix 14.4) or QT prolongation without torsade de pointes (Appendix 14.5) ideally 
should not be increased. Every attempt should be made to minimize the initiation of such 
drugs (Appendix 14.4 or Appendix 14.5). The initiation of any such drugs 
(Appendix 14.4 or Appendix 14.5) requires the medical monitor’s approval. 
Capecitabine 
Refer also to the XELODA® (capecitabine) prescribing information leaflet12 for details 
of drug interactions with capecitabine. 
5.4.10.1 Prohibited Medication/Therapy 
Prohibited medications during this study will include 
• any other antitumor treatment 
• proton pump inhibitors 
• warfarin 
• strong CYP3A4 inhibitors 
• any other investigational product 
• herbal preparations 
• H2 blocker can be given 3 hours after each dose of varlitinib. 
Please see Appendix 14.3 _Prohibited_Concomitant_Medication/Tfor the list of 
prohibited medication/therapy. 


 
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5.4.11 Treatment Compliance 
The administration of all study medications should be recorded in the appropriate sections 
of the CRF. Patients shall report any self-administered medication. 
Patients will be issued with a diary card, which is to be returned to the study center at the 
next visit. Treatment compliance of self-administered study medication will be assessed 
by regular tablet counts on the patient diary card and the information will be recorded in 
the appropriate section of the CRF. 
In the event of a study related procedure or an intolerable AE or AE ≥ CTCAE 4.03 Grade 
3 (Section 5.4.8.1), patients may be counseled to interrupt dosing permanently or 
temporarily. Doses not taken in such instances do not count as planned dose 
administrations and do not constitute lack of compliance. 
Patients must bring all containers of study medication and any remaining tablets as well 
as the patient diary card with them at each scheduled visit. Patients will be instructed to 
notify the study center personnel of missed doses. Dates of missed or held doses will be 
recorded on the CRF. 
At each visit, patients will be issued a patient diary card, which contains clear instructions 
on how and when to take the study medication and to record the time and date of each 
dose. 
Each patient will record on the patient diary card the number of tablets of study 
medication taken and the time of taking them daily. This diary card will be returned to 
the study center at each scheduled visit. 
The recorded information is required to be entered into the eCRF by study center 
personnel. 
6 
TIMING OF STUDY PROCEDURES 
Patients will provide written informed consent before any study-related procedures are 
performed.  
The timing and details of study assessments for the Safety lead-in are provided in Table 
1 and for Part 1 and Part 2 in Table 2.
6.1 
Study Visits – Safety Lead-in 
6.1.1 Screening Visit – Safety Lead-in 
Screening will be performed up to 14 days prior to the first administration of the 
study medication and background medication (Cycle 1 Day 1). Prior to any 
evaluations being performed, written informed consent must be obtained and a 
screening number assigned. Patients will then be assessed for compliance with the 
inclusion and exclusion criteria. The following assessments will be performed: 


 
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• Demographic information 
• Medical history, concomitant medication(s) and prior treatment(s) 
• Physical examination and weight 
• Vital signs 
• Triplicate central 12-lead ECG 
• ECOG performance status 
• Collection of AEs 
• Blood collected for hematology, clinical chemistry, coagulation, and serology 
• Urine collected for urinalysis 
• Blood collected for pregnancy test for female patients of childbearing potential 
• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions may be 
scanned, if applicable. 
Any of these investigations may be repeated to allow patients to qualify for the study. 
If appropriate, and with prior approval from the sponsor or their designee, patients who 
fail screening or who pass screening but have not been treated may be re-screened. 
Where investigations are repeated, the most recent investigations should meet all 
inclusion and exclusion criteria.  
6.1.2 Treatment Visits – Safety Lead-in 
Cycle 1 Day 1, Day 8 and Day 14 
Refer to Table 1 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry   
• Urine collected for urinalysis 
• Pre-dose triplicate central 12-lead ECG at 45 minutes pre-dose and 5 minutes 
pre-dose on Cycle 1 Day 1 and Cycle 1 Day 8 only (NOTE: not required on Day 
14) 
• Pre-dose blood collected for PK analysis at 5 minutes pre-dose on Cycle 1 Day 
1, 20 minutes pre-dose on Cycle 1 Day 8 and 5 minutes pre-dose on Cycle 1 Day 
14 
• Varlitinib administration  
• Capecitabine administration  
• Post-dose triplicate central 12-lead ECG at 1, 2, 3, 4, 5, 6, 8.5, and 12 hours post-
dose (NOTE: not required on Day 14) 
• Post-dose blood collected for PK analysis at 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 
12 hours post-dose 


 
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When ECGs and PK samples are collected at the same time point, the PK samples 
are always collected after the ECGs. 
Subsequent Cycles – Cycle 2 Day 1, Cycle 3 Day 1, etc. (±5 days) 
Refer to Table 1 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Varlitinib administration  
• Capecitabine administration  
• Triplicate central 12-lead ECG (3 hours post-dose) 
• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions may be 
scanned, if applicable every 6 weeks from Cycle 1 Day 1.  
6.1.3 End of Treatment Visit (+ 7 Days) – Safety Lead-in 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Urine or blood collected for pregnancy test for female patients of childbearing 
potential 
• Blood collected for hematology, clinical chemistry, and coagulation 
• Urine collected for urinalysis 
EOT assessments should be performed before the start of new anti-tumor treatment. 
6.1.4 Safety Follow up Visit 28 Days Post Last Study Medication Administration 
(+ 7 Days) – Safety Lead-in 
• Physical examination and weight 
• Vital signs 
• Triplicate central 12-lead ECG 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry 


 
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If the patient needs to start a new anti-tumor treatment within 28 days post last study 
medication administration, the safety follow-up assessments should be performed 
within 1 day before the start of the new anti-tumor treatment. 
 
6.2 
Study Visits – Part 1 
6.2.1 Screening Visit – Part 1 
Screening will be performed up to 14 days prior to randomization (Cycle 1 Day 1). 
It may be extended up to 21 days subjected to a case by case review and approval by 
the Sponsor. Prior to any evaluations being performed, written informed consent must 
be obtained and screening number assigned. 
Patients will then be assessed for compliance with the inclusion and exclusion criteria.  
The following assessments will be performed: 
• Demographic information 
• Medical history, concomitant medication(s), and prior treatment(s) 
• Physical examination and weight 
• Vital signs 
• Triplicate central 12-lead ECG 
• ECOG performance status 
• Collection of AEs 
• Blood collected for hematology, clinical chemistry, coagulation, serology, cancer 
antigen 19.9 (CA19.9), and CEA 
• Urine collected for urinalysis 
• Blood collected for pregnancy test for female patients of childbearing potential 
• Blood collected for retrospective analysis of biomarkers 
• Information on acquired tumor mutations if available as part of medical history 
or during study participation 
• Archival paraffin-embedded tumor tissues collected for future analysis (the 
minimum archival tumor tissue to be collected is 19 unstained slides of 5 microns) 
• Biopsy for those patients who do not have enough archival tumor tissue 
(additional consent to be provided) 
• CT/MRI of the chest, abdomen, and pelvis images must be performed within 21 
days prior to Cycle 1 Day 1, brain and/or bone lesions may be scanned, if 
applicable. 
 
6.2.2 Treatment Visits – Part 1 
Cycle 1 Day 1 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 


 
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• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Pre-dose triplicate central 12-lead ECG at 45 minutes pre-dose and 5 minutes 
pre-dose 
• Pre-dose blood collected for PK analysis at 5 minutes pre-dose  
• Varlitinib or placebo administration  
• Capecitabine administration 
• Post-dose triplicate central 12-lead ECG at 1.5, 3, 5, and 8 hours post-dose  
• Post-dose blood collected for PK analysis at 1.5, 3, 5, and 8 hours post-dose  
When ECGs and PK samples are collected at the same time point, the PK samples 
are always collected after the ECGs. 
 
Cycle 1 Day 8 (±1 day) 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry including weekly liver 
function tests 
• Urine collected for urinalysis 
• Pre-dose triplicate central 12-lead ECG at 45 minutes pre-dose and 5 minutes 
pre-dose 
• Pre-dose blood collected for PK analysis at 20 minutes pre-dose  
• Varlitinib or placebo administration  
• Capecitabine administration 
• Post-dose triplicate central 12-lead ECG at 1.5, 3, 5, and 8 hours post-dose  
• Post-dose blood collected for PK analysis at 1.5, 3, 5, and 8 hours post-dose 
When ECGs and PK samples are collected at the same time point, the PK samples are 
always collected after the ECGs. 
Cycle 1 Day 15 (±1 day) 
Refer to Table 2 for assessment details and timing of the following assessment: 
• Blood collected for weekly liver function tests 
• Varlitinib or placebo administration  


 
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Cycle 2 Day 1 (±5 days) 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Varlitinib or placebo administration  
• Capecitabine administration 
• Post-dose triplicate central 12-lead ECG at 3 hours post-dose 
Cycle 3 Day 1 (±5 days) 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Varlitinib or placebo administration  
• Capecitabine administration 
• Blood collected for retrospective analysis of biomarkers 
• Blood collected for CA19.9 and CEA 
• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions as 
applicable 
Subsequent Cycles from Cycle 4 Day1, Cycle 5 Day 1, etc. (±5 days) 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  


 
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• Urine collected for urinalysis 
• Varlitinib or placebo administration  
• Capecitabine administration 
• Blood collected for CA19.9 and CEA every 6 weeks from Cycle 1 Day 1 
• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions as 
applicable every 6 weeks from Cycle 1 Day 1 
• Post-dose triplicate central 12-lead ECG at 3 hours post-dose every 2 cycles from 
Cycle 4 Day 1 
 
End of Treatment Visit (+ 7 days) – Part 1 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Urine or blood collected for pregnancy test for female patients of childbearing 
potential 
• Urine collected for urinalysis 
• Blood collected for hematology, clinical chemistry and coagulation 
• Blood collected for CA19.9 and CEA. If the reason for EOT is due to 
radiological disease progressions and CA19.9/CEA have already been assessed 
with the most recent scans, then CA19.9/CEA at EOT can be omitted. 
EOT assessments should be performed before the start of new anti-tumor treatment. 
6.2.3 Safety Follow-up Visit 28 Days Post Last Study Medication Administration 
(+ 7 Days) – Part 1 
• Physical examination and weight 
• Vital signs 
• Triplicate central 12-lead ECG 3 hours after light snack 
• Blood collected for PK analysis within 25 minutes after ECG evaluation 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
If the patient needs to start a new anti-tumor treatment within 28 days post last study 
medication administration, the safety follow-up assessments should be performed 
within 1 day before the start of the new anti-tumor treatment. 
6.2.4 Disease Status Follow-up Visit Every 6 Weeks (± 5 Days) Post End of 
Treatment until Disease Progression – Part 1 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 


 
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• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions as 
applicable 
6.2.5 Survival Follow-up Visit, Every 12 Weeks (± 7 Days) Post Disease 
Progression – Part 1 
• Survival status contact 
• Details of anti-cancer treatment  
Note: Survival calls may be made in the week following the date of DCOs for the 
analyses, and if subjects are confirmed to be alive or if the death date is after the 
DCOs, these subjects will be censored at the date of the DCOs. 
6.3 
Study Visits – Part 2 
6.3.1 Screening Visit – Part 2 
Screening will be performed up to 14 days prior to randomization (Cycle 1 Day 1). 
It may be extended up to 21 days subjected to a case by case review and approval by 
the Sponsor. Prior to any evaluations being performed, written informed consent must 
be obtained and screening number assigned. 
Patients will then be assessed for compliance with the inclusion and exclusion criteria.  
The following assessments will be performed: 
• Demographic information 
• Medical history, concomitant medication(s), and prior treatment(s) 
• Physical examination and weight 
• Vital signs 
• Triplicate central 12-lead ECG 
• ECOG performance status 
• Collection of AEs 
• Blood collected for hematology, clinical chemistry, coagulation, serology, cancer 
antigen 19.9 (CA19.9), and CEA 
• Urine collected for urinalysis 
• Blood collected for pregnancy test for female patients of childbearing potential 
• Blood collected for retrospective analysis of biomarkers 
• Information on acquired tumor mutations if available as part of medical history 
or during study participation 
• Archival paraffin-embedded tumor tissues collected for future analysis (the 
minimum archival tumor tissue to be collected is 19 unstained slides of 5 microns) 
• Biopsy for those patients who do not have enough archival tumor tissue 
(additional consent to be provided) 
• CT/MRI of the chest, abdomen, and pelvis images must be performed within 21 
days prior to Cycle 1 Day 1, brain and/or bone lesions may be scanned, if 
applicable. 


 
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6.3.2 Treatment Visits – Part 2 
Cycle 1 Day 1 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Pre-dose triplicate central 12-lead ECG (before a snack) 
• Pre-dose blood collected for PK analysis at 5 minutes pre-dose 
• Varlitinib or placebo administration  
• Capecitabine administration 
• Post-dose blood collected for PK analysis at 1-3 hours post dose, 3-5 hours post 
dose, and 5-8 hours post dose (Sparse PK sampling) 
Cycle 1 Day 8 (±1 day) 
Refer to Table 2 for assessment details and timing of the following assessment: 
• Blood collected for weekly liver function tests 
• Varlitinib or placebo administration  
• Capecitabine administration 
 
Cycle 1 Day 15 (±1 day) 
Refer to Table 2 for assessment details and timing of the following assessment: 
• Blood collected for weekly liver function tests 
• Varlitinib or placebo administration  
 
Cycle 2 Day 1 (±5 days) 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 


 
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• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Pre-dose blood collected for PK analysis at 20 minutes pre-dose 
• Varlitinib or placebo administration  
• Capecitabine administration 
• Post-dose triplicate central 12-lead ECG at 3 hours post-dose 
• Post-dose blood collected for PK analysis at 1-3 hours post dose, 3-5 hours post 
dose, and 5-8 hours post dose (Sparse PK sampling) 
Cycle 3 Day 1 (±5 days) 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Varlitinib or placebo administration  
• Capecitabine administration 
• Blood collected for retrospective analysis of biomarkers 
• Blood collected for CA19.9 and CEA 
• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions as 
applicable 
Subsequent Cycles from Cycle 4 Day 1, Cycle 5 Day 1, etc. (±5 days) 
Refer to Table 2 for assessment details and timing of the following assessments: 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Blood collected for hematology and clinical chemistry  
• Urine collected for urinalysis 
• Varlitinib or placebo administration  
• Capecitabine administration  
• Blood collected for CA19.9 and CEA every 6 weeks from Cycle 1 Day 1 
• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions as 
applicable every 6 weeks from Cycle 1 Day 1 


 
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• Post-dose triplicate central 12-lead ECG at 3 hours post dose every 2 cycles from 
Cycle 4 Day 1 
 
End of Treatment Visit (+ 7 days) – Part 2 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
• Urine or blood collected for pregnancy test for female patients of childbearing 
potential 
• Urine collected for urinalysis  
• Blood collected for hematology, clinical chemistry and coagulation 
• Blood collected for CA19.9 and CEA. If the reason for EOT is due to radiological 
disease progressions and CA19.9/CEA have already been assessed with the most 
recent scans, then CA19.9/CEA at EOT can be omitted. 
EOT assessments should be performed before the start of new anti-tumor treatment. 
6.3.3 Safety Follow-up Visit 28 Days Post Last Study Medication Administration 
(+ 7 Days) – Part 2 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• Collection of AEs 
• Concomitant medication review 
If the patient needs to start a new anti-tumor treatment within 28 days post last study 
medication administration, the safety follow-up assessments should be performed 
within 1 day before the start of the new anti-tumor treatment. 
6.3.4 Disease Status Follow-up Visit Every 6 Weeks (± 5 Days) Post End of 
Treatment until Disease Progression – Part 2 
• Physical examination and weight 
• Vital signs 
• ECOG performance status 
• CT/MRI of the chest, abdomen, and pelvis. Brain and/or bone lesions as 
applicable 
6.3.5 Survival Follow-up Visit, Every 12 Weeks (± 7 Days) Post Disease 
Progression – Part 2 
• Survival status contact 
• Details of anti-cancer treatment 


 
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6.4 
Duration of Treatment 
The duration of each patient’s study involvement will be as follows: 
Screening Period: Up to 14 days. It may be extended up to 21 days subjected to a case by 
case review and approval by the Sponsor. 
Treatment Period:  
• Safety lead-in: Study treatment will be given in 21-day cycles. Patients will 
receive investigational product and background medication until disease 
progression, development of unacceptable toxicity, withdrawal of consent or 
death. Patients will be followed for disease status every 6 weeks.  
• Part 1 and Part 2: Study treatment will be given in 21-day cycles. Patients will 
receive investigational product and background medication until disease 
progression, development of unacceptable toxicity, withdrawal of consent or 
death. Patients will be followed for disease status every 6 weeks. After disease 
progression, all patients will be followed for survival every 12 weeks until death 
or until the DCO for Part 2 OS analysis. 
Safety Follow-Up Period: Patients will complete a safety follow-up visit 28 days after the 
last dose of investigational product. If the patient needs to start a new anti-tumor treatment 
within 28 days post last study medication administration, the safety follow-up assessments 
should be performed within 1 day before the start of the new anti-tumor treatment. 
Only in Part 1 and 2: 
Follow-up Period: If patients have not experienced radiological progression at the time 
of treatment discontinuation, radiological assessments should continue every 6 weeks 
(± 5 days) until disease progression (Disease Status Follow-Up). After disease 
progression, all patients will be followed for survival every 12 weeks until death or until 
the DCO for the final OS analysis (Survival Follow-Up) 
7 
SAFETY, 
EFFICACY, 
PHARMACOKINETIC 
AND 
BIOMARKER 
VARIABLES 
The planned schedule of assessments is presented in Section 6, Table 1 (Safety lead-in) 
and Table 2 (Part 1 and Part 2). 


 
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7.1 
Safety, Efficacy Pharmacokinetic and Pharmacodynamic Measurements 
Assessed 
7.1.1 Safety Assessments 
7.1.1.1 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study patient 
administered a medicinal product which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not it is related to the 
medicinal (investigational) product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction or the significant worsening 
of the indication under investigation that is not recorded elsewhere in the CRF under 
specific efficacy assessments. Fluctuations of pre-existing conditions that do not 
represent a clinically significant exacerbation or worsening need not be considered AEs. 
Surgical procedures planned before enrollment of the patient in the study are not 
considered AEs if the condition(s) was known before study inclusion. In the latter case, 
the medical condition should be reported in the patient’s medical history. 
Progression of the cancer of target disease under study is generally not considered an AE. 
It is the responsibility of the Investigator to document all AEs that occur during the study. 
AEs will be elicited by asking the patient a non-leading question; for example, “Have you 
experienced any new or changed symptoms since we last asked/since your last visit?” 
Adverse events should be reported on the appropriate page of the CRF. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
• Results in death. 
• Is life-threatening (an AE is life-threatening if the patient was at immediate risk 
of death from the event as it occurred, i.e., it does not include a reaction that might 
have caused death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization.) 
• Results in persistent or significant disability/incapacity. (An AE is incapacitating 
or disabling if it results in a substantial and/or permanent disruption of the 
patient’s ability to carry out normal life functions). 
• Results in a congenital anomaly/birth defect. 


 
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In addition, medical and scientific judgement is required to decide if prompt notification 
is required in situations other than those defined for SAEs above. This may include any 
event that the Investigator regards as serious that did not strictly meet the criteria above 
but may have jeopardized the patient or required intervention to prevent one of the 
outcomes listed above, or that would suggest any significant hazard, contraindication, 
side effect, or precaution that may be associated with the use of the study medication. 
Events related to disease progression will not be reported as SAEs unless the events lead 
to death, and the death will be reported as an SAE. 
Hospitalization due to the following reasons does not need to be reported as an SAE: 
• Reasons described in the protocol (i.e., drug administration, protocol required 
procedures); 
• Surgery or procedure planned prior to entry into the study; 
• Surgery or procedure planned for pre-existing conditions that do not worsen after 
entry into the study; 
• Social/administrative reasons (i.e., due to distance between home and hospital, 
hospice placement for terminal care due to progressive disease, etc.). 
Assessment of Severity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the CTCAE 4.03 criteria. The assessments will be based on the 
Investigator’s clinical judgment. The severity of each AE and SAE recorded in the CRF 
should be assigned to one of the categories: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2: 
Moderate; minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living  
Grade 3: 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
All changes in severity must be recorded in the eCRF. 
Assessment of Causality 
Every effort will be made by the Investigator to assess the relationship of the AE, if any, 
to the investigational product (varlitinib/placebo) and the background therapy 


 
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(capecitabine). For both investigational product and background therapy, causality should 
be assessed using the categories presented as follows: 
Definitely Related: A clinical event, including clinical laboratory test abnormality, 
occurring in a plausible time relationship to the medication 
administration, and which cannot be explained by concurrent disease 
or other drugs or chemicals. The response to withdrawal of the drug 
should be clinically plausible. 
Probably Related: 
A clinical event, including clinical laboratory test abnormality, with 
a reasonable time sequence to the medication administration, 
unlikely to be attributes to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on 
withdrawal. 
Possibly Related: 
A clinical event, including clinical laboratory test abnormality, with 
a reasonable time sequence to the medication administration, but 
which could also be explained by concurrent disease or other drugs 
or chemicals. Information on the drug withdrawal may be lacking 
or unclear. 
Unlikely Related: 
A clinical event, including clinical laboratory test abnormality, with 
little or no temporal relationship to medication administration, and 
which other drugs, chemicals or underlying disease provide 
plausible explanations. 
Not Related: 
A clinical event, including clinical laboratory test abnormality that 
has no temporal relationship to the medication or has more likely 
alternative etiology. 
NOTE: AEs listed as ‘possibly, probably or definitely’ related to the investigational 
product are considered to have a suspected ‘reasonable causal relationship’ to the 
investigational product. Adverse events listed as ‘unlikely or unrelated” are considered 
have a suspected “unrelated” causal relationship to the investigational agent/intervention. 
Action Taken 
The Investigator will describe the action taken in the appropriate section of the CRF, as 
follows: 
• None 
• Varlitinib/placebo permanently withdrawn 
• Capecitabine permanently withdrawn 
• Varlitinib/placebo temporarily interrupted 
• Capecitabine temporarily interrupted 
• Varlitinib/placebo dose modified 
• Capecitabine dose modified 
• Concomitant medication/therapy 
• Other, specify. 


 
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Follow-up of Adverse Events 
All Investigators should follow up patients with AEs until the event is resolved, the patient 
is lost to follow-up or until, in the opinion of the Investigator, the event is stabilized or 
determined to be chronic. Details of AE resolution must be documented in the CRF. 
Documentation and Reporting of Adverse Events 
Adverse events will be recorded and reported from the patient’s signing of the informed 
consent to the safety follow-up assessment. Prior to receiving study medication, only 
AEs that were assessed as related to study procedures will be recorded and reported.  
If a patient begins a new anti-tumor therapy within 28 days after the last administration 
of study medication, the AE reporting period for non-serious AEs ends at the time the 
new therapy is started. 
All AEs per the definition stated in the protocol that are observed, elicited by the 
Investigator or reported by the patient, regardless of their causal relation to study 
medication will be documented in source documents, captured in CRF and will be 
evaluated by the Investigator. All new AEs, as well as those that worsen in intensity or 
frequency relative to baseline, which occur during the defined AE collection period must 
be recorded. 
Each AE should be described in detail: A medical diagnosis of the event (if a medical 
diagnosis cannot be determined, a description of each sign or symptom characterizing the 
event should be recorded), onset date, resolution date, a determination of whether the 
event is serious or not, severity, relationship to the study medication, action taken and 
outcome. 
The minimum information required for each AE includes the following: 
• Type of event 
• Duration (start and end dates) 
• Severity 
• Changes in severity 
• Seriousness 
• Causality in relation to varlitinib/placebo 
• Causality in relation to capecitabine 
• Action taken in relation to varlitinib/placebo 
• Action taken in relation to capecitabine 
• Treatments in relation to event 
• Outcome 
Outcome 
The Investigators are to record the ‘Outcome to Date’ using the following categories: 


 
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Fatal 
The termination of life as a result of an AE 
Not Resolved 
One of the possible results of an AE outcome that indicates that the event 
has not improved or the patient has not recuperated 
Resolved 
One of the possible results of an AE outcome that indicates that the event 
has improved or the patient has recuperated 
Resolved with 
Sequelae 
One of the possible results of an AE outcome where the patient 
recuperated but retained pathological/clinical conditions resulting from 
the prior disease or injury (AE) 
Unknown 
Not known, not observed, not recorded, or refused 
7.1.1.2  Reporting of Serious Adverse Events 
Collection of SAEs starts from signing of ICF until 28 days after the last administration 
of study medication. Prior to receiving investigational product, only SAEs that were 
assessed as related to study procedures will be reported.  
If a patient begins a new anti-tumor therapy within 28 days after the last administration 
of study medication, the SAE reporting period for SAEs ends at the time the new therapy 
is started. 
The following information regarding SAEs should be captured by the site where possible: 
• Date AE met criteria for SAE 
• Date Investigator became aware of SAE 
• Reason AE considered serious 
• Date of hospitalization 
• Date of hospital discharge 
• Probable cause of death (if applicable) 
• Date of death (if applicable) 
• Autopsy performed (if applicable) 
• Causality assessment in relation to study procedure(s) 
• Causality assessment in relation to other medication 
• Causality assessment in relation to varlitinib/placebo 
• Causality assessment in relation to capecitabine 
The sponsor has a legal responsibility to notify the appropriate regulatory authorities 
about the safety of the study medication. Accordingly, the Investigator must report all 
SAEs per the definition stated in the protocol, regardless of presumed causal relationship, 
on the SAE page of the eCRF within 24 hours of becoming aware of the event. During eCRF 
downtime, the paper SAE form should be sent to the sponsor’s assigned safety 
representative by email within 24 hours of becoming aware of the event. 


 
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Email: 
ASLANSafety@parexel.com 
For medical emergencies contact: 
Name: 
Mei Ling Long 
Mobile: 
+65 9888 9987 
Name: 
Chih Yi Hsieh 
Mobile: 
+886 975 865 105 
The Investigator should not wait to receive additional information to document fully the 
event before notification of a SAE, though additional information may be requested. 
Where applicable, information from relevant laboratory results, hospital case records, and 
autopsy reports should be obtained. 
The sponsor and/or the sponsor’s assigned safety representative will promptly notify all 
relevant Investigators and the regulatory authorities of findings that could adversely affect 
the safety of patients, impact on the conduct of the study or alter the IEC/institutional 
review board (IRB) approval/favorable opinion of the study. In addition, the sponsor’s 
assigned safety representative, on behalf of the sponsor, will expedite the reporting to all 
concerned Investigators, to the IECs/IRBs, where required, and to the regulatory 
authorities of all adverse reactions that are serious, unexpected, and considered related to 
the study medication (See Section 7.1.1.1). 
Details of the procedures to be followed if a pregnancy occurs are provided in 
Section 5.3.5. 
7.1.1.3 Unexpected Adverse Reactions 
Unexpected Adverse Reaction Definition 
An unexpected adverse reaction is any untoward and unintended response that is related 
to the administration of the study drug at any dose that is not consistent with the applicable 
product information (e.g., Investigator’s Brochure for an unauthorized investigational 
medicinal product or summary of product characteristics for an authorized product). 
All suspected (i.e., related to the medication), unexpected serious adverse reactions 
(SUSARs) will be the subject of expedited reporting. The sponsor and/or the sponsor’s 
assigned safety representative shall ensure that all relevant information about a SUSAR 
that is fatal or life-threatening is reported to the relevant competent authorities and 
IEC/IRB within 7 days after knowledge by the sponsor of such a case and that relevant 
follow-up information is communicated within an additional 8 days. All other SUSARs 
will be reported to the relevant competent authorities and IEC/IRB within 15 days after 
knowledge by the sponsor of such a case. All Investigators should follow up SUSARs 
until the event is resolved or until, in the opinion of the Investigator, the event is stabilized 
or determined to be chronic. Post study SUSARs that occur after the patient has completed 
the clinical study must be reported by the Investigator to the sponsor. 


 
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7.1.1.4 Clinical Laboratory Evaluation 
The clinical laboratory tests specified below will be performed with the timing detailed 
in Table 1 (Safety lead-in) and Table 2 (Part 1 and Part 2). All clinical laboratory samples 
will be processed and evaluated by the site’s local laboratory. Analysis of biomarkers will 
be performed by a central laboratory. 
During the study, all out of range (abnormal) laboratory values must be evaluated and 
commented on by the Investigator for clinical significance. The clinical laboratory 
samples to be evaluated are presented in Table 13. 
Table 13: 
Clinical Laboratory Parameters 
Safety Clinical Laboratory Parameters (Using Local Laboratory) 
Hematology 
 
Hemoglobin, hematocrit, red blood cell count, white blood cell, 
platelet count, white blood cell subset count (neutrophils, 
eosinophils, basophils, lymphocytes, and monocytes), mean 
corpuscular volume, mean corpuscular hemoglobin, mean cell 
hemoglobin concentration 
Clinical Chemistry 
[fasted]  
 
Albumin, total protein, blood glucose, sodium, potassium, blood 
urea nitrogen, creatinine, AST, ALT, alkaline phosphatase, gamma 
glutamyl transferase, total bilirubin, direct bilirubin, triglyceride, 
total cholesterol, lactate dehydrogenase, calcium, and uric acid 
Liver Function Test 
AST, ALT, alkaline phosphatase, gamma glutamyl transferase, total 
bilirubin, direct bilirubin 
Coagulation 
 
Prothrombin time/International Normalized Ratio, activated partial 
thromboplastin time 
Urinalysis  
 
Specific gravity, pH, protein, leucocytes, red blood cells, Nitrite, 
ketones, urobilinogen and bilirubin. Microscopy will be performed 
when necessary. 
Pregnancy Screen 
 
Females of childbearing potential will be screened for pregnancy. 
The screening pregnancy test will be by blood sample to detect the 
presence of β-HCG (collected as part of biochemistry sample).  
Serum or urine pregnancy tests are acceptable at subsequent visits 
at the Investigator’s discretion. 
Viral Serology  
 
Hepatitis B surface antigen and Hepatitis B deoxyribonucleic acid 
viral load if Hepatitis B surface antigen returns positive, Hepatitis C 
virus antibody and human immunodeficiency virus antibody.  
Tumor Markers – For Part 1 and Part 2 of the study only (Using Local Laboratory) 
Tumor 
Markers 
 
CEA, CA19.9 
Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, β-HCG = beta human chorionic 
gonadotropin CA19.9 = cancer antigen 19.9, CEA = carcinoembryonic antigen. 
Additional and repeat testing may be performed at the discretion of the Investigator. 


 
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All laboratory reports must be reviewed, signed, and dated by the Investigator.  
Any clinical laboratory test result considered by the Investigator to be clinically 
significant should be considered an AE. Significant abnormal values that are drug-related 
occurring during the study will be followed until repeat test results return to normal, 
stabilize, or are no longer clinically significant. 
7.1.1.5 Vital Signs 
Blood pressure (systolic and diastolic), heart rate, respiratory rate, and temperature will 
be measured manually or automatically in a standardized manner in a sitting position after 
the patient has rested comfortably for 5 minutes.  
7.1.1.6 Physical Examination 
Physical examinations will be performed by a physician and/or delegated qualified 
personnel according to local legislation if applicable and will include the examination of 
the following: general appearance, eyes, ears, nose, throat, chest/respiratory, 
heart/cardiovascular, 
gastrointestinal/liver, 
musculoskeletal/extremities, 
dermatological/skin, thyroid/neck, lymph nodes, and neurological/psychiatric systems. 
The patients’ height will be checked at screening visit, and body weight will be checked 
at the start of each cycle during the study.  
All clinically significant treatment-emergent findings that were not present at baseline or 
described in the medical history will be recorded as AEs. 
7.1.1.7 12-lead ECG 
A 12-lead ECG will be taken in the supine position, after the patient has been lying down 
for at least 10 minutes in a quiet environment. There should be no significant external 
stimulation (TV, radio, interaction with other subjects). Detailed instructions, including 
the allowable window of time to complete the ECGs, will be described in the ECG manual. 
The ECG machines supplied by the Core ECG Laboratory will be used for all ECG 
collection, and the digital files of each tracing will be archived. 
General Principles (Safety Lead-in and Part 1) 
The following parameters will be assessed: heart rate, PR, QRS, QT, QTcF (Fridericia’s 
formula), and QTcB (Bazzett’s formula). While the Investigator (or a qualified observer 
at the investigational site) will interpret the ECG using one of the following categories: 
within normal limits, abnormal but not clinically significant, or abnormal and clinically 
significant, the final ECG assessments (including interval measurements) will be made 
by the Core ECG laboratory.  
Baseline will be defined as the mean of the triplicate QT/QTc readings performed pre-
dose on Day 1. On Day 1, pre-dose is defined as 2 sets of triplicate ECGs taken 45 minutes 


 
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and 5 minutes prior to dosing. The ECG values from these 2 sets of ECGs will be averaged 
to create the baseline values. Similarly, for all other time points, for each ECG parameter, 
each patient’s mean will be calculated from the triplicate readings and the mean value 
will be used. 
 
Safety Lead-In 
Any analysis of ECG data from the Safety lead-in is considered exploratory.  
On Cycle 1 Day 1 and Day 8, the following parameter will be determined at the following 
time points:  
- 
Absolute heart rate, pulse rate, QRS, QT/QTc values at 45 minutes pre-dose, 
5 minutes pre-dose, 1, 2, 3, 4, 5, 6 8.5, and 12 hours post dose  
- 
Heart rate, pulse rate, QRS, QT/QTc change from baseline at 1, 2, 3, 4, 5, 6, 
8.5, and 12 hours post-dose 
 
QTc will be reported for both Fridericia and Bazett’s corrections. 
Triplicate ECGs will also be collected 3 hours post-dose Day 22 (Cycle 2 Day 1) and 
onwards every cycle while the subject remains in the study. 
Due to the non-randomized, open label design of the Safety lead-in, data from the Safety 
lead-in will be presented separately from data from Part 1 of the study. Furthermore, 
ECG/QT outputs will be made available to the DSMB for consideration when 
determining whether the study should progress to Part 1. 
Part 1 
The Part 1 electrocardiographic Core ECG Laboratory assessments constitute the study’s 
primary assessment of ECG/QTc. The time-based electrocardiographic analysis will be 
performed in Part 1 at baseline, Cycle 1 Day 1, Cycle 1 Day 8, and safety follow-up visit.  
On Cycle 1 Day 1 and Day 8, the following parameters will be determined at the following 
time points: 
- 
Absolute heart rate, pulse rate, QRS, and QT/QTc values at 45 minutes pre-
dose, 5 minutes pre-dose, 1.5, 3, 5, 8 hours post-dose. 
- 
Heart rate, pulse rate, QRS, and QT/QTc change from baseline at 1.5, 3, 5, 
and 8 hours post-dose. 
Twenty-eight days after the last dose of study drug (after full drug washout), a set of 
triplicate ECGs will be collected 3 hours after a light snack. 
In addition, triplicate safety ECGs will be collected 3 hours post-dose on Day 22 (Cycle 
2 Day 1), Day 64 (Cycle 4 Day 1) and every 2 cycles while the subject remains in the 


 
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study. This data will not be analyzed by the Core ECG Laboratory but will be assessed 
by the investigator. 
 
Part 2 
ECGs will be collected in Part 2 of the study as part of standard safety monitoring at 
screening, baseline (before a snack), and 3 hours post-dose on Day 22 (Cycle 2 Day 1), 
Day 64 (Cycle 4 Day 1) and every 2 cycles while the subject remains in the study.  These 
data will not be analyzed by the Core ECG Laboratory but assessed by investigators. 
7.1.1.8 ECOG Performance Status 
The ECOG performance status will be recorded using the scale provided in 
Appendix 14.2. 
7.1.2 Efficacy Variables  
7.1.2.1 Tumor Evaluation 
Tumor evaluations will be performed to evaluate the efficacy of treatment according to 
RECIST version 1.1 (Appendix 14.1). Tumor response will be assessed by means of 
computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and every 
6 weeks  from Cycle 1 Day 1 during the treatment period until EOT (Safety Lead-in) or 
disease progression (Part 1 and Part 2).  
Baseline CT/MRI of the chest, abdomen, and pelvis images must be performed within 21 
days prior to Cycle 1 Day 1, brain and/or bone lesions may be scanned if applicable. 
For Part 1 and 2 of the study, radiological assessments should continue until the patient 
experiences disease progression, regardless of whether the patient discontinues 
randomized therapy or starts a subsequent anti-cancer therapy. 
All tumor responses should be assessed at every assessment time point using the same 
methods (contrast-enhanced CT or MRI) used to characterize the lesions identified at 
baseline. Apart from the radiological reading at the site to determine disease progression, 
for Part 1 of the study all images will be assessed by a blinded ICR, and the ICR must 
confirm the presence of measurable disease in order to confirm a patient’s eligibility at 
baseline screening prior to a patient being randomized into the study. Central radiological 
reading will not interfere with Investigator’s judgment on disease progression.  
For Part 1 only, the co-primary endpoints of ORR and PFS and other secondary endpoints 
(except OS) will be based on the blinded ICR of all radiological data. Objective response 
rate as determined by the site review will also be reported as a secondary endpoint. 


 
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7.1.2.2 Cancer Antigen Evaluation 
For Part 1 and 2 of the study, blood will be collected for analysis of CA19.9 and 
carcinoembryonic antigen (CEA) at screening and every 6 weeks  (±5 days) from Cycle 
1 Day 1. Collection of blood for these analysis stops at EOT.  
Archival paraffin-embedded tumor tissues will be collected during screening for future 
analysis if the patient has provided the optional tumor tissue consent.  
Biopsies will be performed during screening for those patients who did not have enough 
archival tumor tissue if the patient has provided the optional tumor tissue consent. 
7.1.3 Pharmacokinetic Variables  
7.1.3.1 Determination of Drug Concentrations in Biological Samples 
Safety Lead-in Part 
Analysis of plasma samples for the determination of varlitinib (and any relevant 
circulating metabolites), capecitabine and 5-FU will be performed in Safety Lead-in Part. 
Other relevant circulating metabolites of capecitabine (5’-DFCR, 5’-DFUR and FBAL) 
will only be determined if this is considered necessary based on the pharmacokinetic and 
safety findings of the study. Relevant circulating metabolites of varlitinib will not be 
determined at this Safety Lead-in because they remain unknown. 
Part 1 and 2 
Analysis of plasma samples for the determination of varlitinib and its relevant circulating 
metabolites will be performed in Part 1 and Part 2. Capecitabine and 5-FU will not be 
determined in Parts 1 and Part 2 of the study if no relevant pharmacokinetic interactions 
between varlitinib and capecitabine/5-FU are observed in the Safety Lead-in part of the 
study. 
7.1.3.2 Pharmacokinetic Sampling 
Safety Lead-in 
Blood samples for PK analysis of varlitinib (and any relevant circulating metabolites),  
capecitabine, and 5-FU (active capecitabine metabolite) will be collected at the following 
time points in the Safety lead-in part only: 
• Cycle 1 Day 1: 5 minutes pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours post-
dose  
• Cycle 1 Day 8: 20 minutes pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours post-
dose 


 
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• Cycle 1 Day 14: 5 minutes pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours post-
dose 
Patients must withhold taking the morning dose of varlitinib and capecitabine until 
pre-dose PK sample is collected. The actual sample date and time of all PK samples must 
be recorded in the CRF. 
In addition, unscheduled PK collected 7 days following dose reduction of varlitinib at any 
cycle of treatment: up to 5 minutes pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8.5, 10, and 12 hours 
post-dose if required.  
 
Part 1 and Part 2 
In Part 1 and Part 2, PK samples will be obtained for the PK evaluation of varlitinib (and 
any relevant circulating metabolites). PK samples will be collected at the following time 
points: 
 
Part 1 (All patients) 
• Cycle 1 Day 1: 5 minutes pre-dose, 1.5, 3, 5, and 8 hours post-dose 
• Cycle 1 Day 8: 20 minutes pre-dose, 1.5, 3, 5, and 8 hours post-dose 
• End of study after full drug washout:  28 days after last dose at the patient’s safety 
follow-up visit 
 
Part 2 (Sparse Sampling) 
• Cycle 1 Day 1: 5 minutes pre-dose, 1-3 hours post-dose, 3-5 hours post-dose, and 
5-8 hours post-dose 
• Cycle 2 Day 1: 20 minutes pre-dose, 1-3 hours post-dose, 3-5 hours post-dose, 
and 5-8 hours post-dose 
 
In order to maintain the double-blind design of the study, blood samples will be collected 
from all subjects in Part 1 for plasma measurements of varlitinib and its potential relevant 
circulating metabolites. For the sparse PK sampling in Part 2, the double-blind design 
will also be maintained and blood samples will be collected for a selected number of 
subjects, without limiting the sampling to the varlitinib subjects only. 
All PK data will be analyzed according to treatment received. Deviations that have the 
potential to significantly affect the PK will be reviewed. The population, and decisions 
regarding which profiles are usable, will be defined by the Study Team Physician, 
Pharmacokineticist, and Statistician prior to any analyses being performed. 
In addition, unscheduled PK samples will be collected at least 7 days following dose 
reduction of varlitinib at any cycle of treatment: up to 5 minutes pre-dose and 3-5 hours 
post-dose. 


 
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Handling and processing details, including the allowable window of time to complete the 
PK blood draws, will be outlined in the Laboratory Manual. 
 
7.1.3.3 Pharmacokinetic Analysis 
Safety Lead-in 
The PK of varlitinib (and any relevant circulating metabolites), capecitabine and 5-FU 
(active metabolite) will be determined at selected time points. The following PK 
parameters will be evaluated where possible: 
Cycle 1 Day 1, Day 8, and Day 14: 
• maximum plasma concentration (Cmax) 
• time to Cmax(tmax) 
• plasma concentration before next dose (Ctrough) 
• area under the plasma concentration-time curve from 0 to 12 hours (AUC0-τ) 
• half-life (t1/2) 
• apparent clearance (Cl/F) 
• apparent volume of distribution (Vz/F) 
• apparent volume of distribution at the steady state (Vss/F) 
where τ = 12 hours (dosing interval) 
 
Cycle 1 Day 8 
• accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 8/Day 1) 
• accumulation ratio of Cmax RacCmax (Day 8/Day 1) 
Cycle 1 Day 14 
• accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 14/Day 1) 
• accumulation ratio of Cmax RacCmax (Day 14/Day 1) 
Summary statistics for varlitinib (and any relevant circulating metabolites) will be 
tabulated for the PK parameters by study day. The mean, standard deviation (SD), 
coefficient of variation (%CV), geometric mean, %CV geometric mean, median, 
minimum, and maximum will be presented for relevant PK parameters indicated above. 
Median, minimum, and maximum will be presented for Tmax. Profile plots of patient data 
will be presented on both linear and log scale. 
Pharmacokinetic parameters in plasma will be derived using standard non-compartmental 
methods with WinNonlin® Professional Version 5.2 or higher (Pharsight Corp., Mountain 
View, California, US) or SAS® Version 9.2 or higher (SAS Institute, Inc., Cary, North 
Carolina, US). Actual elapsed time from dosing will be used for final plasma PK 
parameter calculations. 
 
 


 
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Part 1 and Part 2 
Using appropriate PK software depending on whether comprehensive PK sampling or 
sparse PK sampling is obtained in practice, the PK data will be used to derive PK 
parameters such as, but not restricted to, Cmax, AUC, and t1/2 for varlitinib. 
Population PK evaluation in Part 1 and Part 2 of the study will be performed by nonlinear 
mixed effects model (NLME) using NONMEM program version VII (Globomax LLC, 
Ellicott City, MD, US) and SAS® Version 9.2 or higher (SAS Institute, Inc., Cary, North 
Carolina, US). Actual elapsed time from dosing will be used for final plasma PK 
parameter calculations. 
The final PK analyses will be the responsibility of the CRO. Pharmacokinetic analyses 
will be conducted according to CRO Standard Operating Procedures (SOPs) for PK 
analyses unless otherwise specified. The actual PK sampling times will be used in the PK 
calculations.  
The varlitinib concentration-time profiles, along with the derived PK variables, will be 
listed for each patient per dose and dosing day and summarized appropriately. Population 
PK models may be used to derive the PK parameters and will aim to characterize 
variability in the population by investigating the influence of covariates such as weight, 
age, smoking status and/or concomitant medications. In addition, if the data are suitable, 
potential relationships between plasma varlitinib and efficacy or safety endpoints will be 
investigated using a graphical approach and/or appropriate PK/PD modeling techniques. 
7.1.4 Biomarker Variables 
Blood samples for retrospective analysis of potential biomarkers will be collected at 
baseline and post week 6 treatment tumor assessment. 
For Part 1 and 2 of the study, optional donation of archival/fresh tumor biopsy samples 
can be provided (a separate consent to be signed). The minimum archival tumor tissue to 
be collected is 19 unstained slides of 5 microns. The collected tumor tissue and blood 
samples, as well as, matched normal tissue will be stored for further analyses for mRNA, 
proteins and genes. 
Refer to the Bioanalytical Laboratory Manual for detailed sample collection, labeling, 
storage, and shipment instructions for further analysis of tumor tissues. 
Exploratory variables will be evaluated in Part 1 only. 
Possible relationships between protein and phospho-protein expression levels and clinical 
outcome, and gene mutational status and clinical outcome will be explored using proteins 
and genes including, but not limited to: 
• Via IHC: 
- epidermal growth factor receptor (EGFR), pEGFR  


 
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- HER2, pHER2  
- HER3, pHER3 
- HER4, pHER4 
• Via PCR/Sequencing 
- Mutational status of genes, such as KRAS, NRAS, BRAF, EGFR, HER2 and other 
genetic factors that may affect response to therapy. 
The protein and gene studies will be conducted using archival material (and if not 
available, biopsy tissue samples). 
If a relationship is found between biomarker(s) expression and clinical outcomes in Part 1 
of the study, the biomarker(s) could be prospectively evaluated in Part 2 of the study. 
7.2 
Data Safety Monitoring Board and Independent Central Review 
A DSMB consisting of independent experts will be convened on 2 specified occasions to 
review the accumulating safety date for the study. 
The first DSMB meeting will occur after the first 12 patients in the Safety lead-in have 
completed the 21 days of follow-up, and before initiating Part 1 of the study.  
The second DSMB meeting will occur at a selected time point during Part 1 of the study 
according to DSMB Charter. 
The composition, specific responsibilities, scope and plan of the DSMB will be defined 
in the DSMB Charter.  
Radiological images collected in the Part 1 of the study will be assessed by ICR. Details 
of the ICR will be defined in the ICR Charter. 
 
 


 
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8 
STATISTICAL ANALYSIS 
8.1 
General Statistical Considerations 
All statistical analyses will be performed by the designated CRO, using SAS®, version 
9.3 or higher.  
Unless specified otherwise, data from the Safety lead-in, Part 1, and Part 2 of the study 
will be presented separately in the tables, figures, and listings. Patients whose data 
contributed to the Part 1 analysis will not be included in the Part 2 analysis. 
For Parts 1 and 2, for the purpose reporting all FAS and EFR--based endpoints (efficacy 
data and demography), Study Day 1 is defined as the date of randomization to study 
treatment. For visits (or events) that occur on or after randomization, study day is 
defined as (date of visit [event] -date of randomization + 1). For visits (or events) that 
occur prior to randomization, study day is defined as (date of visit [event] -date of 
randomization). There is no Study Day 0. 
 
For Parts 1 and 2, for the purpose of reporting all safety set based endpoints (e.g. AEs, 
laboratory findings, vital signs, ECG, exposure and dose intensity) and PK set-based 
endpoints, Dose Day 1 is defined as the date of first dose of study treatment (referred to 
in the protocol as Cycle 1 Day 1). For visits (or events) that occur on or after first dose, 
dose day is defined as (date of visit [event] -date of first dose of study treatment + 1). 
For visits (or events) that occur prior to first dose, dose day is defined as (date of visit 
[event] -date of first dose of study treatment). There is no Dose Day 0. For listings (such 
as for AEs) that include the derivation of “days since last dose,” this is defined as (event 
date -date of last dose). Events that occur on the same day as the last dose of study drug 
will therefore be described as occurring zero days from the last dose of study drug. 
 
The database for the Safety lead-in will be locked at the time of the Part 1 analyses. 
However, interim data from the Safety lead-in will be made available to the DSMB prior 
to the final DCO to enable the DSMB to review the emerging safety and tolerability data 
and to advise whether the study can proceed to Part 1. Details of the data to be provided 
to the DSMB will be provided in the DSMB charter. 
The primary analysis of Part 1 will be the later of 3 months after last Patient in or when 
70% of the patients (84 patients) have experienced a PFS event. The primary analysis of 
all primary and secondary endpoints, with the exception of OS, will be performed at this 
time.  
For Part 1, a preliminary analysis of OS will be performed at the time of the primary 
analysis of ORR and PFS. It is anticipated that the OS data at this time will be immature, 
thus a second analysis of OS is planned for when approximately 95 patients (approx. 79%) 
have an OS event. The second analysis of OS will be considered the primary analysis of 
OS for the trial. 


 
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The DCO for Part 2 will be when 247 OS events have occurred. All secondary endpoints, 
including ORR, PFS and DoR, will be reported at the time of the primary analysis of OS. 
8.2 
Sample Size Derivation 
8.2.1 Safety Lead-in Sample Size 
The Safety lead-in is not formally powered to assess any statistical hypotheses. In this 
part, 12 to 20 eligible patients (6-12 from US, 6-8 from ROW) will be enrolled to receive 
varlitinib plus capecitabine. 
Patients in this group will be replaced if study medication compliance is < 85% in the 
first 14 days. 
8.2.2 Part 1 Sample Size 
Part 1 is designed with co-primary endpoints ORR and PFS. In order to maintain an 
overall, 1-sided 10% type I error rate for Part 1, a Hochberg procedure15 will be used, 
such that the study will be deemed to have met its primary objective if either endpoint is 
significant at the 1-sided 5% level or if both endpoints are significant at the 1-sided 
10% significance level. 
One hundred and twenty patients provide approximately 80% power to detect a true 
difference of 17% in response rate, based on a 1-sided 5% significance level and assuming 
10% response rate for the placebo group and a 27% response rate for varlitinib. To ensure 
the adequate data are available to evaluate the effects of varlitinib on both co-primary 
endpoints, the DCO for the primary analysis will be the later of 3 months after last patient 
in and when 70% of patients (84 patients) have experienced a PFS event. Based on a 
minimum of 84 PFS events at the time of the primary analysis, the study would have a 
minimum of 80% power to detect a true HR of 0.58 for PFS based on a 1-sided 5% 
significance level. 
Furthermore, if the primary objective of the study is met, the following approach to type 
I error control will be applied in order to support marketing approval: 
• The overall type I error rate for marketing approval will be controlled at the two-
sided 5% level, using a Hochberg procedure 
• Using this approach, statistical significance may be claimed if either ORR or PFS 
is significant at the two-sided 2.5% significance level or if both ORR and PFS are 
significant at the two-sided 5% significance level.  
One hundred and twenty patients provide approximately 80% power to detect a true 
difference of 20% in response rate, based on a 2-sided 5% significance level and assuming 
10% response rate for the placebo group and a 30% response rate for varlitinib. 


 
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A total of 84 PFS events provides 80% power to detect a true HR of 0.54, based on a two-
sided 5% significance level. Assuming a 8-month non-linear recruitment period, a 2.67 
month median PFS for capecitabine alone, and a true HR of 0.54, it is estimated that the 
DCO for the primary analysis of Part 1 will occur approximately 12 months after the first 
patient is randomized into the study (first patient in). 
Overall Survival is a secondary endpoint in Part 1. A preliminary analysis of OS will be 
performed at the time of the primary analysis of ORR and PFS. It is anticipated that the 
OS data at this time will be immature, thus a second analysis of OS is planned for when 
approximately 95 patients (approx. 79%) have an OS event. Due to the number of OS 
events expected at the time of the first analysis, this initial analysis of OS will be 
considered exploratory only. Although a p-value may be presented, for the purpose of 
marketing authorization, no claims of statistical significance will be based on the initial 
analysis. For the purpose of type I error control across the two analyses of OS in support 
of marketing authorization, the OS update analysis will be considered the primary 
analysis of OS for Part 1 of the study, and statistical significance will be assessed at the 
two-sided 5% significance level. 
8.2.3 Part 2 Sample Size 
Part 2 is designed with a primary endpoint of OS. Approximately 350 patients will be 
randomized into Part 2 to obtain 247 death events (70% maturity). If the true OS HR for 
the comparison of varlitinib+capecitabine versus placebo+capecitabine is 0.7 (likely to 
correspond to a 43% prolongation of OS), the study has 80% power to demonstrate a 
statistically significant difference for OS, assuming a 2-sided 5% significance level. 
Assuming non-linear recruitment of 350 patients over a twenty-four month period, and 
median OS times of 8.6 months and 6 months for the varlitinib and placebo arms 
respectively, it is estimated that 247 OS events will occur approximately 31 months after 
the first patient in for Part 2. 
All secondary endpoints will be analyzed at the time of the primary analysis of OS. 
8.3 
Analysis Populations 
8.3.1 Safety Population 
For each part of the study, the safety population includes all patients in that part of the 
study who received at least 1 dose of randomized therapy (or study medication in the 
Safety lead-in) and will be the primary analysis set for the assessment of safety and 
tolerability in the study.  
For the purpose of data summaries, patients will be included in the safety population 
according to the treatment arm and dose level initially received, regardless of any 
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8.3.2 Full Analysis Set 
For each part of the study, the full analysis set is based on the intention-to-treat principle 
and includes all randomized patients (or treated patients for the Safety lead-in) analyzed 
in accordance with the intended treatment arm, regardless of the treatment actually 
received.  
With the exception of Part 1, Tumor Size which is not considered a key secondary 
endpoint (See Section 8.4.6 and 8.5.2.1), for all study parts, the primary analysis of all 
primary and key secondary efficacy endpoints, will be based on the full analysis set (FAS). 
8.3.3 Evaluable for Response Set (Part 1 only) 
The EFR set is defined as a subset of the FAS and includes patients with measurable 
disease at baseline, as determined by ICR assessments of radiological data based on the 
RECIST criteria, version 1.1. For Part 1 only, a sensitivity analysis of ORR and DCR will 
be performed in the evaluable for response (EFR) set to investigate the impact of patients 
without measurable disease on the primary endpoint. Since measurability is an inclusion 
criteria, all patients in Parts 1 should have measurable disease at baseline. Thus, if no 
patients were randomised in error, results in the EFR set will not be presented.  
Since tumor size is an endpoint based on patients’ tumor measurements, it can only be 
defined for the subset of the FAS with measurable disease at baseline. Thus the EFR set 
will be the primary analysis set used for the assessment of tumor size for Part 1 (See 
Section 8.4.6). 
8.3.4 Per Protocol Analysis Population 
The per protocol (PP) analysis population is defined for Part 1. Efficacy is not the focus 
of the Safety lead-in and Part 2 will be assessed on an intention-to-treat basis only. Thus 
PP analyses are not required for the Safety lead-in and Part 2 of the study. 
The PP analysis population will include all randomized patients according to the 
treatment actually received, and excluding any patients with major deviations. Major 
deviations that would lead to exclusion from the PP analysis population include:  
• Patients who did not have the intended disease (failure of inclusion criteria 2) 
• Subjects who did not have the intended indication, i.e. were not second line 
patients (failure of inclusion criteria 3) 
• Patients who did not received any randomized therapy  
• Patients with baseline radiological scan performed before the start of 
protocol-specified interval prior to randomization 
• Patients who did not have measurable disease at baseline as determined by ICR 
• Subjects who have not received at least six doses of gemcitabine in a first line 
setting (i.e. failure of inclusion criteria 4, protocol version 4.0 onwards) 


 
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• Subjects with multiple (≥2) peritoneal metastases at baseline or ascites at baseline 
which cannot be attributed to a non-malignant cause (i.e. failure of exclusion 
criteria 3, protocol version 4.0 onwards), based on ICR review 
• Subjects with baseline albumin <3 g/dL (failure of the albumin component of 
inclusion criteria 9c)     
In addition to the programmatic determination of the major deviations, monitoring notes 
or summaries will be reviewed to determine any important post entry deviations that are 
not identifiable via programming, and to check that those identified via programming are 
correctly classified. The final classification will be made blinded, prior to database lock.  
Patients who received the incorrect randomized therapy should be included in the PP 
analysis set according to the therapy actually received. Similarly, subjects who were mis-
stratified at randomization will be included in the PP analyses according to the correct 
stratification levels, regardless of the levels declared at randomization. 
Failure of an inclusion/exclusion criterion will not automatically be classified as a major 
deviation. 
The PP analysis population will be the used to assess the sensitivity of the Part 1 ORR, 
DoR, DCR, PFS and OS analyses to major deviations. 
8.3.5 PK Analysis Set 
The PK population contains all patients who have been dosed with varlitinib and provided 
at least one usable PK profile. All PK data will be analyzed according to treatment 
received. 
For the Safety lead-in, this population will comprise all data patients who receive study 
treatment as per protocol (300 mg BID) and did not violate or deviate from the protocol 
and planned dosing regimen (300 mg) in ways that would significantly affect the PK 
analyses (for example skipping doses, or taking reduced doses or taking concomitant 
medications with the potential to cause a drug-drug interaction) during the PK sampling 
period. Patients who did deviate from the planned dosing regimen may still provide some 
data for inclusion in the PK set if they have at least one usable PK profile. The population, 
and decisions regarding which profiles are usable, will be defined by the Study Team 
Physician, Pharmacokineticist, and Statistician prior to any analyses being performed. 
PK sampling of all patients is planned for Part 1 the study, while sparse PK sampling is 
planned for Part 2. The number of patients who will provide samples in Part 2 for the PK 
analysis will be defined based on the results of Part 1 of the study. All PK data will be 
analyzed according to the treatment received. Deviations that have the potential to 
significantly affect the PK will be reviewed, and patients, or specific PK profiles for a 
patient, may be excluded from the PK set if appropriate. The population, and decisions 
regarding which profiles are usable, will be defined by the Study Team Physician, 
Pharmacokineticist, and Statistician. Since the PK sample analysis may be performed 
following the primary analyses of efficacy, the CRO responsible for the analysis of the 


 
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PK samples will mask the subject ID prior to any discussion regarding deviations, in order 
to ensure that decisions regarding which samples to include/exclude from the PK set are 
made blinded to clinical outcomes. 
Population PK models may be used to derive the PK parameters. 
Table 14: 
Summary of Outcome Variables and Analysis Populations 
Outcome Variable 
Analysis Population 
(Sensitivity Analysis Population) 
Efficacy Data (Primary and key secondary 
endpoints) 
 
ORR, DCR 
FAS (EFR and PP Part 1 only) 
 
PFS, OS, DoR 
 
FAS (PP Part 1 only) 
Part 1 ORR based on site data 
FAS 
Part 1 Tumor size1 
EFR 
Demography 
FAS 
 
 
Pharmacokinetics 
 
PK 
PK 
 
 
Safety 
 
Exposure 
Safety 
Adverse Events 
Safety 
Laboratory measurements 
Safety 
Vital Signs 
Safety 
ECG 
Safety 
Physical Examination 
Safety 
1 Tumor size, by definition, is only defined in patients with measurable disease.  For marketing authorization, no 
statistical claims will be based on tumor size (See Section 8.5.2.1). 
 
Abbreviations: DCR = disease control rate, DoR = duration of response, ECG = electrocardiogram, 
EFR = evaluable for response, FAS = full analysis set, ORR = objective response rate, OS = overall 
survival. PFS = progression- free survival, PK = pharmacokinetics, PP = per protocol 
8.4 
Study Endpoints 
8.4.1 Objective Response Rate 
Objective response rate is a co-primary endpoint in Part 1 and a secondary endpoint in 
Part 2, and the Safety lead-in cohort. 
Objective response rate is defined as the number (%) of patients with at least one visit 
response of CR or PR. Data obtained up until progression, or last evaluable assessment 


 
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in the absence of progression, will be included in the assessment of ORR. This will be 
irrespective of whether or not patients discontinued treatment or received a subsequent 
therapy prior to progression. For all study parts, ORR will be evaluated based on the FAS 
set (Section 8.3.2).  
8.4.2 Progression-Free Survival 
Progression-free survival is a co-primary endpoint in Part 1, and is a secondary endpoint 
in Part 2. 
Progression-free survival is defined as the time from randomization (or start of treatment 
in 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 patient withdraws from 
randomized therapy (study treatment in the Safety lead-in) or receives another antitumor 
therapy prior to disease progression. Patients who have not experienced disease 
progression or died at the time of analysis will be censored at the time of the latest date 
of assessment from their last evaluable RECIST assessment. However, if the patient 
progresses or dies after 2 or more missed visits, the patient will be censored at the time 
of the latest evaluable RECIST version 1.1 assessment. 
The PFS time will always be derived based on the scan/assessment dates rather than visit 
dates and the following rules will be applied: 
• Date of disease progression will be determined based on the earliest of the dates of 
the component that triggered the disease progression, i.e., if both the target lesions 
and the non-target lesions indicate disease progression but were scanned on different 
days, the earlier of the 2 dates would be applied. 
• When censoring a patient for PFS, the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment. 
For Part 1, the co-primary endpoint, PFS, will be derived programmatically using data 
from the ICR. To support sensitivity analyses, PFS will also be derived programmatically 
using the site assessments of the Part 1 radiological data. 
For Part 2 and the Safety lead-in, PFS will be derived programmatically using the site 
radiological data.  
Further details will be provided in the SAP. 
8.4.3 Overall Survival 
Overall survival is a secondary endpoint in Part 1, and the primary endpoint in Part 2 of 
the study. 


 
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Overall survival is defined as the time from the date of randomization until death due to 
any cause. Any patient not known to have died at the time of DCO will be censored based 
on the last recorded date on which the patient was known to be alive.  
Note, survival calls may be made in the week following the date of DCO for the analysis, 
and if patients are confirmed to be alive or if the death date is after the DCO these patients 
will be censored at the date of DCO.  
8.4.4 Duration of Response 
Duration of response is secondary endpoint in all study parts. 
The DoR is defined as the time from the date of first documented response until the date 
of documented disease progression or death in the absence of disease progression. The 
end of response should coincide with the date of disease progression or death from any 
cause used for the PFS endpoint. For Part 1, DoR will be calculated using the ICR data, 
and for Part 2 and the Safety lead-in, DoR will be calculated from the site radiological 
data. 
The time of the initial response will be defined as the latest of the dates contributing 
towards the first visit response of PR or CR. For example, if the patient was first noted to 
have a PR at week 6, and the target and non-target lesions were assessed on different dates 
at this visit, then the later of the 2 assessment dates would be used as the start date of the 
response. 
If a patient does not progress following a response, then their DoR will use the PFS 
censoring time. 
Duration of response will not be defined for those patients who do not have documented 
response. 
8.4.5 Disease Control Rate 
Disease control rate is a secondary endpoint in all study parts. 
Disease control rate is defined as the number (%) of patients with at least one visit 
response of CR or PR, or with stable disease for a minimum of twelve weeks (± 5 days) 
from randomization (Parts 1 and 2) or starting treatment (Safety lead-in only). Data 
obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of DCR. This will be irrespective of whether or not 
patients discontinued treatment or received a subsequent therapy prior to progression. For 
all study parts, DCR will be evaluated based on the FAS set (Section 8.3.2). For Part 1, 
DCR will be calculated based on the ICR data. For Part 2 and the Safety lead-in, DCR 
will be calculated from the site radiological data.  


 
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8.4.6 Tumor Size 
The percentage change from baseline in tumor size at Week 12 (%ΔTSWk12) is a 
secondary endpoint for Part 1, and will be used to help evaluate the exploratory objectives 
of investigating the possible role of baseline biomarker levels as predictors of clinical 
benefit. It will be evaluated using the Evaluable for Response set (EFR) (Section 8.3.3). 
Tumor size is not considered to be a key secondary endpoint; for the purpose of marketing 
authorization, no statistical claims will be made based on tumor size.   
The %ΔTSWk12 will be defined as follows: 
• Baseline tumor size: defined as the sum of longest diameters of target lesions at 
baseline 
• Week 12 TS: defined as the sum of longest diameters of target lesions at week 12 
 
%∆𝑇𝑇𝑇𝑇𝑊𝑊𝑊𝑊12 = 100 × 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊 12 𝑇𝑇𝑇𝑇−𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑇𝑇𝑇𝑇
𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑇𝑇𝑇𝑇
 
An increase from baseline of 20% will be imputed for any patients who die by any cause, 
or withdraw from the study due to symptomatic disease progression prior to Week 12. 
Any patients who withdraw from the study due to radiological disease progression prior 
to Week 12 will be included in the analysis, and will be assigned a percentage change 
from baseline of 20%, or the value that was observed at the time of disease progression 
(whichever is larger). Full details of data imputation rules will be provided in the SAP. 
8.4.7 Safety Endpoints 
Patient safety will be evaluated based on physical examination, vital signs (blood pressure 
[systolic and diastolic], heart rate, respiratory rate, and body temperature), ECG 
parameters, clinical laboratory tests (hematology, clinical chemistry, coagulation, and 
urinalysis), and AEs. 
8.4.8 ECG Parameters 
The ECG parameters of interest are QT including QTcF and QTcB, HR (heart or 
ventricular rate), PR, and QRS intervals. 
8.5 
Methods of Statistical Analysis 
8.5.1 Primary Endpoints 
8.5.1.1 Part 1 - Objective Response Rate 
The primary analysis will test for the superiority of varlitinib-containing treatment arm 
relative to the placebo-containing arm. 
Objective response rate will be analyzed using a stratified exact binomial test 16,17 that 
extends Fisher’s Exact test to more than one stratum. The analysis will be stratified by 


 
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primary tumor location (gallbladder/NonGB). The 2-sided p-value will be obtained by 
doubling the 1-sided p-value.  
The conditional maximum likelihood estimate of the odds ratio will be presented together 
with its exact 2-sided 95% confidence limit, which excludes one if and only if the 
stratified exact binomial test is significant at a 2-sided 5% level. Corresponding 
significance levels and confidence intervals (CIs) will be calculated using tests performed 
at a 1-sided 10% level. The 1-sided p-value will also be presented. 
To test for heterogeneity across strata, the exact test of Zelen18 will be performed testing 
whether the treatment effect differs between the 2 strata included in the primary analysis. 
For Part 1 only, subgroup analyses will be conducted comparing ORR between treatments 
in the subgroups of the FAS set defined by the stratification factors declared at 
randomization, Region (US/Non-US) and primary tumor location (GB/Non-GB), plus the 
following factors: 
• Gender (male vs female) 
• Race (Asian/Caucasian/Other) 
• Baseline ECOG status (0/1) 
• Extent of disease (locally advanced/metastatic) 
• Age (<60/>=60) 
• Baseline HER2 expression (positive defined as +++ or above by IHC, otherwise 
negative)  
• Any HER positivity (positive defined as + or higher by IHC for HER1, HER2, 
HER3, HER4, or otherwise negative) 
Note: The sub-group analyses based on IHC biomarker data will be reported outside of 
the main CSR. 
 
Other baseline variables may also be included if there is clinical justification or an 
imbalance is observed across the treatment arms. For each sub-group, the odds ratio and 
corresponding 80% CI will be presented on a forest plot including the odds ratio and 80% 
CI from the overall population. Additionally, if the primary analysis of ORR is significant 
at the 2-sided 5% level in the overall population, the forest plot will be replicated using 
95% CI. 
No adjustment to the significance level for testing will be made since all these analyses 
will be considered supportive of the primary analysis of ORR. 
8.5.1.2 Part 1 – Progression-Free Survival 
In Part 1, the primary analysis will test for the superiority of varlitinib-containing 
treatment arm relative to the placebo-containing arm, as assessed by PFS. The DCO for 
the primary analysis of PFS will be the later of 12 weeks after last patient in and 84th 
documented PFS event. 


 
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Progression-free survival will be analyzed using a stratified log-rank test using the 
Breslow method to handle ties.19 The stratification factor is primary tumor location 
(GB/Non-GB). The results will be presented in terms of the HR (with a HR <1 favoring 
the varlitinib-containing arm) and associated 2-sided 95 CI and 2-sided p-value. For Part 
1 only, the 80% CI and 1-sided p-value will also be presented. The HR and its CI can be 
estimated from the log-rank as follows20,21,22: 
 
Kaplan-Meier (KM) plots of PFS, with tick marks to identify censored observations, will 
be presented by treatment group. Summaries of the number and percentage of patients 
experiencing a PFS event, and the type of event (RECIST 1.1 or death) will be provided 
along with median PFS for each treatment. 
The assumption of proportionality will be assessed. 
For Part 1 only, subgroup analyses will be conducted comparing PFS between treatments 
in the subgroups of the full analysis set defined by the stratification factors declared at 
randomization, Region (US/Non-US) and primary tumor location (GB/Non-GB), plus the 
following factors: 
• Gender (male vs female) 
• Race (Asian/Caucasian/Other) 
• Baseline ECOG status (0/1) 
• Extent of disease (locally advanced/metastatic) 
• Age (<60/>=60) 
• Baseline HER2 expression (positive defined as +++ or above by IHC, otherwise 
negative)  
• Any HER positivity (positive defined as + or higher by IHC for HER1, HER2, 
HER3, HER4, or otherwise negative) 
Note: The sub-group analyses based on IHC biomarker data will be reported outside of 
the main CSR. 
 
Other baseline variables may also be assessed if there is clinical justification. For each 
subgroup, the HRs (varlitinib: placebo) and associated CIs will be calculated from a log 
rank test within each individual subgroup. These will be presented on a forest plot 
including the HR and 80% CI from the overall population. The purpose of the subgroup 


 
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analyses is to assess the consistency of treatment effect across expected and possible 
prognostic factors. 
No adjustment to the significance level for testing will be made since all these analyses 
will be considered supportive of the primary analysis of PFS. 
For both Part 1 and Part 2, Cox proportional hazards modeling will be employed to assess 
the effect of covariates on the HR estimate. Before embarking on more detailed modeling, 
an initial model will be constructed, containing treatment and the stratification factor 
primary tumor location alone, to ensure any output from the Cox modeling is likely to be 
consistent with the results of the stratified log-rank test. 
The presence of quantitative interactions will be assessed formally by means of an overall 
global interaction test. This will be performed in the full analysis set by comparing the fit 
of a Cox proportional hazards model including treatment, all covariates, and all covariate-
by treatment interaction terms, with one that excludes the interaction terms and will be 
assessed at the 2-sided 10% significance level. If the fit of the model is not significantly 
improved then it will be concluded that overall the treatment effect is consistent across 
the subgroups. 
If the global interaction test is found to be statistically significant, an attempt to determine 
the cause and type of interaction will be made. Stepwise backwards selection will be 
performed on the saturated model, whereby (using a 10% 2-sided level throughout) the 
least significant interaction terms are removed one-by-one and any newly significant 
interactions re-included until a final model is reached where all included interactions are 
significant and all excluded interactions are non-significant. Throughout this process all 
main effects will be included in the model regardless of whether the corresponding 
interaction term is still present. This approach will identify the factors that independently 
alter the treatment effect and prevent identification of multiple correlated interactions. 
Any quantitative interactions identified using this procedure will then be tested to rule out 
any qualitative interaction using the approach of Gail and Simon.23 
The primary analysis of PFS will be based on the programmatically derived PFS based 
on an ICR of radiological data and using all scans regardless of whether they were 
scheduled or not. To assess the potential impact of informative censoring on the primary 
analysis of PFS, a sensitivity analysis using PFS derived from site assessments will be 
performed. Full details of the planned sensitivity analyses will be provided in the SAP. 
The primary analysis will be performed on the FAS.  
Patients whose data contributed to the Part 1 analysis will not contribute to the Part 2 
analysis. 


 
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8.5.1.3 Part 2 – Overall Survival 
In Part 2, the primary analysis will test for the superiority of varlitinib-containing 
treatment arm relative to the placebo-containing arm, as assessed by OS.  
The primary analysis of OS will be performed after the 247th documented OS event. OS 
will be analyzed using the methods described in Section 8.5.1.2 for PFS. 
Patients whose data contributed to the Part 1 analysis will not contribute to the Part 2 
analysis. 
8.5.2 Secondary Endpoints 
8.5.2.1 
Efficacy Endpoints 
Progression-free survival based on site assessments 
In all study parts, PFS based on the site review of radiological data is a secondary endpoint. 
PFS based on site data will be analyzed using the same model and methodology as 
described in Section 8.5.1.2 for PFS based on ICR. 
Further details will be provided in the SAP. 
Duration of Response 
The DoR will not be formally analyzed. Duration of response will be listed and presented 
using KM curves. Descriptive statistics, based on the KM estimates, will be presented by 
treatment group. 
Overall Survival (Part 1) 
In Part 1, OS will be analyzed using the methods described in Section 8.5.1.2 for PFS. 
OS will be analyzed twice. The initial analysis of OS will be performed at the time of the 
primary analysis of ORR and PFS. Due to the number of OS events expected at the time 
of the first analysis, this initial analysis of OS will be considered exploratory only. 
Although a p-value may be presented, for the purpose of marketing authorization, no 
claims of statistical significance will be based on the initial analysis. A further OS update 
analysis is performed when approximately 95 OS events have occurred.  To support 
marketing authorization, for the purpose of type I error control across the two analyses of 
OS, the OS update analysis will be considered the primary analysis of OS in the study. 
Disease Control Rate 
Disease control rate will be analyzed using a stratified exact binomial test16 that extends 
Fisher’s Exact test to more than 1 stratum. The analysis will be stratified by primary tumor 
location (GB/Non-GB). The 2-sided p-value will be obtained by doubling the 1-sided p-
value.  


 
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The conditional maximum likelihood estimate of the odds ratio will be presented together 
with its exact 2-sided 95% confidence limit, which excludes one if and only if the 
stratified exact binomial test is significant a 2-sided 5% level. Corresponding significance 
levels and CIs will be calculated using tests performed at a 1-sided 10% level. The 1-
sided p-value will also be presented. 
To test for heterogeneity across strata, the exact test of Zelen will be performed testing 
whether the treatment effect differs between the 2 strata included in the primary analysis. 
Tumor Size 
The percentage change from baseline in tumor size at Week 12 (%ΔTSWk12) is a 
secondary endpoint for Part 1. Tumor size is not considered to be a key secondary 
endpoint; for the purpose of marketing authorization no statistical claims will be based 
on tumor size. 
Tumor size will be presented graphically using waterfall plots for each treatment arm, 
presenting each patient’s Week 12 percentage change in tumor size as a separate bar with 
the bars ordered from the largest increase to the largest decrease. Reference lines at the 
+20% and –30% change in tumor size levels will be added to the plots, which correspond 
with the definitions of disease progression and PR, respectively. In these waterfall plots, 
the patients whose Week 12 percentage change in tumor size is based on an imputation 
will be clearly shown. The 2 treatment arms will be plotted separately, but presented side-
by-side on a single page. 
Waterfall plots of the best percentage change from baseline will also be presented, as 
described above for the Week 12 percentage change from baseline.  
Tumor size will also be used to help evaluate the exploratory objectives of exploring 
relationships between baseline biomarker levels and clinical outcomes (e.g., baseline 
HER2 status and clinical outcome, and other HER family statuses and clinical outcomes).  
In line with the exploratory objectives of the study, the statistical analysis of tumor size 
in Part 1 will be also be used to help evaluate the role of HER family expression levels 
status as a predictor of benefit to varlitinib. If a relationship is found between biomarker(s) 
expression and clinical outcomes in Part 1 of the study, the biomarker(s) could be 
prospectively evaluated in Part 2 of the study. 
These analyses will be exploratory, and may be driven by the data observed, and 
specifically the prevalence of the HER family sub-groups of interest. However, the 
analysis principles to be followed are outlined below. 
1. ASLAN will create and document a list of the key biomarkers of interest, based 
upon the biological plausibility of predictivity for clinical outcomes. The list will 
be limited to those biomarkers, or combinations of biomarkers for which a 
scientific hypothesis exists. These will represent the biomarkers that will be used 


 
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to assess the listed exploratory objectives, providing that there is sufficient 
prevalence of that biomarker in the study population. 
2. For each biomarker of interest, each patient’s baseline biomarker status will be 
independently evaluated blinded to study treatment and clinical outcome 
3. For each biomarker sub-group, or combination of biomarkers identified on the 
prospectively defined list (step 1), if at least 15 patients in the EFR population are 
determined to be expressors, then the role of that biomarker as a predictor of 
clinical outcome (tumor size) will be evaluated as described below. 
For each biomarker of interest (or combination of biomarkers), the absolute values at 
baseline and Week 12, along with the percentage change from baseline target lesion size 
at Week 12 will be summarized using descriptive statistics and presented by treatment 
arm and baseline biomarker status.  
The number and percentage of patients in each treatment arm whose Week 12 data is 
imputed will also be presented (split by biomarker sub-group). 
The effect of varlitinib on percentage change in tumor size will be estimated from an 
analysis of covariance (ANCOVA) model fitting the Week 12 percentage change from 
baseline as the response variable, and treatment, primary tumor location (GB/Non-GB), 
baseline biomarker status (positive or negative), the interaction treatment x baseline 
biomarker status, baseline tumor size, and the time from the baseline scan to 
randomization as covariates. 
The significance of the interaction term will be evaluated at the 1-sided 10% level to 
determine whether there is evidence of a treatment by biomarker interaction. Regardless 
of the significance of the interaction term, the number of patients, unadjusted mean and 
adjusted least squares (LS) means for each treatment arm will be presented for each level 
of biomarker status factor (positive or negative), together with the difference in adjusted 
LS means between treatment arms for each level of the biomarker status factor and 
corresponding p-value and 80% and 95% CIs for the difference.  
If the interaction term is not significant at the 1-sided 10% level, the number of patients, 
unadjusted mean and adjusted least squares (LS) means for each treatment arm will also 
be presented together with the difference in adjusted LS means between treatment arms 
and corresponding p-value and 80% and 95% CIs for the difference.  
If, at blind review, it is judged that the data do not adequately follow a normal distribution 
assumption, then a log-transformation may be used. Specifically in place of percent 
change in Week 12 value the ANCOVA model will use loge (Week 12/baseline). In this 
situation, the ratio of the geometric LS means corresponding CI and p-value will be 
presented. 
As a sensitivity analysis, a nonparametric analysis will be performed. The Hodges 
Lehmann estimate of the median difference and corresponding 80% CI will be derived 
and presented. The median percentage change and range will be presented for each 


 
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treatment arm, together with the number of patients and percentage of patients in each 
treatment arm whose Week 12 data is imputed in the nonparametric analysis.  
For all biomarkers of interest (step 1), waterfall plots color-coded by baseline biomarker 
status will be produced. 
Note, due to the differing timeframes of the endpoints being available for analysis, the 
above statistical analyses of the biomarker data will be reported outside of the study 
CSR. 
 
8.5.2.2 Safety Data Analysis 
For each study part, safety data will be assessed for the safety population.  
All AE data will be listed along with information regarding initial study dose, dose at 
onset, onset time (study day), duration, severity, and relationship to study treatment.  
Treatment emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of treatment. The following summaries will be produced, by treatment group and 
overall for all TEAEs:  
• An overview table of the incidence of TEAEs, grade 3+ TEAEs, SAEs, TEAEs 
leading to treatment discontinuation and TEAEs leading to death, by treatment arm 
and overall. For each summary category, the results will be shown overall (regardless 
of causality), and for the incidence of causally-related TEAEs. For example, the 
overall incidence of TEAEs will be presented, as well as the incidence of TEAEs 
related to randomized therapy, the incidence of TEAEs related to capecitabine and the 
incidence TEAEs related to both randomized therapy and capecitabine. 
• Summary of TEAEs by system organ class and preferred term: Both the number and 
percentage of patients in each category (patient-level summary) and the number of 
episodes (episode-level summary). This summary table will be repeated for TEAEs 
attributed as causally related to randomized therapy (varlitinib or placebo)  
• Summary of TEAEs occurring in at least 10% of patients, sorted in descending order 
of frequency (i.e., most frequent event shown first). The order of frequency will be 
determined by the most frequent preferred term across both arms, regardless of CTC 
grade. For each event, the results will be presented for all CTC grades, and also split 
by grade 1-2, and grade 3+. 
• Summary of TEAEs attributed as causally related to randomized therapy occurring 
in at least 10% of patients, sorted in descending order of frequency (i.e., most frequent 
event shown first). The order of frequency will be determined by the most frequent 
preferred term across both arms. For each event, the results will be presented for all 
CTC grades, and also split by grade 1-2, and grade 3+. 


 
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• Summary of CTC grade 3 and above TEAEs sorted in descending order of frequency 
(i.e., most frequent event shown first). The order of frequency will be determined by 
the most frequent preferred term across both arms. 
• A summary or CTC grade 3 and above TEAEs attributed as causally related to 
randomized therapy sorted in descending order of frequency (i.e., most frequent event 
shown first). The order of frequency will be determined by the most frequent preferred 
term across both arms. 
• Summary of SAEs by preferred term  
• Summary of SAEs attributed as causally related to randomized therapy, sorted by 
preferred term 
• Categorical Analysis of ECG findings (See Section 8.5.2.3)  
 
Additionally, the following will be listed:  
• AEs with outcome of death along with the date of onset, dosing day, dose at onset, 
treatment status at onset (pre-treatment, ongoing or post-treatment) and Investigator’s 
assessment of severity and relationship to study drug  
• All SAEs along with the date of onset, dosing day, dose at onset, treatment status at 
onset (pre-treatment, ongoing or post-treatment), date of resolution (if AE is resolved), 
Investigator’s assessment of severity and relationship to study drug 
• AEs leading to discontinuation of study medication, listed along with the date of onset, 
dosing day, dose at onset, treatment status at onset (pre-treatment, ongoing or post-
treatment) and Investigator’s assessment of severity and relationship to study drug  
If an AE is reported more than once during the study period, the greatest severity and the 
worst-case attribution will be presented in summary tables. Any AEs commencing 
> 28 days after discontinuation of study treatment will not be included in the tabulations 
of AE data.  
All clinical laboratory data (clinical chemistry, hematology and urinalysis data), vital 
signs and ECG data will be listed. Data tabulations and graphical displays of clinical 
laboratory data (clinical chemistry, hematology, and urinalysis data), vital signs and ECG 
data, will include all assessments from screening up to (and including) 28 days after 
discontinuation of study treatment.  In addition, all data measured on a continuous scale 
(except respiration rate and pulse) will be displayed graphically as described below:  
Safety lead-in:  


 
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• Patient profile plots of laboratory data over time, including reference lines at the LLN 
and ULN. Any dose reductions will be indicated on the plots using a change in line-
type. 
• Patient profile plots of the change from baseline over time, including a horizontal 
reference line at zero. Any dose reductions will be indicated on the plots using a 
change in line-type. 
Parts 1 and 2:  
• Box plots of laboratory data over time, by treatment, including reference lines at the 
LLN and ULN  
• Box plots of the change from baseline over time, by treatment, including a horizontal 
reference line at zero  
To enable assessment of the potential for drug-induced liver injury, for all study parts the 
following outputs will be produced: 
• A scatter plot of maximum on-treatment ALT versus maximum on-treatment total 
bilirubin (x-axis), both expressed as multiples of the upper limit of normal (ULN), 
including reference lines at 3×ULN for ALT, and 2×ULN for total bilirubin. For each 
patient, the maximum ALT and maximum total bilirubin may occur at different visits  
• A scatter plot of maximum on-treatment AST versus maximum on-treatment total 
bilirubin (x-axis), both expressed as multiples of the upper limit of normal (ULN), 
including reference lines at 3 × ULN for AST, and 2 × ULN for total bilirubin. For 
each patient, the maximum AST and maximum total bilirubin may occur at different 
visits. 
In the event that the scatter plots of ALT or AST against bilirubin identify any potential 
Hy’s law cases (patients with either both ALT > 3 × ULN and total bilirubin > 2 × ULN, 
or both AST > 3 × ULN and total bilirubin > 2 × ULN), profile plots over time will be 
produced for these patient’s liver function tests (ALT, AST, ALP, and total bilirubin), 
expressed in multiples of the ULN, showing all 4 LFT parameters on the same plot. 
Physical examination data will be listed.  
To further assess the tolerability of varlitinib, exposure and dose intensity will be listed 
and summarized by treatment arm. Further details will be provided in the study SAP.  
8.5.2.3 ECG/QT Analysis 
For the Safety lead-in, exploratory descriptive and categorical analyses, including change 
from baseline will be performed to investigate the impact of varlitinib and capecitabine 
treatments on the changes from baseline in ECG parameters. 
 


 
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For Part 1 of the study, a multi-step approach will be applied to evaluate the effect of 
capecitabine alone and varlitinib in combination with capecitabine on the ECG 
parameters at different time points post-dose. The comparisons will be done between 
ECG values at each time point post-dose and baseline and between treatment arms with 
and without varlitinib for each time point individually. The evaluation of the 
cardiodynamic effects of capecitabine and varlitinib may be explored using exposure-
response modeling if there appears to be a meaningful effect of varlitinib when added to 
capecitabine on the ECG parameters including QTcF.  This will be further described in 
the SAP. 
 
Central Tendency Analysis will be performed for both the Safety lead-in and Part 1 of the 
study, the change from baseline in QTcF, PR, QRS, QTcB, and heart rate, will be 
summarized by time point (and treatment arm for Part 1) using descriptive statistics (n, 
mean, SD, min, median, max, 90% confidence intervals).  
 
For both the Safety lead-in and Part 1, the following categorical data will be summarised: 
- 
The proportion of patients obtaining treatment-emergent absolute QTcF values > 450 
msec and ≤ 480 msec; > 480 msec and ≤ 500 msec; and > 500 msec 
- 
The proportion of patients obtaining a QTcF increase from baseline values ≥ 30 and 
<60 msec and ≥ 60 msec 
- 
The proportion of patients obtaining a QRS change from baseline > 25% resulting in 
QRS > 120 msec 
- 
The proportion of patients obtaining a PR interval change from baseline >25% 
reaching a value >220 msec 
- 
The proportion of patients obtaining a > 25% decrease from baseline in heart rate 
resulting in a heart rate < 50 beats per minute (bpm) or a > 25% increase from baseline 
in heart rate resulting in a heart rate > 100 bpm 
For Part 1 of the study, the above categorical data summaries will be presented by 
treatment arm. 
Following this, categorical analyses will be applied to the categorical data summaries 
above.  
Additionally, T-wave morphology will be analyzed. The morphological T-wave analysis 
will be focusing on the change from baseline, i.e., treatment emergent changes. 
Following Part 1 of the study, a formal statistical analysis will be performed to assess the 
potential impact of varlitinib and capecitabine on changes in the ECG parameters.  
The statistical stepwise approach will be used to separate the cardiodynamic effect of 
varlitinib from normal circadian fluctuation in the ECG values and from the effect of 
capecitabine: 
 
1. ANOVA mixed effects comparison of the absolute values of ECG 
parameters at each time point vs baseline using treatment as a fixed 
effect in order to evaluate the contribution of circadian fluctuation and 


 
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to determine how treatment differences contribute to the changes. The 
ECG parameter values will be log-transformed and the resulting output 
will include the geometric mean ratio for test vs reference with the 
corresponding confidence interval and p-value. Interaction term, time 
point x treatment, will be also evaluated if the data allow. 
 
2. ANOVA comparison of the absolute values of ECG parameters as well 
as change from baseline (ΔECG) between treatments for each post-
dose time point assessed separately in order to separate the varlitinib 
effect from that of capecitabine. The ECG parameter values will be 
log-transformed and the resulting output will include the geometric 
mean ratio for test vs reference with the corresponding confidence 
interval and p-value.  ΔECG will be tested as untransformed and log-
transformed parameters to avoid bias from discarding 0 ΔECG values 
from the comparisons. 
 
3. Exposure-Response Analysis:  Linear mixed effect model between 
ΔQTcF and time matched concentrations of varlitinib and other 
potential metabolites if measured and as appropriate.  Other ECG 
variable may be similarly analyzed and other models used, if 
appropriate. 
3.1 ΔQTcF will be calculated as the difference between each time 
point value and the average baseline value for each arm with the 
combination varlitinib/capecitabine treatment.  
 
3.2 ΔΔQTcF will be calculated for each patient in the combination 
arm individually as the difference between the ΔQTcF value for 
the arm with combination varlitinib/capecitabine treatment and 
the average value of all patients in the capecitabine alone arm 
matching time point. Other ECG parameters may also be used in 
the analysis including QTcB, heart rate, etc to provide supporting 
information. 
 
3.3 Base linear mixed effect model will include patients as a random 
effect. 
 
3.4 The total dose of capecitabine may be included as a fixed effect 
in the model to account for differences in total doses received by 
subjects with different body surface area. 
 
4. Linear mixed effect model between ΔQTcF parameters and time matched 
concentrations of capecitabine and 5-FU (metabolite of capecitabine) and 
other potential metabolites if measured and as appropriate 


 
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4.1. ΔQTcF will be calculated for all patients in both arms as the 
difference between each time point value and the average baseline 
value. 
4.2. Base linear mixed effect model will include patients as a random 
effect and treatment (capecitabine alone or in combination with 
varlitinib) as a fixed effect; the total capecitabine dose may also be 
used as a fixed effect. 
5. Different covariates may be included in the complex models in addition 
to the base model as fixed effects such as time point in order to ensure 
the model feasibility and to evaluate covariates influential to ECG 
parameters. 
The results of the fitted models will be presented using statistical parameters such as the 
geometric mean ratios and corresponding confidence intervals (for ANOVA) and 
estimates of the slope, and associated confidence interval for the linear mixed effect 
models. 
 
In addition, the following graphic exploration of the exposure-ECG relationship may be 
performed: 
• 
Residual plots to predict results 
• 
Double Y plots with time on the X axis and time matched values of PK 
concentrations for varlitinib and capecitabine on the Y1 axis, ΔECG on the Y2 axis to 
determine the possibility of hysteresis between drug concentration and cardiodynamic 
effects 
• 
Regression/scatter plots with time matched concentrations of varlitinib and 
capecitabine on the X axis and ΔECG on the Y axis 
• 
Regression/scatter plots with varlitinib or capecitabine non-compartmental PK 
parameters of Cmax, Ctrough,  AUCtau and others on the X axis and maximum ΔECG on the 
Y axis 
• 
Forest plots for different categories in ECG changes vs mean (SD) non-
compartmental PK parameters for varlitinib or capecitabine on the X axis 
 
9 
 QUALITY ASSURANCE AND QUALITY CONTROL 
9.1 
Audit and Inspection 
Study centers and study documentation may be patient to Quality Assurance audit during 
the course of the study by the sponsor or its nominated representative. In addition, 
inspections may be conducted by regulatory authorities at their discretion. 
9.2 
Monitoring 
Data for each patient will be recorded on a CRF. Data collection must be completed for 
each patient who signs an ICF and is administered study drug. 


 
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In accordance with GCP and ICH guidelines, the study monitor will carry out source 
document verification at regular intervals to ensure that the data collected in the CRF are 
accurate and reliable.  
The Investigator must permit the monitor, the IEC/IRB, the sponsor’s internal auditors, 
and representatives from regulatory authorities direct access to all study-related 
documents and pertinent hospital or medical records for confirmation of data contained 
within the CRFs.  
9.3 
Data Management and Coding 
The designated CRO will be responsible for activities associated with the data 
management of this study. This will include setting up a relevant database and data 
transfer mechanisms, along with appropriate validation of data and resolution of queries. 
Data generated within this clinical study will be handled according to the relevant 
standard operating procedures (SOPs) of the data management and biostatistics 
departments of sponsor or the designated CRO. 
Study centers will enter data directly into an EDC system by completing the CRF via a 
secure internet connection. Data entered into the eCRF must be verifiable against source 
documents at the study center. Data to be recorded directly on the eCRF will be identified 
and the eCRF will be considered the source document. Any changes to the data entered 
into the EDC system will be recorded in the audit trail and will be FDA CFR 21 Part 11 
compliant. 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) for 
concomitant diseases and AEs and WHO Drug for medications. 
Missing or inconsistent data will be queried in writing to the Investigator for clarification. 
Subsequent modifications to the database will be documented. 
 
 


 
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10 RECORDS AND SUPPLIES 
10.1 Drug Accountability 
On receipt of the study medication (varlitinib, placebo, and capecitabine), the Investigator 
(or deputy) will conduct an inventory check of the supplies and verify that study drug 
supplies are received intact and in the correct amounts as in the patient dosing diary, 
before completing a supplies receipt. The Investigator will retain a copy of this receipt at 
the study center and return the original receipt to the study monitor. The monitor may 
check the study supplies at each study center at any time during the study. 
It is the responsibility of the study monitor to ensure that the Investigator (or deputy) has 
correctly documented the amount of the study drug received, dispensed, and returned on 
the dispensing log that will be provided. A full drug accountability log will be maintained 
at the study center at all times. The study monitor will arrange collection of unused study 
drug returned by the patient. The study monitor will also perform an inventory of study 
drug at the close-out visit to the study center. All discrepancies must be accounted for and 
documented. 
10.2 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between 
the designated CRO and the sponsor. 
11 ETHICS 
11.1 Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written 
material given to the patients, and any other relevant study documentation will be 
submitted to the appropriate IEC/IRB. Written approval of the study and all relevant study 
information must be obtained before the study center can be initiated or the study drug is 
released to the Investigator. Any necessary extensions or renewals of IEC/IRB approval 
must be obtained for changes to the study such as amendments to the protocol, the ICF or 
other study documentation. The written approval of the IEC/IRB together with the 
approved ICF must be filed in the study files. 
The Investigator will report promptly to the IEC/IRB any new information that may 
adversely affect the safety of the patients or the conduct of the study. The Investigator 
will submit written summaries of the study status to the IEC/IRB as required. On 
completion of the study, the IEC/IRB will be notified that the study has ended. 
11.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the 
participating countries, according to local/national requirements, for review and approval 


 
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before the beginning of the study. On completion of the study, the regulatory authorities 
will be notified that the study has ended. 
11.3 Ethical Conduct of the Study 
The Investigators and all parties involved in this study should conduct the study in 
adherence to the ethical principles based on the Declaration of Helsinki, GCP, ICH 
guidelines, and the applicable national and local laws and regulatory requirements. 
Study ASLAN001-009 will be performed in compliance with the protocol, International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use Good Clinical Practice (ICH GCP) and local regulatory requirements. Aspects of the 
study concerned with the study medication will meet the requirements of Good 
Manufacturing Practice. 
11.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable 
regulatory requirements and must adhere to GCP.  
The Investigator is responsible for ensuring that no patient undergoes any study related 
examination or activity before that patient has given written informed consent to 
participate in the study. 
The Investigator or designated personnel will inform the patient of the objectives, 
methods, anticipated benefits and potential risks and inconveniences of the study. The 
patient should be given every opportunity to ask for clarification of any points s/he does 
not understand and, if necessary, ask for more information. At the end of the interview, 
the patient will be given ample time to consider the study. Patients will be required to 
sign and date the ICF. After signatures are obtained, the ICF will be kept and archived by 
the Investigator in the Investigator’s study file. A signed and dated copy of the patient 
ICF will be provided to the patient or their authorized representative. 
Patients who agree to provide an optional tumor tissue sample (Section 7.1.4) will need 
to give written informed consent, in addition to consenting in the main part of the study. 
It should be emphasized that the patient may refuse to enter the study or to withdraw from 
the study at any time, without consequences for their further care or penalty or loss of 
benefits to which the patient is otherwise entitled. Patients who refuse to give or who 
withdraw written informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the patient’s willingness to 
continue participation in the study, a new ICF will be approved by the IECs/IRBs (and 
regulatory authorities, if required). The study patients will be informed about this new 
information and re-consent will be obtained. 


 
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11.5 Patient Confidentiality 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IECs/IRBs approving this research, and the US FDA, as well as that of any other 
applicable agencies, will be granted direct access to the study patients’ original medical 
records for verification of clinical study procedures and/or data, without violating the 
confidentiality of the patients to the extent permitted by the law and regulations. In any 
presentations of the results of this study or in publications, the patients’ identity will 
remain confidential. 
All personal data collected and processed for the purposes of this study should be 
managed by the Investigator and his/her staff with adequate precautions to ensure 
confidentiality of those data, and in accordance with the Health Insurance Portability and 
Accountability Act), applicable to national and/or local laws and regulations on personal 
data protection. 
 
 
 


 
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12 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit 
evaluation of the study and quality of the data produced. After completion of the study 
(end of study defined as the date of the last visit of the last patient), all documents and 
data relating to the study, including digital ECGs, will be kept in an orderly manner by 
the Investigator in a secure study file. This file will be available for inspection by the 
sponsor or its representatives. Essential documents should be retained for 2 years after 
the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the study medication. It is the responsibility of 
the sponsor to inform the study center when these documents no longer need to be retained. 
The Investigator must contact the sponsor before destroying any study related 
documentation. In addition, all patient medical records and other source documentation 
will be kept for the maximum time permitted by the hospital, institution, or medical 
practice. 
The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the Investigator(s). Published data must not compromise the 
objectives of the study. Data from individual study centers in multicenter studies must 
not be published separately. 


 
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13 REFERENCES 
1. 
Valle J, Wasan H, Palmer DH, et al; ABC-02 Trial Investigators. Cisplatin plus 
Gemcitabine versus Gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 
8;362(14):1273-81. 
2. 
Ciombor KK, Goff LW. Advances in the management of biliary tract cancers. Clin 
Adv Hematol Oncol. 2013 Jan;11(1):28-34. 
3. 
Ghosn M, Kourie HR, El Rassy E, eEt al. Optimum chemotherapy for the 
management of advanced biliary tract cancer. World J Gastroenterol. 2015 Apr 
14;21(14):4121-5. 
4. 
Subbiah IM, Subbiah V, Tsimberidou AM, et al. Targeted therapy of advanced 
gallbladder cancer and cholangiocarcinoma with aggressive biology: eliciting early 
response signals from phase 1 trials. Oncotarget. 2013 Jan 27;4(1):153-62. 
5. 
Yang X, Wang W, Wang C, et al. Characterization of EGFR family gene aberrations 
in cholangiocarcinoma. Oncol Rep. 2014 Aug;32(2):700-8. 
6. 
Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. 
Biochimicaetbiophysicaacta.1994;1198(2-3):165-184. 
7. 
Klapper LN, Kirschbaum MH, Sela M, Yarden Y. Biochemical and clinical 
implications of the ErbB/HER signaling network of growth factor receptors. Adv 
ances in Ccancer Rresearch. 2000;77:25-79. 
8. 
Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related 
peptides and their receptors in human malignancies. Critical Rreviews in Ooncol 
ogy/Hhematology. 1995;19(3):183-232. 
9. 
Geynisman DM, Catenacci DV. Toward personalized treatment of advanced biliary 
tract cancers. Discov Med. 2012 Jul;14(74):41-57. 
10. Investigator’s Brochure Varlitinib (ASLAN001). Version 11, dated 11 Feb 2017. 
11. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-
positive advanced breast cancer. N Engl J Med. 2006;355(26):2733-2743. 
doi:10.1056/NEJMoa064320. 
12. XELODA® (capecitabine) prescribing information leaflet. 
13. Patt YZ, Hassan MM, Aguayo A, et al. Oral capecitabine for the treatment of 
hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 
2004;101(3):578-586. doi:10.1002/cncr.20368. 
14. FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers 
(accessed 
8 
th 
March 
2017): 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/dr
uginteractionslabeling/ucm093664.htm. 
15. Hochberg, Y. A Sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;75: 800-802. 
16. Mehta CR, Patel NR, Gray R. Computing an exact confidence interval for the 
common odds ratio in several contingency tables. Journal of the American 
Statistical Assoc.iation 1985;80:969 -973. 
17. Emerson JD. Combining estimates of the odds ratio: the state of the art. Statistical 
Methods in Medicadl Res.earch 1994;3:157-178. 
18. Zelen M. The analysis of several 2x2 contingency tables. Biometrika. 1971;58:129-
137. 


 
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19. Breslow, NE. Covariance aAnalysis of cCensored sSurvival dData. Biometrics. 
1974; 30:89-–99. 
20. Berry G, Kitchin RM, Mock PA. A comparison of two simple hazard ratio 
estimators based on the logrank test. Statistics in Med.icine 1921091; 10:749-755. 
21. Collett D. Modelling Survival Data in Medical Research. 2nd ed. Boca Raton (FL): 
Chapman & Hall/CRC; 2003. 
22. Sellke, T,. and Siegmund, D. Sequential analysis of the proportional hazards model. 
Biometrika 1983;70: 315-26.326, 1983 
23. Gail M, Simon R. Testing for qualitative interactions between treatment effects and 
patient subsets. Biometrics 1985;41:361-72. 
24. Lee SY, Kim HS, Choi YJ, et al. A prognostic index to identify patients with 
intrahepatic cholangiocarcinoma who could benefit from gemcitabine plus cisplatin. 
Am J Ther. 2016;23(6):e1449-e1455. 
25. Waghray A, Sobotka A, Marrero CR et al. Serum albumin predicts survival in 
patients with hilar cholangiocarcinoma. Gastroenterol Rep (Oxf). 2017;5(1):62-66. 
26. Garrison RN, Kaelin LD, Galloway RH, and Heuser LS. Malignant ascites. Clinical 
and experimental observations. Ann Surg. 1986;203(6):644-51. 
27. Saif MW, Siddiqui IA, and Sohail MA. Management of ascites due to 
gastrointestinal malignancy. Ann Saudi Med. 2009; 29(5): 369–377. 
28. Ayantunde AA and Parsons SL. Pattern and prognostic factors in patients with 
malignant ascites: a retrospective study. Ann Oncol. 2007;18(5):945-9.  
29. Weber SM, DeMatteo RP, Fong Y, et al. Staging laparoscopy in patients with 
extrahepatic biliary carcinoma. Analysis of 100 patients. Ann Surg. 
2002;235(3):392-9 
 


 
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14 APPENDICES 
14.1 RECIST Criteria 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
 


 
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14.2 ECOG Performance Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed > 50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
 
 


 
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14.3 Prohibited Concomitant Medication/Therapy 
Category 
Wash-out Period 
Examples of prohibited 
concomitant medication 
*included but not 
limited to: 
Strong CYP3A4 
Inhibitors 
21 days before first dose of 
study medication 
Clarithromycin,  
Darunavir,  
Indinavir,  
Itraconazole,  
Ketoconazole,  
Lopinavir,  
Nefazodone,  
Nelfinavir,  
Ritonavir,  
Saquinavir,  
Telithromycin, 
Tipranavir,  
Grapefruit juice 
Proton Pump Inhibitors 
Not Applicable 
Esomeprazole, 
Lansoprazole, 
Omeprazole, 
Pantoprazole, 
Rabeprazole 
H2 antagonist 
Can only be taken 3 hours 
after investigational product 
Cimetidine, 
Famotidine, 
Nizatidine, 
Ranitidine 
Any other investigational 
Product/Device 
14 days before first dose of 
study medication 
 
Anti-emetic drugs with 
QT prolongation effects 
Safety Lead-In (Cycle 1 Day 
1 to Cycle 2 Day 1) 
Part 1 (Cycle 1 Day 1 to 
Cycle 2 Day 1) 
Metoclopramide, 
Dolasetron, 
Granisetron, 
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14.4 Use with Caution: Drugs Associated with Torsade de Pointes and QT 
Prolongation 
 
Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Amiodarone 
Cordarone, 
Pacerone, 
Nexterone 
Antiarrhythmic 
Abnormal heart rhythm 
Anagrelide 
Agrylin, Xagrid 
Phosphodiester
ase 3 inhibitor 
Thrombocythemia 
Arsenic 
trioxide 
Trisenox 
Anticancer 
Cancer (leukemia) 
Astemizole 
(Removed from 
Market) 
Hismanal 
Antihistamine 
Allergic rhinitis 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bacterial infection 
Bepridil 
(Removed from 
Market) 
Vascor 
Antianginal 
Angina Pectoris (heart pain) 
Chloroquine 
Aralen 
Antimalarial 
Malaria 
Chlorpromazin
e 
Thorazine, 
Largactil, 
Megaphen 
Antipsychotic / 
Antiemetic 
Schizophrenia, nausea, many 
others 
Cilostazol 
Pletal 
Phosphodiester
ase 3 inhibitor 
Intermittent claudication 
Ciprofloxacin 
Cipro, Cipro-XR, 
Neofloxin 
Antibiotic 
Bacterial infection 
Cisapride 
(Removed from 
Market) 
Propulsid 
GI stimulant 
Increase GI motility 
Citalopram 
Celexa, Cipramil 
Antidepressant, 
SSRI 
Depression 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Bacterial infection 
Cocaine 
Cocaine 
Local 
anesthetic 
Anesthesia (topical) 
Disopyramide 
Norpace 
Antiarrhythmic 
Abnormal heart rhythm 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Abnormal heart rhythm 
Domperidone 
Motilium, 
Motillium, 
Motinorm Costi, 
Nomit 
Antinausea 
Nausea, vomiting 
Donepezil 
Aricept 
Cholinesterase 
inhibitor 
Dementia (Alzheimer's 
Disease) 
Dronedarone 
Multaq 
Antiarrhythmic 
Abnormal heart rhythm 


 
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Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Droperidol 
Inapsine, 
Droleptan, 
Dridol, Xomolix 
Antipsychotic / 
Antiemetic 
Anesthesia (adjunct), nausea 
Erythromycin 
E.E.S., 
Robimycin, 
EMycin, Erymax, 
Ery-Tab, Eryc 
Ranbaxy, Erypar, 
Eryped, 
Erythrocin 
Stearate Filmtab, 
Erythrocot, E-
Base, 
Erythroped, 
Ilosone, MY-E, 
Pediamycin, 
Zineryt, 
Abboticin, 
Abboticin-ES, 
Erycin, PCE 
Dispertab, 
Stiemycine, 
Acnasol, Tiloryth 
Antibiotic 
Bacterial infection, increase 
GI motility 
Escitalopram 
Cipralex, 
Lexapro, Nexito, 
Anxiset-E 
(India), Exodus 
(Brazil), Esto 
(Israel), Seroplex, 
Elicea, Lexamil, 
Lexam, Entact 
(Greece), Losita 
(Bangladesh), 
Reposil (Chile), 
Animaxen 
(Colombia), 
Esitalo 
(Australia), 
Lexamil (South 
Africa) 
 
 
 
Antidepressant, 
SSRI 
Depression (major), anxiety 
disorders 


 
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Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Flecainide 
Tambocor, 
Almarytm, 
Apocard, Ecrinal, 
Flécaine 
Antiarrhythmic 
Abnormal heart rhythm 
Fluconazole 
Diflucan, Trican 
Antifungal 
Fungal infection 
Gatifloxacin 
(Removed from 
Market) 
Tequin 
Antibiotic 
Bacterial infection 
Grepafloxacin 
(Removed from 
Market) 
Raxar 
Antibiotic 
Bacterial infection 
Halofantrine 
Halfan 
Antimalarial 
Malaria 
Haloperidol 
Haldol (US & 
UK), Aloperidin, 
Bioperidolo, 
Brotopon, Dozic, 
Duraperidol 
(Germany), 
Einalon S, 
Eukystol, 
Halosten, 
Keselan, Linton, 
Peluces, 
Serenace, 
Serenase, 
Sigaperidol 
Antipsychotic 
Schizophrenia, agitation 
Ibogaine (Only 
on Non US 
Market) 
None 
Psychedelic 
Narcotic addiction, unproven 
Ibutilide 
Corvert 
Antiarrhythmic 
Abnormal heart rhythm 
Levofloxacin 
Levaquin, 
Tavanic 
Antibiotic 
Bacterial infection 
Levomepromaz
ine (Only on 
Non US 
Market) 
Nosinan, 
Nozinan, 
Levoprome 
Antipsychotic 
Schizophrenia 
Levomethadyl 
acetate 
(Removed from 
Market) 
 
 
 
Orlaam 
Opioid agonist 
Narcotic dependence 


 
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Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Levosulpiride 
(Only on Non 
US Market) 
Lesuride, 
Levazeo, Enliva 
(with 
rabeprazole) 
Antipsychotic 
Schizophrenia 
Mesoridazine 
(Removed from 
Market) 
Serentil 
Antipsychotic 
Schizophrenia 
Methadone 
Dolophine, 
Symoron, 
Amidone, 
Methadose, 
Physeptone, 
Heptadon 
Opioid agonist 
Narcotic dependence, pain 
Moxifloxacin 
Avelox, Avalox, 
Avelon 
Antibiotic 
Bacterial infection 
Ondansetron 
Zofran, Anset, 
Ondemet, 
Zuplenz, 
Emetron, 
Ondavell, 
Emeset, 
Ondisolv, 
Setronax 
Antiemetic 
Nausea, vomiting 
Oxaliplatin 
Eloxatin 
Antineoplastic 
Agent 
Cancer 
Papaverine HCl 
(Intra-
coronary) 
none 
Vasodilator, 
Coronary 
Diagnostic adjunct 
Pentamidine 
Pentam 
Antifungal 
Fungal infection 
(Pneumocystis pneumonia) 
Pimozide 
Orap 
Antipsychotic 
Tourette's Disorder 
Probucol 
(Removed from 
Market) 
Lorelco 
Antilipemic 
Hypercholesterolemia 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 
Abnormal heart rhythm 
Propofol 
Diprivan, 
Propoven 
Anesthetic, 
general 
Anesthesia 
Quinidine 
Quinaglute, 
Duraquin, 
Quinact, 
Quinidex, Cin-
Quin, Quinora 
 
Antiarrhythmic 
Abnormal heart rhythm 


 
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Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Roxithromycin 
(Only on Non 
US Market) 
Rulide, Xthrocin, 
Roxl-150, Roxo, 
Surlid, Biaxsig, 
Roxar, 
Roximycinv, 
Roxomycin, 
Rulid, Tirabicin, 
Coroxin 
Antibiotic 
Bacterial infection 
Sevoflurane 
Ulane, Sojourn 
Anesthetic, 
general 
Anesthesia 
Sotalol 
Betapace, 
Sotalex, Sotacor 
Antiarrhythmic 
Abnormal heart rhythm 
Sparfloxacin 
(Removed from 
Market) 
Zagam 
Antibiotic 
Bacterial infection 
Sulpiride (Only 
on Non US 
Market) 
Dogmatil, 
Dolmatil, 
Eglonyl, 
Espiride, Modal, 
Sulpor 
Antipsychotic, 
atypical 
Schizophrenia 
Sultopride 
(Only on Non 
US Market) 
Barnetil, 
Barnotil, Topral 
Antipsychotic, 
atypical 
Schizophrenia 
Terfenadine 
(Removed from 
Market) 
Seldane 
Antihistamine 
Allergic rhinitis 
Terlipressin 
(Only on Non 
US Market) 
Teripress, 
Glypressin, 
Terlipin, 
Remestyp, Tresil, 
Teriss and others 
Vasoconstricto
r 
Septic shock 
Terodiline 
(Only on Non 
US Market) 
Micturin, Mictrol 
(not bethanechol) 
Muscle 
relaxant 
Bladder spasm 
Thioridazine 
Mellaril, 
Novoridazine, 
Thioril 
Antipsychotic 
Schizophrenia 
Vandetanib 
Caprelsa 
Anticancer 
Cancer (thyroid) 


 
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14.5 Drugs that Prolong the QTc and are Not Clearly Associated with Torsade de 
Pointes 
Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Alfuzosin 
Uroxatral 
Alpha1-blocker 
Benign prostatic hyperplasia 
Apomorphine 
Apokyn, Ixense, 
Spontane, Uprima 
Dopamine agonist 
Parkinson's disease 
Aripiprazole 
Abilify, Aripiprex 
Antipsychotic, 
atypical 
Schizophrenia, depression 
(adjunct) 
Artenimol+piperaq
uine 
Eurartesim 
Antimalarial 
Malaria 
Asenapine 
Saphris, Sycrest 
Antipsychotic, 
atypical 
Schizophrenia 
Atomoxetine 
Strattera 
Norepinephrine 
reuptake inhibitor 
ADHD 
Bedaquiline 
Sirturo 
Antibiotic 
Tuberculosis, Multi-drug 
resistant 
Buprenorphine 
Butrans,  Belbuca,   
Bunavail,  Buprenex,  
Suboxone,  Zubsolv 
Opioid receptor 
modulator 
Narcotic addiction and pain 
Clomipramine 
Anafranil 
Antidepressant, 
Tricyclic 
Depression 
Clozapine 
Clozaril, Fazaclo, 
Versacloz 
Antipsychotic, 
atypical 
Schizophrenia 
Cyamemazine 
(cyamepromazine) 
(Only on Non US 
Market) 
Tercian 
Antipsychotic 
Schizophrenia, sedation 
Delamanid (Only 
on Non US 
Market) 
Deltyba 
Antibiotic 
Tuberculosis, drug resistant 
Desipramine 
Pertofrane, 
Norpramine 
Antidepressant, 
Tricyclic 
Depression 
Dexmedetomidine 
Precedex,  Dexdor,  
Dexdomitor 
Sedative 
Sedation 
Dolasetron 
Anzemet 
Antiemetic 
Nausea, vomiting 
Efavirenz 
Sustiva and others 
Antiretroviral 
HIV 
Ezogabine 
(Retigabine) 
Potiga,  Trobalt 
Anticonvulsant 
Seizures, Partial 
Famotidine 
Pepcid, Fluxid, 
Quamatel 
H2-receptor 
antagonist 
Gastric hyperacidity, GERD 
Felbamate 
Felbatol 
Anticonvulsant 
Epilepsy 
Fingolimod 
Gilenya 
Sphingosine 
phospate receptor 
modulator 
 
Multiple Sclerosis 


 
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Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Flupentixol (Only 
on Non US 
Market) 
Depixol, Fluanxol 
Dopamine 2 and 
5HT2a antagonist 
Schizophrenia 
Foscarnet 
Foscavir 
Antiviral 
Viral infection (HIV/AIDS) 
Gemifloxacin 
Factive 
Antibiotic 
Bacterial infection 
Granisetron 
Kytril,  Sancuso, 
Granisol 
Antiemetic 
Nausea, vomiting 
Hydrocodone - ER 
Hysingla™ ER,  
Zohydro ER 
Analgesic 
Pain, severe 
Iloperidone 
Fanapt, Fanapta, 
Zomaril 
Antipsychotic, 
atypical 
Schizophrenia 
Imipramine 
(melipramine) 
Tofranil 
Antidepressant, 
Tricyclic 
Depression 
Isradipine 
Dynacirc 
Antihypertensive 
Hypertension 
Lithium 
Eskalith, Lithobid 
Antimania 
Bipolar disorder 
Melperone (Only 
on Non US 
Market) 
Bunil, Buronil, 
Eunerpan 
Antipsychotic, 
atypical 
Schizophrenia 
Mifepristone 
Korlym, Mifeprex 
Progesterone 
antagonist 
Pregnancy termination 
Mirabegron 
Myrbetriq 
Beta3 adrenergic 
antagonist 
Bladder spasm 
Mirtazapine 
Remeron 
Antidepressant, 
Tetracyclic 
Depression 
Moexipril/HCTZ 
Uniretic, Univasc 
Antihypertensive 
Hypertension 
Nicardipine 
Cardene 
Antihypertensive 
Hypertension 
Norfloxacin 
Noroxin, Ambigram 
Antibiotic 
Bacterial infection 
Nortriptyline 
Pamelor, Sensoval, 
Aventyl, Norpress, 
Allegron, Noritren, 
Nortrilen 
Antidepressant, 
Tricyclic 
Depression 
Ofloxacin 
Floxin 
Antibiotic 
Bacterial infection 
Paliperidone 
Invega, Xepilon 
Antipsychotic, 
atypical 
Schizophrenia 
Pasireotide 
Signifor 
Somatostatin 
analog 
Cushings Disease 
Perphenazine 
Trilafon,   
Etrafon/Triavil,  
Decentan 
Antipsychotic 
Schizophrenia 
Pilsicainide (Only 
on Non US 
Market) 
 
 
Sunrythm 
Anti-arrhythmic 
Arrhythmia 


 
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Generic Name 
Brand Names 
(Partial List) 
Drug Class 
Therapeutic Use 
Pipamperone (Only 
on Non US 
Market) 
Dipiperon (E.U),  
Propitan (Japan),  
Dipiperal,  Piperonil,  
Piperonyl 
Antipsychotic 
Schizophrenia 
Promethazine 
Phenergan 
Antipsychotic / 
Antiemetic 
Nausea, vomiting 
Prothipendyl (Only 
on Non US 
Market) 
Dominal,  
Largophren,  
Timoval,  Timovan,  
Tumovan 
Antipsychotic 
Schizophrenia 
Rilpivirine 
Edurant, Complera, 
Eviplera 
Antiviral 
Viral infection (HIV/AIDS) 
Risperidone 
Risperdal 
Antipsychotic, 
atypical 
Schizophrenia 
Saquinavir 
Invirase(combo) 
Antiviral 
Viral infection (HIV/AIDS) 
Sertindole (Only 
on Non US 
Market) 
Serdolect, Serlect 
Antipsychotic, 
atypical 
Schizophrenia, anxiety 
Solifenacin 
VESIcare 
Muscle relaxant 
Bladder spasm 
Tacrolimus 
Prograf, Prograf, 
Advagraf, Protopic 
Immunosuppressa
nt 
Immune suppression 
Telavancin 
Vibativ 
Antibiotic 
Bacterial infection 
Telithromycin 
Ketek 
Antibiotic 
Bacterial infection 
Tetrabenazine 
Nitoman, Xenazine 
Monoamine 
Transporter 
Inhibitor 
Chorea (Huntington's disease) 
Tiapride (Only on 
Non US Market) 
Tiapridal,  Italprid,  
Sereprile,  Tialaread,  
Tiaryl,  Tiaprim,  
Tiaprizal,  Sereprid,  
Tiapridex 
Selective D2, D3 
dopamine 
antagonist 
Alcoholism, withdrawal 
Tizanidine 
Zanaflex, Sirdalud 
Muscle relaxant 
Muscle spasticity 
Tolterodine 
Detrol, Detrusitol 
Muscle relaxant 
Bladder spasm 
Trimipramine 
Surmontil, 
Rhotrimine, Stangyl 
Antidepressant, 
Tricyclic 
Depression 
Tropisetron (Only 
on Non US 
Market) 
Navoban,  Setrovel 
Antiemetic 
Nausea, vomiting 
Venlafaxine 
Effexor, Efexor 
Antidepressant, 
SNRI 
Depression 
Zotepine (Only on 
Non US Market) 
Losizopilon,  
Lodopin,  Setous and 
Zoleptil 
Antipsychotic, 
atypical 
Schizophrenia 


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ASLANOOl-009 
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13Aug2019 
Page 137 of 140 
Abbreviated Protocol Treatment Oppo1iunity with Varlitinib in Biliary Tract Cancer 
Title: 
(TreeTopp) 
Protocol Title: 
Protocol Number: 
Protocol Version 
Number and Date: 
A multicenter, double-blind, randomized, placebo-controlled study of 
varlitinib plus capecitabine versus placebo plus capecitabine in patients 
with advanced or metastatic biliary tract cancer as second-line systemic 
therapy 
ASLANOOJ-009 
Version 6.0, 13 Aug 2019 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), the International Council on Harmonisation (ICH) guidelines for current 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
Sponsor Signatory 
 
Head ofR&D 
ASLAN Pharmaceuticals Pte. Ltd. 
 
Acting CMO 
ASLAN Pharmaceuticals Pte. Ltd. 
Signature 
Date 
Signature 
Date 
Confidential © 20 I 8 AS LAN Pharmaceuticals Pte. Ltd., al I rights reserved 


 
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14.7 Investigator Signature Page 
Abbreviated Protocol 
Title: 
Treatment Opportunity with Varlitinib in Biliary Tract Cancer 
(TreeTopp) 
Protocol Title: 
A multicenter, double-blind, randomized, placebo-controlled study of 
varlitinib plus capecitabine versus placebo plus capecitabine in patients 
with advanced or metastatic biliary tract cancer as  second-line systemic 
therapy 
Protocol Number: 
ASLAN001-009 
Protocol Version 
Number and Date: 
Version 6.0, 13 Aug 2019 
Confidentiality and GCP Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including appendices, 
and I will conduct the study as described in compliance with this protocol (and 
amendments), GCP, and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol 
without obtaining prior approval of ASLAN and of the IEC/IRB. I will submit the 
protocol amendments and/or any ICF modifications to ASLAN and IEC/IRB, and 
approval will be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to 
the patients’ state of health will be regarded as confidential. No patients’ names will be 
disclosed. All patients will be identified by assigned numbers on all CRFs, laboratory 
samples, or source documents forwarded to the sponsor. Clinical information may be 
reviewed by the sponsor or its agents or regulatory agencies. Agreement must be obtained 
from the patient before disclosure of patient information to a third party. 
Information developed in this clinical study may be disclosed by ASLAN 
Pharmaceuticals Pte. Ltd., to other clinical Investigators, regulatory agencies, or other 
health authority or government agencies as required. 
Investigator Signature 
Date 
Printed Name 
Institution 


 
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14.8 Study Personnel 
14.8.1 Sponsor Personnel 
ASLAN Medical Vice President 
Name: 
 
Title: 
VP Medical 
Address: 
ASLAN Pharmaceuticals Pte. Ltd. 
Room 3202, 32F, 333 Keelung Road 
Section 1 Taipei 110 
Taiwan 
Telephone No.: 
 
 
ASLAN Clinical Operations Vice President 
Name: 
 
Title: 
VP Clinical Operations 
Address: 
ASLAN Pharmaceuticals Pte. Ltd. 
83 Clemenceau Avenue 
#12-03 UE Square 
Singapore 239920 
Telephone No.: 
 
 
 


 
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14.8.2 Clinical Research Organization Personnel 
Asia and Europe  
Name: 
 
Title: 
Company: 
Project Manager 
Syneos Health (Formerly known as INC Research) 
Address: 
21 Biopolis Road 
#03-03 North Tower 
Nucleos 
Singapore 138567 
Telephone No.: 
 
 
United States 
Name: 
 
Title: 
Company: 
Project Manager 
BIORASI, LLC 
Address: 
One Turnberry Place 
19495 Biscayne Blvd. 
Suite #900, Aventura 
Florida 33180 
USA 
Telephone No.: 
 
 
Japan 
Name: 
 
Title: 
Company: 
Project Manager 
CMIC Co.,Ltd.   
Address: 
Hamamatsucho Building 
1-1-1 Shibaura, Minato-ku 
Tokyo 105-0023 
Japan 
Telephone No.: 
 
 

SAP_003.pdf: 


 
ASLAN Pharmaceuticals  
 
Version 3.0 06 December 2018 
ASLAN001-009 Statistical Analysis Plan 
 
 Page 1 of 63 
 
Confidential © 2018 ASLAN Pharmaceuticals, all rights reserved 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PLACEBO 
CONTROLLED STUDY OF VARLITINIB PLUS CAPECITABINE 
VERSUS PLACEBO PLUS CAPECITABINE IN PATINTS WITH 
ADVANCED OR METASTATIC BILIARY TRACT CANCER AS 
SECOND LINE SYSTEMIC THERAPY 
Date:   
06 December 2018 
Version: 
3.0 
SAP Approvals:  
 
 
____________________________________ 
_________________ 
 
 
 
 
 
 
Date 
Chief Medical Officer, ASLAN Pharmaceuticals 
 
 
 
 
 
____________________________________ 
_________________ 
  
 
 
 
 
 
Date 
 
 
 
Senior Director of Biostatistics, ASLAN Pharmaceuticals   
 
 
 
 
 
 


 
ASLAN Pharmaceuticals  
 
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TABLE OF CONTENTS 
1. 
STUDY OBJECTIVES ....................................................................................... 9 
1.1 
Primary Objectives ..................................................................................... 9 
1.2 
Secondary Objectives ................................................................................ 9 
1.3 
Exploratory Objectives ............................................................................. 10 
2. 
Study Design ................................................................................................... 10 
2.1 
Overall Study Design ............................................................................... 10 
2.2 
Methods of Assigning Subjects to Treatment Groups ............................... 13 
2.2.1 
Procedures for Randomization .......................................................... 14 
3. 
ENDPOINTS ................................................................................................... 15 
3.1 
Efficacy Endpoints .................................................................................... 15 
3.1.1 
Objective Response Rate.................................................................. 15 
3.1.2 
Progression-Free Survival ................................................................. 17 
3.1.3 
Overall Survival ................................................................................. 17 
3.1.4 
Duration of Response ....................................................................... 18 
3.1.5 
Disease Control Rate ........................................................................ 18 
3.1.6 
Tumor Size ....................................................................................... 18 
3.2 
Safety and Tolerability .............................................................................. 19 
3.2.1 
Safety Endpoints ............................................................................... 20 
3.2.1.1 
General Considerations for Safety Assessments ........................ 21 
3.2.2 
Treatment Exposure and Dose Intensity ........................................... 22 
3.3 
Pharmacokinetic Endpoints ...................................................................... 24 
3.4 
Biomarker Endpoints ................................................................................ 25 
4. 
Analysis Populations ....................................................................................... 25 
4.1 
Safety Population ..................................................................................... 25 
4.2 
Full Analysis Set ...................................................................................... 25 
4.3 
Evaluable for Response Set (Part 1 only) ................................................. 26 


 
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4.4 
Per Protocol Analysis Population ............................................................. 26 
4.5 
PK Analysis Set ....................................................................................... 27 
4.6 
Summary of Analysis Populations ............................................................ 27 
5. 
Protocol Deviations.......................................................................................... 28 
5.1 
Major Deviations ...................................................................................... 28 
5.2 
Important Deviations ................................................................................ 29 
6. 
General Statistical Considerations ................................................................... 31 
6.1 
Sample Size Estimation ........................................................................... 31 
6.1.1 
Safety Lead-in ................................................................................... 31 
6.1.2 
Part 1 ................................................................................................ 31 
6.1.3 
Part 2 ................................................................................................ 32 
6.1.4 
Sample Size Re-estimation ............................................................... 32 
6.2 
Adjustments for Covariates ...................................................................... 32 
6.3 
Handling of Dropouts or Missing Data ...................................................... 33 
6.4 
Monitoring and Interim Analyses .............................................................. 33 
6.4.1 
Monitoring ......................................................................................... 33 
6.4.2 
Interim Analysis ................................................................................. 33 
6.5 
Multiple Testing Strategy .......................................................................... 34 
6.5.1 
Part 1 ................................................................................................ 34 
6.5.2 
Part 2 ................................................................................................ 34 
6.6 
Examination of Subgroups ....................................................................... 35 
6.7 
Stratification Factors ................................................................................ 35 
7. 
Methods of Analysis ........................................................................................ 36 
7.1 
Objective Response Rate ......................................................................... 36 
7.2 
Progression-Free Survival ........................................................................ 37 
7.2.1 
Sensitivity Analyses for PFS – Part 1 only ......................................... 39 
7.2.1.1 
Assessment of Major Deviations ................................................. 39 


 
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7.2.1.2 
Assessment of Informative Censoring ......................................... 40 
7.2.1.3 
Evaluation-Time Bias Assessment .............................................. 40 
7.2.1.4 
Attrition-Bias Assessment ........................................................... 40 
7.3 
Overall Survival ........................................................................................ 40 
7.4 
Duration of Response .............................................................................. 41 
7.5 
Disease Control Rate ............................................................................... 41 
7.6 
Tumor Size............................................................................................... 41 
7.7 
Assessment of Safety and Tolerability ...................................................... 43 
7.7.1 
Assessment of Adverse Events ......................................................... 43 
7.7.2 
Clinical Laboratory Data .................................................................... 44 
7.7.3 
ECG Data ......................................................................................... 45 
7.7.4 
Physical Examination ........................................................................ 46 
7.7.5 
Exposure, Dose Intensity and General Tolerability ............................ 46 
7.8 
Disposition of Subjects ............................................................................. 46 
7.9 
Demographics and Baseline Characteristics ............................................ 46 
7.10 
Medical History and Prior and Concomitant Medications .......................... 47 
7.11 
Pharmacokinetic Data .............................................................................. 47 
7.11.1 
Concentration Values ........................................................................ 47 
7.11.2 
Calculation of the Actual Sampling Times ......................................... 48 
7.11.3 
Pharmacokinetic Analysis ................................................................. 48 
7.11.4 
PK/PD Analyses with special consideration of effects on QT ............ 48 
7.11.4.1 
General Principles ....................................................................... 48 
7.11.4.2 
Methods of Analysis .................................................................... 49 
7.11.5 
Biomarker Analysis ........................................................................... 51 
8. 
Changes in the Conduct of the Study or Planned Analysis .............................. 51 
9. 
REFERENCES ................................................................................................ 52 
10. LIST OF TABLES, FIGURES AND LISTINGS ................................................. 53 


 
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10.1 
Tables ...................................................................................................... 53 
10.2 
Listings ..................................................................................................... 57 
10.3 
Figures ..................................................................................................... 60 
 
 


 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AKT 
protein kinase b 
ANOVA 
Analysis of Variance 
ANCOVA 
Analysis of Covariance 
AUC 
area under the plasma concentration-time curve 
AUCτ 
area under the plasma concentration-time curve during a dosage 
interval (τ) 
BID 
twice daily 
BMI 
body mass index 
BP 
blood pressure 
BTC 
biliary tract cancer 
CI 
confidence interval 
CL 
observed systemic plasma clearance 
Cmax 
maximum concentration 
Ctrough 
Trough plasma concentration (measured concentration 
at the end of a dosing interval at steady state [taken 
directly before next administration]) 
CRF 
case report form 
CRO 
contract research organization 
CTC 
Common Toxicity Criteria 
DCO 
Data cut-off 
DCR 
disease control rate 
5’-DFCR 
5’-Deoxy-5-fluorocytidine 
5’-DFUR 
5’-Deoxy-5-fluorouridine 
DoR 
duration of response 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EFR 
Evaluable for Response 
EGFR 
epidermal growth factor receptor 
FAS 
FDA 
Full Analysis Set 
Food and Drug Administration 
5-FU 
5-Fluorouracil 


 
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GB 
gall bladder 
GCP 
Good Clinical Practice 
HER 
human epidermal growth factor receptor 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
ICR 
Independent central review 
KM 
Kaplan Meier 
MAD 
multiple ascending dose 
MedDRA 
NTL 
ORR 
Medical Dictionary for Regulatory Activities 
Non-Target Lesion 
objective response rate 
OS 
overall survival 
PFS 
progression free survival 
PK 
pharmacokinetic  
PP 
Per Protocol 
Rac AUC 
Accumulation ratio calculated from AUCτ,ss and AUCτ 
after single dosing 
Rac Cmax 
Accumulation ratio calculated from Cmax,ss and Cmax after single 
dosing 
ROW 
rest of the world 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SLI 
Safety lead-in 
SOP 
standard operating procedure 
SRC 
safety review committee 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal elimination half-life 
Tmax 
time of maximum concentration 
TL 
TS 
Target Lesion 
tumour size 
%ΔTSWk12 
percentage change from baseline in tumor size at week 12 
%ΔTSbest 
best percentage change from baseline in tumor size at any time 
point 
US 
United States 


 
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Vz 
Apparent volume of distribution during terminal 
phase 
Vss 
steady-state volume of distribution 
 
 
 


 
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1. 
STUDY OBJECTIVES 
1.1 
Primary Objectives 
The primary objectives of the study are: 
Safety lead-in: 
• 
To assess the safety and tolerability of varlitinib 300 mg BID (every day), in 
combination with capecitabine 1000 mg/m2 (BID for 14 days followed by a 7-day 
rest) as measured by incidence of AEs, and changes from baseline in safety 
parameters. 
Part 1: 
• 
To assess the efficacy of varlitinib in combination with capecitabine as measured 
by co-primary endpoints of objective response rate (ORR) and progression-free 
survival (PFS), both assessed by Independent Central Review (ICR). 
Part 2: 
• 
To assess the efficacy of varlitinib in combination with capecitabine as measured 
by OS 
1.2 
Secondary Objectives 
Safety lead-in 
1. To evaluate the pharmacokinetics (PK) of varlitinib and capecitabine (and its 
metabolite 5-FU) when given in combination  
2. To evaluate the effect of varlitinib on QT/QTc 
3. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by ORR, DoR and DCR, all based on site assessment 
Part 1  
1. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by OS, DoR, and DCR as assessed by ICR and ORR as assessed 
by site 
2. To assess the safety and tolerability of varlitinib when combined with 
capecitabine 
3.  To explore exposure-response relationships for varlitinib (and any relevant 
circulating metabolites) for measures of efficacy, safety, and pharmacological 
responses.  
4. To examine the effects of varlitinib, when added to capecitabine on ECG 
parameters including QTcF, QTcB, HR, PR, and QRS  


 
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Part 2 
1. To evaluate the efficacy of varlitinib in combination with capecitabine, as 
measured by ORR, DoR, DCR and PFS, all based on site assessment 
2. To assess the safety and tolerability of varlitinib when combined with 
capecitabine 
3. To explore exposure-response relationships for varlitinib (and any relevant 
circulating metabolites) for measures of efficacy, safety, and pharmacological 
responses via sparse PK sampling and population PK analyses 
1.3 
Exploratory Objectives 
Part 1: 
1. To explore the role of human epidermal growth factor receptor (HER) status as 
a predictor of benefit to varlitinib 
2. To explore possible relationships between HER family and downstream 
signaling protein and phospho-protein expression levels and clinical outcomes 
3. To explore possible relationships between gene mutational status and clinical 
outcomes 
Part 2: 
If a relationship is found between biomarker(s) expression and clinical outcomes in 
Part 1 of the study, the biomarker(s) could be prospectively evaluated in Part 2 of the 
study. 
2. 
Study Design 
2.1 
Overall Study Design 
This study is designed as a multicenter, double-blind, randomized, placebo controlled, 
study of varlitinib plus capecitabine versus placebo plus capecitabine in subjects, with 
advanced or metastatic BTC as second line of systemic therapy. 
Safety Lead-in: 
This study will commence initially with a Safety lead-in group (Figure 1). This part of 
the study is a single arm, open label design to assess the safety of varlitinib (BID, every 
day) plus capecitabine (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 evaluation.  At least 6 subjects will be from the US. Treatment will 
continue until disease progression or development of toxicity or consent withdrawal or 
death. 


 
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A data safety monitoring board (DSMB) meeting will occur after the first 12 patients in 
the Safety lead-in have completed 21 days of follow-up in order to review the safety 
and tolerability data prior to commencement of Part 1 of the study. 
Figure 1: Safety Lead-in Study Design 
 
Part 1: 
Part 1 of the study is designed as double-blind, randomized, placebo controlled study 
to assess the efficacy and safety of varlitinib plus capecitabine in comparison with 
placebo plus capecitabine in approximately 120 subjects (Figure 2). Eligible subjects 
will be randomized to varlitinib or placebo (BID, every day) ), each in combination with 
capecitabine (administered BID every day for 14 days, followed by a 7 day rest period). 
Treatment will continue until disease progression or development of toxicity or consent 
withdrawal or death. A DSMB will meet at a selected time point (to be confirmed) during 
Part 1 for review of safety data. 


 
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Figure 2: Part 1 Study Design 
 
Part 2: 
Part 2 of the study is designed as double-blind, randomized, placebo controlled study 
to confirm the efficacy of varlitinib plus capecitabine compared to capecitabine in 
approximately 350 subjects (Figure 3). Part 2 will follow the same design and treatment 
schedule as Part 1. This part of the study will commence following review of Part 1 
results and will be independently powered. 
Figure 3: Part 2 Study Design 


 
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2.2 
Methods of Assigning Subjects to Treatment Groups 
Safety Lead-in: 
This is a non-randomized single arm design. All eligible subjects will receive varlitinib 
300 mg twice daily, every day plus capecitabine 1000mg/m2 twice daily, Day 1 to 14, 
followed by a 7-day rest period (21 day cycle). 
Each subject’s eligibility will be reviewed by medical monitor during screening period, 
subjects will be sequentially enrolled after being screened for eligibility and providing 
consent. 
In the case of discontinuation of chemotherapy owing to toxic effects, varlitinib or 
placebo therapy will be continued until disease progression, the development of 
unacceptable toxic effects, withdrawal of consent or death. 
At screening, potential subjects will be assigned a unique screening number that starts 
with “S” and 4 digits (i.e. S1001) by electronic data capture system. 
Parts 1 and 2 
At the initial screening visit, the investigator or suitably trained delegate will: 
1. Obtain signed informed consent (main study) from the potential subject before 
any study specific procedures are performed. 


 
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2. Potential subjects will be assigned a unique screening number that starts with 
“S” and 4 digits (i.e. S1001) by electronic data capture system. This screening 
number will be sequential from safety lead in, and will not be repeated. 
3. Determine subject eligibility in accordance with the protocol. Once the subject 
is confirmed to be eligible, the PI or suitably trained delegate will: 
4. Assign eligible subject a unique randomization number via Randomization and 
Trial Supply Management (RTSM) system. Randomization numbers will start 
with “R” followed by 4 digits (i.e., R1001) and will be assigned strictly 
sequentially by RTMS (starting at R1001 for Part 1 and R2001 for Part 2), as 
subjects are eligible for randomization. This number is the subject’s unique 
identifier and is used to identify the subject with the assigned treatment. This 
randomization number will be available to the investigator in electronic data 
capture system. 
2.2.1 
Procedures for Randomization 
Subjects must not be randomized unless all eligibility criteria have been met. 
Subjects who satisfy all the entry criteria will be centrally assigned to study treatment 
by the RTSM, according to the randomization scheme generated by the CRO. Subjects 
will be randomized in a 1:1 ratio to either varlitinib or placebo, both on a background 
of capecitabine. The random scheme will be stratified by the following two covariates: 
• 
Geographical region - US or Rest of World (ROW) 
• 
Primary tumor location – Gall bladder (GB) or non-GB 
The actual treatment given to subjects will be determined by the randomization 
scheme in RTSM. The randomization scheme will be produced using SAS® version 
9.4, which incorporates a standard procedure for generating randomization numbers. 
One randomization list will be produced containing sufficient random numbers for each 
of the four randomization strata. A blocked randomization will be generated and all 
centers will use the same list in order to minimize any imbalance in the number of 
subjects assigned to each treatment group. 
The dose and regimen of randomized therapy to be administered is as follows: 
• 
Varlitinib 300 mg twice daily, every day 
• 
Placebo twice daily, every day 
Subjects in both arms will receive background chemotherapy with capecitabine 
1000 mg/m2 twice daily, Day 1 to 14, followed by a 7-day rest period (21 day cycle). 
Subjects will be identified to the Centralized Randomization Center using site number, 
screening number, randomization number, gender and date of birth. Subjects will be 
randomized strictly sequentially within each stratum, as subjects are eligible for 
randomization. The RTSM will inform the investigator of the Kit ID number to be 
allocated to the subject at each dispensing visit via electronic data capture (EDC). 


 
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For both study parts, the primary and key secondary endpoints will be evaluated using 
the Full Analysis Set (FAS) based on the intention-to-treat principle. 
3. 
ENDPOINTS 
3.1 
Efficacy Endpoints 
3.1.1 
Objective Response Rate 
Objective Response Rate is a co-primary endpoint in Part 1 and a secondary endpoint 
in Part 2, and the Safety lead-in cohort. 
ORR rate is defined as the number (%) of subjects with at least one visit response of 
CR or PR.  Data obtained up until progression, or last evaluable assessment in the 
absence of progression, will be included in the assessment of ORR.  This will be 
irrespective of whether or not subjects discontinued treatment or received a 
subsequent therapy prior to progression.  
In all study parts, the primary assessment of ORR will be based on the full analysis set 
(FAS). Sensitivity analysis populations are described in Section 4.  
The ORR is derived programmatically from the Best overall RECIST Response (BoR) 
for each subject.  
Best overall RECIST Response (BoR) is calculated based on the overall visit 
responses from each RECIST assessment.  It is the best response a subject has had 
following randomization and prior to RECIST progression or the last evaluable 
assessment in the absence of RECIST progression. 
Categorization of BoR will be based on the RECIST criteria using the following 
response categories (listed in hierarchical order): complete response (CR), partial 
response (PR), stable disease (SD), progressive disease (PD) and inevaluable (NE) 
(CR>PR>SD>PD>NE).  
 
Target Lesions 
(TL) 
Non-Target Lesions 
(NTL) 
New Lesions 
Overall 
Response 
CR 
CR 
NO 
CR 
CR 
Non-CR/Non- PD 
NO 
PR 
CR 
Not evaluated 
NO 
PR 
PR 
Non- 
PD 
or 
not 
all 
evaluated 
NO 
PR 


 
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Target Lesions 
(TL) 
Non-Target Lesions 
(NTL) 
New Lesions 
Overall 
Response 
SD 
Non- 
PD 
or 
not 
all 
evaluated 
NO 
SD 
Not all evaluated 
Non- PD 
NO 
NE 
PD 
ANY 
YES or NO 
PD 
ANY 
PD 
YES or NO 
PD 
ANY 
ANY 
YES 
PD 
 
For the evaluation of the co-primary endpoint ORR in Part 1 of the study, all radiological 
data will be assessed by an Independent Central Review (ICR), and the BoR will be 
determined programmatically using the data provided by the ICR. For Part 2, the Safety 
lead-in and for the Part 1 secondary endpoint, ORR based on site assessments, BoR 
will be determined programmatically using data from the site assessments 
For determination of a best response of SD, the earliest of the dates contributing 
towards a particular overall visit assessment will be used.  A best response of SD 
cannot be assigned unless a visit response of SD has been recorded at least 6 weeks 
(-5 days) after randomization (day 1), i.e. at least 38 days (to allow for the assessment 
window). For CR/PR, the initial overall visit assessment that showed a response will 
use the latest of the dates contributing towards a particular overall visit assessment. 
For subjects whose progression event is death, BoR will be calculated based on data 
up until the last evaluable RECIST assessment prior to death. 
For subjects who die with no evaluable RECIST assessments, if the death occurred ≤ 
12 weeks + 5 days after randomization, then BoR will be assigned to the progression 
(PD) category.  For subjects who die with no evaluable RECIST assessments, if the 
death occurred >12 weeks +5 days after randomization then BoR will be assigned to 
the inevaluable (NE) category. 
Progression events that have been censored due to them being more than two missed 
visits after the last evaluable assessment will not contribute to the BOR derivation.   
A subject will be classified as a responder if the RECIST criteria for a CR or PR are 
satisfied at any time following randomization, prior to RECIST progression (regardless 
of the number of missing visits prior to the assessment of CR or PR). In accordance 
with RECIST 1.1, response confirmation is not required. 
For each treatment group, the objective response rate (ORR) is the number of 
responders divided by the number of subjects in the treatment group in the FAS 
analysis set. This will be irrespective of whether or not subjects discontinued treatment 
or received a new antitumor therapy prior to disease progression.   
The NE category will be assigned in the following circumstances: 


 
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• 
For subjects who die with no evaluable post-baseline assessments, if the death 
occurred > 12 weeks + 5 days after randomization (i.e., if more than 2 
assessments are missed). 
o Note: Subjects who die up to the week 12 assessment (scheduled up 
to 12 weeks + 5 days after randomization), with no evaluable post-
baseline assessment will be classified as progressors and will be 
treated as progressors for the waterfall plots of the percentage change 
from baseline in tumor size, and the statistical analysis of tumor size 
(see 3.1.6 and Section 7.6) 
o For subjects with no evaluable post-baseline assessments, and for 
whom the date of progression (including death) is either unknown or 
censored due to missed assessments (see Section 3.1.2). 
3.1.2 
Progression-Free Survival 
PFS is 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 withdraws from 
randomized therapy or receives another antitumor therapy prior to disease 
progression.  Subjects who have not experienced disease progression or died at the 
time of analysis will be censored at the time of the latest date of assessment from their 
last evaluable RECIST assessment.  However, if the subject progresses or dies after 
2 or more missed visits (12 weeks + 5 days maximum), the subject will be censored at 
the time of the latest evaluable RECIST Version 1.1 assessment.   
The PFS time will always be derived based on the scan/assessment dates rather than 
visit dates and the following rules will be applied: 
• 
Date of disease progression will be determined based on the earliest of the 
dates of the component that triggered the disease progression, i.e., if both the 
target lesions and the non-target lesions indicate disease progression but were 
scanned on different days, the earlier of the 2 dates would be applied.   
• 
When censoring a subject for PFS the subject will be censored at the latest of 
the dates contributing to a particular overall visit assessment.   
For Part 1, the co-primary endpoint, PFS, will be derived programmatically using data 
from the ICR. To support sensitivity analyses, PFS will also be derived 
programmatically using the site assessments of the Part 1 radiological data. 
For Part 2 and the Safety lead-in, PFS will be derived programmatically using the site 
assessments of the radiological data. 
In all study parts, the primary analysis of PFS will be assessed based on the FAS (see 
Section 4.2). 
3.1.3 
Overall Survival 
OS is 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 will be censored 
based on the last recorded date on which the subject was known to be alive.  


 
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Note, survival calls may be made in the week following the date of Data Cut Off (DCO) 
for the analysis, and if subjects are confirmed to be alive or if the death date is after 
the DCO these subjects will be censored at the date of DCO. 
3.1.4 
Duration of Response 
The DoR is defined as the time from the date of first documented response until the 
date of documented disease progression or death in the absence of disease 
progression. The end of response should coincide with the date of disease progression 
or death from any cause used for the PFS endpoint.  
For Part 1, DoR will be calculated based on data from the ICR of radiological data. For 
Part 2 and the Safety lead-in, DoR will be calculated based on the site assessments 
of radiological data. 
The time of the initial response will be defined as the latest of the dates contributing 
towards the first visit response of PR or CR. For example, if the subject was first noted 
to have a PR at week 6, and the target and non-target lesions were assessed on 
different dates at this visit, then the later of the two assessment dates would be used 
as the start date of the response. 
If a subject does not progress following a response, then their DoR will use the PFS 
censoring time. 
Duration of response will not be defined for those subjects who do not have 
documented response. 
3.1.5 
Disease Control Rate 
DCR rate is defined as the number (%) of subjects with at least one visit response of 
CR or PR, or with stable disease for a minimum of twelve weeks (−5 days) from 
randomization. Data obtained up until progression, or last evaluable assessment in the 
absence of progression, will be included in the assessment of DCR.  This will be 
irrespective of whether or not subjects discontinued treatment or received a 
subsequent therapy prior to progression. For all study parts, the primary assessment 
of DCR will be based on the FAS. For Part 1, DCR will be calculated based on data 
from the ICR. For Part 2 and the Safety lead-in, DCR will be calculated from the site 
radiological data. 
3.1.6 
Tumor Size 
The percentage change from baseline in tumor size at Week 12 (%ΔTSWk12) is a 
secondary endpoint for Part 1, and will be used to present waterfall plots of the target 
lesion data in the Evaluable for Response (EFR) set (see Section 4.3), and also to help 
evaluate the exploratory objectives of investigating the possible role of HER family 
expression levels as predictors of clinical benefit. Tumor size is not considered to be a 
key secondary endpoint; for the purpose of marketing authorization, no statistical 
claims will be made based on tumor size.   
The %ΔTSWk12 will be defined as follows: 


 
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• 
Baseline tumor size (TS): defined as the sum of longest diameters of target 
lesions at baseline 
• 
Week 12 TS: defined as the sum of longest diameters of target lesions at week 
12 
%∆𝑇𝑆𝑊𝑘12 = 100 × 𝑊𝑒𝑒𝑘 12 𝑇𝑆−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑇𝑆
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑇𝑆
 
An increase from baseline of 20% will be imputed for any subjects who die by any 
cause, or withdraw from the study due to symptomatic disease progression prior to 
Week 12 (+5 days).  Any subjects who withdraw from the study due to radiological 
disease progression prior to Week 12 will be included in the analysis, and will be 
assigned a percentage change from baseline of 20%, or the value that was observed 
at the time of disease progression (whichever is larger).  
The best percentage change from baseline in tumor size (%ΔTSbest) at any time point, 
will also be calculated and presented using waterfall plots. 
The %ΔTSbest will be defined as follows: 
• 
Baseline tumor size (TS): defined as the sum of longest diameters of target 
lesions at baseline 
• 
Best TS: defined as the smallest sum of longest diameters of target lesions as 
observed at any time point post-randomization up until disease progression 
(regardless of whether it was a scheduled assessment). 
%∆𝑇𝑆𝑏𝑒𝑠𝑡= 100 × 𝐵𝑒𝑠𝑡 𝑇𝑆−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑇𝑆
𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑇𝑆
 
Subjects in the EFR set without any evaluable post-randomization target lesion data 
will be excluded from the waterfall plot of %ΔTSbest, except if the subject is known to 
have died or withdrawn from the study due to symptomatic disease progression prior 
to Week 12 (+ 5 days), or if non-target lesion or new lesion data is available prior to 
week 12 (+5 days) which is indicative of disease progression.  In such cases, the 
subject will have an increase from baseline of 20% imputed. 
3.2 
Safety and Tolerability 
The safety and tolerability endpoints of the study, including the ECG parameters, are 
listed in the following sections. Further details of the schedule of assessments for these 
endpoints can be found in the Clinical Study Protocol. 
Due to the non-comparative design and small sample size, the evaluation of the impact 
of varlitinib on ECG parameters from the Safety lead-in will be considered exploratory. 
The primary electrocardiographic analysis of the protocol will be from the time-based 
ECG analysis performed in Part 1 at baseline, Cycle 1 Day 1, Cycle 1 Day 8, and the 
safety follow-up visit. Triplicate ECGs will be collected with a PK sample collected 
immediately following ECG acquisition at the time points outlined in the Clinical Study 
Protocol. ECGs will be analyzed by a Core ECG Laboratory. The planned methods of 
analysis for the ECG parameters, including the exposure-response modeling, are 
outlined in Sections 7.7.3 and 7.11.4. 


 
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3.2.1 
Safety Endpoints 
The assessment of safety and tolerability is the primary objective of the Safety lead-
in, and a secondary objective of Parts 1 and 2. In all study parts, the safety of 
varlitinib 300 mg BID in combination with capecitabine, in subjects with BTC, will be 
assessed using the following endpoints:  
 
• 
Adverse Events (AEs) 
• 
Vital Signs (blood pressure [systolic and diastolic], heart rate, respiration rate, 
and body temperature) 
• 
Laboratory assessments (clinical chemistry, hematology, coagulation and 
urinalysis) 
• 
12-lead Electrocardiogram (ECG) (P and QRS duration, HR, PR, RR, PQ, QT 
and QTc intervals using Bazett’s and Fridericia’s formulae)  
• 
Physical examination (including a standard neurological examination and 
assessment of weight) 
In addition, tolerability will be further explored by assessment of dose reductions, 
interruptions and modifications (see Section 3.2.2).  
Adverse events will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA) for concomitant 
diseases and AEs and WHO Drug for medications. All AEs will be evaluated for 
severity according to NCI-CTCAE version 4.03 
Baseline will be defined as the last assessment prior to the start of study treatment. If 
multiple assessments are performed at the same pre-treatment time point, the mean 
of the values will be used as the baseline reading. 
Specifically, for the ECG assessments, on Day 1, pre-dose is defined as 2 sets of 
triplicate ECGs taken 45 minutes prior to dosing and approximately 5 minutes prior to 
dosing. The ECG values from these 2 sets of ECGs will be averaged to create the 
baseline value. Similarly, for all other time points, for each ECG parameter, each 
patient’s mean will be calculated from the triplicate readings and the mean value will 
be used. 
The ECG parameters of interest include, but are not limited to: QT including QTcF and 
QTcB, HR (heart or ventricular rate), PR, QRS intervals. 
Creatinine clearance will be derived as: 
𝑒𝐶𝐶𝑟= (140 −𝐴𝑔𝑒) ×  𝑀𝑎𝑠𝑠 (𝑖𝑛 𝑘𝑖𝑙𝑜𝑔𝑟𝑎𝑚𝑠) ×  𝐶𝑜𝑛𝑠𝑡𝑎𝑛𝑡
𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑖𝑛 𝜇𝑚𝑜𝑙/𝐿)
 
where constant=1.23 for males and 1.04 for females, and will be categorized as 30-
<60 ml/min, 60-<90 ml/min and =>90 ml/min. Creatinine clearance will be included in 
summaries of the clinical chemistry data. 
QTcB will be derived as: 


 
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𝑄𝑇𝑐𝐵= 𝑄𝑇
√𝑅𝑅
 
QTcF will be derived as: 
𝑄𝑇𝑐𝐹= 𝑄𝑇
√𝑅𝑅
3
 
For derivation of post-baseline visit values, taking account of possible visit windows, 
see Section 3.2.1.1. 
3.2.1.1 General Considerations for Safety Assessments 
Missing safety data will not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) or > x (i.e., above the upper 
limit of quantification) will be imputed as “x” in the calculation of summary statistics but 
displayed as “< x” or “> x” in the listings. 
In order to produce data summaries by visit, visit time windows are required, and will 
be derived using the following conventions: 
• 
The time windows will be exhaustive so that data recorded at any time point 
have the potential to be summarized. Inclusion within the time window should 
be based on the actual date and not the intended date of the visit. 
• 
All unscheduled visit data should have the potential to be included in the 
summaries. 
• 
The window for the visits following baseline will be constructed in such a way 
that the upper limit of the interval falls half way between the two visits (the lower 
limit of the first post-baseline visit will be Day 1).  If an even number of days 
exists between two consecutive visits then the upper limit will be taken as the 
midpoint value minus 1 day.   
Furthermore, the following principles will apply to the presentation of safety data: 
• 
For 
summaries 
showing 
the 
maximum 
or 
minimum 
values, 
the 
maximum/minimum value recorded on treatment will be used (regardless of 
where it falls in an interval). 
• 
For summaries of the ECG data, the mean value of the triplicate readings will 
be included in the summaries. 
• 
Listings should display all values contributing to a time point for a subject. 
• 
For visit based summaries: 
o If there is more than one value per subject within a time window then 
the closest value should be summarized, or the earlier in the event the 
values are equidistant from the nominal visit date.  The listings should 
highlight the value for that subject that went into the summary table, 
wherever feasible. 
o For Parts 1 and 2 only, to prevent very large tables or plots being 
produced that contain many cells with sparse data, for each treatment 
group, visit data should only be summarized if the number of 
observations is greater than 1/3 of subjects dosed. 


 
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• 
For summaries at a subject level, all values should be included, regardless of 
whether they appear in a corresponding visit based summary, when deriving a 
subject level statistic such as a maximum.  
• 
Baseline will be defined as the last non-missing measurement prior to dosing 
with study treatment. For laboratory data, any assessments made on day 1 will 
be considered pre-dose unless explicitly indicated otherwise. Where safety 
data are summarized over time, study day will be calculated in relation to date 
of first treatment (which will be termed day 1). 
3.2.2 
Treatment Exposure and Dose Intensity 
To understand the general tolerability of varlitinib 300 mg BID, and the impact of 
interruptions and dose reductions, summaries of treatment exposure and dose 
intensity will be produced. For the purpose of this study, the term exposure relates to 
the number of days of treatment received (regardless of dose reductions), whereas 
dose intensity relates to the proportion of intended dose (300 mg BID) received, taking 
account of interruptions and reductions. 
For all subjects, exposure to the randomized therapy (varlitinib or placebo) in Parts 1 
and 2, or study therapy (varlitinib) in the Safety lead-in, will be calculated. To assess 
treatment exposure, the following will be calculated: 
Intended Exposure to randomized therapy (days) 
• 
Intended Exposure = last dose date – first dose date  + 1 
Actual Exposure to randomized therapy (days) 
• 
Actual exposure  = Intended exposure – total duration of dose interruptions 
where the intended exposure is calculated as defined above, and dose interruptions 
include all days in which the subject receive no study medication, regardless of 
whether the interruption was intentional, or whether the subject forgot to take a dose. 
For capecitabine intended exposure, the calculation of intended exposure and actual 
exposure will take into account the intermittent dosing schedule, as described below: 
For intended exposure, if the last dose date is in the first 14 days of cycle X, then the 
intended exposure will be: 
14 * (X-1) + last dose date – first dose date of cycle X +1 
If the last dose date is in days 15-21 of cycle X (when there should be no dosing), then 
the intended exposure will be 14 * X. 
For actual exposure, this will be determined as the intended exposure minus the total 
duration of any non-protocolled interruptions. The protocolled 7 days off in each cycle 
are accounted for in the derivation of intended exposure so it should not be included 
in the non-protocolled interruptions in this calculation. 


 
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For Parts 1 and 2, dose intensity will be calculated for subjects in both treatment arms, 
and will be calculated for both the randomized therapies (varlitinib vs. placebo) and 
also for the background chemotherapy, capecitabine. 
For the open-label Safety lead-in, dose intensity will be calculated for both the study 
treatment, varlitinib, and for the background chemotherapy, capecitabine. 
Two measures of dose intensity will be calculated: 
1. Percentage of Intended Dose (PID) – defined as the percentage of the actual 
dose delivered relative to the intended dose, until disease progression. 
2. Relative dose intensity (RDI) – defined as the percentage of the actual dose 
intensity delivered, relative to the intended dose intensity, until the earlier of 
treatment discontinuation and progression (as defined by RECIST and based 
on the site assessments). 
The key difference between the two measures outlined above is that the former is 
based on the intended treatment plan of treatment until objective progression, and the 
latter takes account of treatment discontinuations prior to progression, and calculates 
the dose intensity during the actual dosing period. 
In the event that the investigator does not discontinue randomized therapy at disease 
progression, any dosing information beyond progression will not be taken into account 
when calculating either measure of dose intensity. 
PID and RDI will be defined as follows: 
PID = 100% * d/D, where d is the actual cumulative dose delivered up to progression 
(or a censoring event) and D is the intended cumulative dose up to progression (or a 
censoring event).  D is the total dose that would be delivered, if there were no 
modification to dose or schedule. 
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the earlier of 
progression (or a censoring event) or the actual last day of dosing and D is the intended 
cumulative dose up to the earlier of progression (or a censoring event) or the actual 
last day of dosing.  
To account for the intermittent dosing schedule for capecitabine, the intended 
cumulative dose at day x for capecitabine will be calculated as follows: 
If day x is in the first 14 days of a cycle: 
(Ceil(x/21)-1)*14*2*dose level + (x-(Ceil(x/21)-1)*21)*2*dose level 
If day x is day 15 to 21 of a cycle:  
(Ceil(x/21))*14*2*dose level  
 


 
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3.3 
Pharmacokinetic Endpoints 
Safety Lead-in 
The PK of varlitinib (and any relevant circulating metabolites) and capecitabine and 5-
FU (active metabolite of capecitabine) will be determined at selected time points as 
outlined in the Clinical Study Protocol. 
 
The following PK parameters will be evaluated where possible: 
 
Cycle 1 Day 1, Day 8 and Day 14: 
• 
Maximum plasma concentration (Cmax) 
• 
time to Cmax(tmax) 
• 
plasma concentration before next dose (Ctrough) 
• 
area under the plasma concentration-time curve from 0 to 12 hours (AUC0- τ) 
• 
half-life (t1/2) 
• 
apparent clearance (Cl/F) 
• 
apparent volume of distribution (Vz/F) 
• 
apparent volume of distribution at the steady state (Vss/F) 
• 
where τ = 12 hours (dosing interval) 
Cycle 1 Day 8 
• 
accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 8/Day 1) 
• 
accumulation ratio of Cmax RacCmax (Day 8/Day 1) 
Cycle 1 Day 14 
• 
accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 14/Day 1) 
• 
accumulation ratio of Cmax RacCmax (Day 14/Day 1) 
In addition, unscheduled PK samples will be collected at least 7 days following dose 
reduction as described in the clinical study protocol, if required. 
Part 1 and Part 2 
PK samples will be obtained for the PK evaluation of varlitinib (and any relevant 
circulating metabolites). PK samples will be collected at the time points outlined in the 
Clinical Study Protocol.  
 
PK sampling of all patients is planned for Part 1 of the study while sparse PK sampling 
is planned for Part 2.  
In order to maintain the double-bind design of the study, blood samples will be 
collected from all subjects in Part 1 for plasma measurements of varlitinib and its 
potential relevant circulating metabolites. For the sparse PK sampling in Part 2, the 
double-blind design will also be maintained and blood samples will be collected for a 
selected number of subjects, without limiting the sampling to the varlitinib subjects 
only. 
In addition, unscheduled PK samples will be collected at least 7 days following dose 
reduction as described in the clinical study protocol. 


 
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3.4 
Biomarker Endpoints 
The following IHC biomarker endpoints will be assessed, where possible: 
• 
epidermal growth factor receptor (EGFR), pEGFR  
• 
HER2, pHER2  
• 
HER3, pHER3 
• 
HER4, pHER4 
• 
ERK, pERK   
• 
protein kinase b (AKT) AKT, pAKT 
For the HER-family biomarkers (EGFR, pEGFR, HER2, pHER2, HER3, pHER3, 
HER4, pHER4), the original biomarker levels (0, +, ++ or +++) will be used to create 
binary positive/negative categorizations, to support the exploratory analyses to assess 
the role of baseline HER-family expression levels as predictors of clinical benefit. For 
each endpoint, the binary categorizations will be defined as follows: 
Positive: +, ++ or +++ 
Negative: 0 
Biomarkers assessed via PCR/Sequencing, for example the mutational status of 
genes, such as KRAS, NRAS, BRAF, EGFR and other genetic factors that may affect 
response to therapy, will not be reported in the CSR and are not covered in this SAP. 
4. 
Analysis Populations 
4.1 
Safety Population 
For each part of the study, the safety population includes all subjects in that part of the 
study who received at least 1 dose of randomized therapy (or study medication in the 
Safety lead-in) and will be the primary analysis set for the assessment of safety and 
tolerability in the study.  
For the purpose of data summaries, subjects will be included in the Safety Population 
according to the treatment arm and dose level initially received, regardless of any 
subsequent dose adjustments. 
4.2 
Full Analysis Set 
For each study part, the full analysis set is based on the intention-to-treat principle and 
includes all randomized subjects (or treated subjects for the Safety lead-in) analyzed 
in accordance with the intended treatment arm, regardless of the treatment actually 
received.  
With the exception of Tumor Size (which is not considered a key secondary endpoint;  
see Section 3.1.6 and 4.3) in Part 1 of the study, the primary analysis of all primary 
and key secondary efficacy endpoints, will be based on the full analysis set (FAS) for 
all study parts. 


 
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4.3 
Evaluable for Response Set (Part 1 only) 
The EFR set is defined as a subset of the FAS and includes subjects with measurable 
disease at baseline, as determined by ICR assessments of radiological data based on 
the RECIST criteria, version 1.1. For Part 1 only, a sensitivity analysis of ORR and 
DCR will be performed in the evaluable for response (EFR) set to investigate the 
impact of subjects without measurable disease on the primary endpoint. Since 
measurability is an inclusion criteria, all subjects in Parts 1 should have measurable 
disease at baseline. Thus, if no subjects were randomized in error, results in the EFR 
set will not be presented.  
Since tumor size is an endpoint based on subjects’ tumor measurements, it can only 
be defined for the subset of the FAS with measurable disease at baseline. Thus the 
EFR set will be the primary analysis set used for the assessment of tumor size for Part 
1 (See Section 3.1.6).  
4.4 
Per Protocol Analysis Population 
The per-protocol analysis population is defined for Part 1 only. Efficacy is not the focus 
of the Safety lead-in and Part 2 will be assessed on an intention to treat basis only. 
Thus PP analyses are not required for the Safety lead-in and Part 2 of the study. 
The per-protocol analysis population will include all randomized subjects according to 
the treatment actually received, and excluding any subjects with major deviations.  
Major deviations that would lead to exclusion from the per-protocol analysis population 
include:  
• 
Subjects who did not have the intended disease (failure of inclusion criteria 2) 
• 
Subjects who did not have the intended indication, i.e. were not second line 
patients (failure of inclusion criteria 3)  
• 
Subjects who did not received any randomized therapy  
• 
Subjects with baseline radiological scan performed before the start of 
protocol-specified interval prior to randomization 
• 
Subjects who did not have measurable disease at baseline as determined by 
ICR 
• 
Subjects who have not received at least six doses of gemcitabine in a first line 
setting (i.e. failure of inclusion criteria 4, protocol version 4.0 onwards) 
• 
Subjects with multiple (2) peritoneal metastases at baseline or ascites at 
baseline which cannot be attributed to a non-malignant cause (i.e. failure of 
exclusion criteria 3, protocol version 3.0 onwards), based on ICR review 
• 
Subjects with baseline albumin <3 g/dL (failure of the albumin component of 
inclusion criteria 9c)   
In addition to the programmatic determination of the major deviations, monitoring notes 
or summaries will be reviewed to determine any important post entry deviations that 
are not identifiable via programming, and to check that those identified via 
programming are correctly classified.  The final classification will be made blinded, 
prior to database lock. For example, details of disallowed concomitant medication use 
will be reviewed by a physician, blinded to treatment allocation, and may be deemed 
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Subjects who received the incorrect randomized therapy should be included in the PP 
analysis set according to the therapy actually received.  Similarly, subjects who were 
mis-stratified at randomization will be included in the PP analyses according to the 
correct stratification levels, regardless of the levels declared at randomization. 
Note, failure of an inclusion/exclusion criteria will not automatically be classified as a 
major deviation. 
The per-protocol analysis population will be used to assess the sensitivity of the Part 
1 ORR, DoR, DCR, PFS and OS analyses to major deviations. 
4.5 
PK Analysis Set 
The PK population contains all subjects who have been dosed with active drug(s) and 
provided at least one usable post-dose PK sample. All PK data will be analyzed 
according to treatment received.   
For the Safety lead-in, this population will comprise all data subjects who receive study 
treatment as per protocol (300 mg BID) and did not violate or deviate from the protocol 
and planned dosing regimen (300 mg) in ways that would significantly affect the PK 
analyses (for example skipping doses, or taking reduced doses or taking concomitant 
medications with the potential to cause a drug-drug interaction) during the PK sampling 
period. Subjects who did deviate from the planned dosing regimen, may still provide 
some data for inclusion in the PK set, if they have at least one usable post-dose PK 
sample. The population, and decisions regarding which profiles are usable, will be 
defined by the Study Team Physician, Pharmacokineticist and Statistician prior to any 
analyses being performed based on review of protocol deviations. 
PK sampling of all patients is planned for Part 1 of the study while sparse PK sampling 
is planned for Part 2 (See Section 3.3). The number of patients who will provide 
samples in Part 2 for the PK analysis will be defined based on the results of Part 1 of 
the study. All PK data will be analyzed according to the treatment received. Deviations 
that have the potential to significantly affect the PK will be reviewed, and subjects, or 
specific PK profiles for a subject, may be excluded from the PK set if appropriate. The 
population, and decisions regarding which profiles are usable, will be defined by the 
Study Team Physician, Pharmacokineticist and Statistician prior to unblinding and any 
analyses being performed. 
4.6 
Summary of Analysis Populations 
A summary of the study outcome variables, and associated analysis sets is provided 
in Table 1. 
Table 1 Summary of Outcome Variables and Analysis Populations 
Outcome Variable 
Analysis Population 
 (Sensitivity Analysis Population) 
Efficacy Data (Primary and key 
secondary endpoints) 
 
ORR, DCR, 
FAS (EFR and PP Part 1 only) 
PFS, OS, DoR 
FAS (PP Part 1 only) 


 
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Part 1 ORR based on site data 
FAS 
 
Part 1 Tumor Size1 
 
EFR 
Demography 
FAS 
 
 
Pharmacokinetics 
 
PK 
PK 
 
 
Safety 
 
Exposure 
Safety 
Adverse Events 
Safety 
Laboratory measurements 
Safety 
Vital Signs 
Safety 
ECG 
Safety 
Physical Examination 
Safety 
1 Tumor size, by definition, is only defined in patients with measurable disease.  For marketing 
authorization, no statistical claims will be based on tumor size (See Section 3.1.6). 
5. 
Protocol Deviations 
5.1 
Major Deviations 
For Part 1, major protocol deviations are defined as those that would lead to exclusion 
from the per-protocol set (see Section 4): 
• 
Subjects who did not have the intended disease (failure of inclusion criteria 2) 
• 
Subjects who did not have the intended indication, i.e. were not second line 
patients (failure of inclusion criteria 3)  
• 
Subjects who did not received any randomized therapy.  
• 
Subjects with baseline radiological scan performed before the start of 
protocol-specified interval prior to randomization. 
• 
Subjects who did not have measurable disease at baseline as determined by 
ICR 
• 
Subjects who have not received at least six doses of gemcitabine in a first line 
setting (i.e. failure of inclusion criteria 4, protocol version 4.0 onwards) 
• 
Subjects with multiple (2) peritoneal metastases at baseline or ascites at 
baseline which cannot be attributed to a non-malignant cause (i.e. failure of 
exclusion criteria 3, protocol version 4.0 onwards), based on ICR review 
• 
Subjects with baseline albumin <3 g/dL (failure of the albumin component of 
inclusion criteria 9c)     
 For the Safety lead-in and Part 2, the following will be classified as major deviations: 
• 
Subjects who did not have the intended disease (BTC) or indication (2nd line 
patients).  
• 
Subjects who did not received any randomized therapy (Part 2) or Study 
treatment (Safety lead-in).  


 
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• 
Subjects with baseline radiological scan performed before the start of the 
protocol-specified interval prior to randomization (Part 2) or start of treatment 
(Safety lead-in). 
Additionally, the following will be considered major deviations for Part 2 only (but not 
the SLI): 
• 
Subjects who have not received at least six doses of gemcitabine in a first line 
setting (i.e. failure of inclusion criteria 4, protocol version 4.0 onwards) 
• 
Subjects with multiple (2) peritoneal metastases at baseline or ascites at 
baseline which cannot be attributed to a non-malignant cause (i.e. failure of 
exclusion criteria 3, protocol version 4.0 onwards), based on ICR review 
• 
Subjects with baseline albumin <3 g/dL (failure of the albumin component of 
inclusion criteria 9c, protocol version 4.0 onwards)     
For each stage of the study, these protocol deviations will be listed. For Parts 1 and 2, 
major deviations will be summarized by treatment group.  
In addition to the programmatic determination of the major deviations, monitoring notes 
or summaries will be reviewed to determine any important post entry deviations that 
are not identifiable via programming, and to check that those identified via 
programming are correctly classified.  The final classification will be made blinded to 
treatment allocation (Parts 1 and 2) and prior to database lock.  For example, details 
of disallowed concomitant medication use will be reviewed by a physician and may be 
deemed major. 
Note, failure of an inclusion/exclusion criteria will not automatically be classified as a 
major deviation.   
5.2 
Important Deviations 
In addition to the programmatic determination of the major deviations as described in 
Section 5.1, the following important deviations will be programmatically derived and 
listed and summarized: 
• 
Failure of any inclusion/exclusion criteria (with exception of any inclusion/exclusion 
criteria that are already listed as major deviations) 
• 
Prior anti-cancer treatments which stopped less than 4 weeks before 
randomization (Parts 1 and 2)/starting study medication (Safety lead-in).  
• 
Subjects taking concurrent therapies for BTC.  
• 
Subjects taking continuous treatment with proton pump inhibitors during the study 
period 
• 
Subjects taking strong CYP3A4 inhibitors 
• 
For the Safety lead-in only: <85% compliance during the first 14 days 
Errors in dispensing and incorrect stratifications will be summarized and listed as 
important deviations. These include: 
• 
Subjects who receive no study treatment whatsoever for a period of more than 
one week due to errors in dispensing of medication. Note, this is not due to 
tolerability issues where subjects may stop taking drug 


 
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• 
Subjects who at some point receive the incorrect treatment (e.g. varlitinib rather 
than placebo or vice-versa) 
• 
Subjects who were inadvertently dispensed the wrong dose of capecitabine  
The summary will include all subjects with a dispensing error but will also include 
information on how many of those subjects received at least one dose of the incorrect 
treatment (varlitinib rather than placebo or vice-versa) at any time.  Subjects who 
receive the incorrect treatment at any time will be included in the Safety Set as 
described in Section 4.1. 
In addition, other non-programmable important deviations will be collected on the CRF, 
listed and summarized including, but not limited to: 
• 
For the safety-lead-in only, subjects who were replaced due to <85% varlitinib 
compliance during first 14 days 
• 
Subjects of child-bearing potential not practicing acceptable methods of birth 
control from the time they enter the screening period until 3 months after the 
last cycle of treatment. 
• 
Subjects breast feeding at any point between the time they enter the 
screening period until 3 months after the last cycle of treatment. 
Compliance will be assessed by Study Team review of protocol procedures with 
specific attention paid to missed dosing due to reasons other than AEs. (E,g, subjects 
receiving <75% of intended doses) and will not be assessed programmatically. Any 
compliance issues considered likely to impact on the interpretation of safety or efficacy 
will be added to the deviation CRF page. 
Finally, monitoring notes or summaries will be reviewed to determine any important 
post entry deviations that are not identifiable via programming, and to check that those 
identified via programming are correctly classified.  The final classification will be made 
prior to database lock.  For example, details of disallowed concomitant medication use 
will be reviewed by a physician and if deemed important, may also be included in the 
listing of important deviations. 
All subjects who failed any inclusion/exclusion criteria will be listed along with details 
of the failed criteria. This information will also be summarized in terms of the number 
(%) of subject failing any of the inclusion/exclusion criteria and will be based on the 
FAS. Note, failure of an inclusion/exclusion criteria will not automatically be classified 
as a major deviation.   
Other deviations may occur during the trial, which are considered minor and not 
believed to have any significant impact on the interpretation of the study results.  All of 
these deviations will be recorded by the study monitors but will not be listed or 
summarized as part of the CSR. 
Examples of minor deviations include: 
• 
Visits outside of protocol visit windows 
• 
Incomplete assessments 
• 
Use of concomitant medication related to safety 
This list is not exhaustive and other minor deviations may occur.  


 
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6. 
General Statistical Considerations 
All statistical analyses will be performed by or under the direct auspices of ASLAN 
Pharmaceuticals, using SAS®, Version 9.2 or higher.  
Unless specified otherwise, data from the Safety lead-in, Part 1 and Part 2 will be 
presented separately in the Tables, Figures and Listings. Subjects whose data 
contributed to the Part 1 analysis will not be included in the Part 2 analysis. 
The database for the Safety lead-in will be locked at the time of the Part 1 analyses. 
However, interim data from the Safety lead-in will be made available to the DSMB prior 
to the final data cut-off (DCO), in order to enable the DSMB to review the emerging 
safety and tolerability data and to advise whether the study can proceed into Part 1. 
Details of the data to be provided to the DSMB will be provided in the DSMB charter. 
The primary analysis of Part 1 will be the later of 3 months after Last Subject In (LSI) 
or when 70% of the subjects (84 subjects) have experienced a PFS event. At this point, 
there will be a formal database lock, and the primary analysis of all primary and 
secondary endpoints will be performed.  
The data cut-off for Part 2 will be when 247 OS events have occurred. All secondary 
endpoints, including ORR, PFS and DoR, will be reported at the time of the primary 
analysis of OS. 
6.1 
Sample Size Estimation 
6.1.1 
Safety Lead-in 
The Safety lead-in is not formally powered to assess any statistical hypotheses. In this 
part, 12 to 20 eligible subjects (with at least 6 from the US) will be enrolled to receive 
varlitinib plus capecitabine. 
Subjects in this group will be replaced if varlitinib compliance is < 85% in the first 14 
days. 
6.1.2 
Part 1 
Part 1 is designed with co-primary endpoints, ORR and PFS. In order to maintain an 
overall, one-sided 10% type I error rate for Part 1, a Hochberg procedure will be used, 
such that the trial will be deemed to have met its primary objective if either endpoint is 
significant at the one-sided 5% level, or if both endpoints are significant at the one-
sided 10% significance level. 
One hundred and twenty subjects provides approximately 80% power to detect a true 
difference of 17% in response rate, based on a one-sided 5% significance level and 
assuming 10% response rate for the placebo group and a 27% response rate for 
varlitinib. To ensure the adequate data are available to evaluate the effects of varlitinib 
on both co-primary endpoints, the data cut-off for the primary analysis will be the later 
of 3 months after LSI, and when 70% of subjects (84 subjects) have experienced a 
PFS event.  Based on a minimum of 84 PFS events at the time of the primary analysis, 


 
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the trial would have a minimum of 80% power to detect a true HR of 0.58 for PFS, 
based on a one-sided 5% significance level.  
Furthermore, if the primary objective of the study is met, the following approach for 
type I error control will be applied in order to support marketing approval: 
• 
The overall type I error rate for marketing approval will be controlled at the two-
sided 5% level, using a Hochberg procedure 
• 
Using this approach, statistical significance may be claimed if either ORR or 
PFS is significant at the two-sided 2.5% significance level or if both ORR and 
PFS are significant at the two-sided 5% significance level.   
One hundred and twenty subjects provides approximately 80% power to detect a true 
difference of 20% in response rate, based on a two-sided 5% significance level and 
assuming 10% response rate for the placebo group and a 30% response rate for 
varlitinib. 
A total of 84 PFS events provides 80% power to detect a true HR of 0.54, based on a 
two-sided 5% significance level. Assuming an 8 month non-linear recruitment period, 
a 2.67 month median PFS for capecitabine alone, and a true HR of 0.54, it is estimated 
that the data cut-off for the primary analysis of Part 1 will occur approximately 12 
months after the first subject is randomized into the study (FSI). 
6.1.3 
Part 2 
Part 2 is designed with a primary endpoint of OS. Approximately 350 subjects will be 
randomized into Part 2 to obtain 247 death events (70% maturity). If the true OS HR 
for the comparison of varlitinib+capecitabine versus placebo+capecitabine is 0.7 (likely 
to correspond to a 43% prolongation of OS), the study has 80% power to demonstrate 
a statistically significant difference for OS, assuming a two-sided 5% significance level. 
Assuming non-linear recruitment of 350 subjects over a twenty-four month period, and 
median OS times of 8.6 months and 6 months for the varlitinib and placebo arms 
respectively, it is estimated 247 OS events will occur approximately 31 months after 
FSI for Part 2. 
All secondary endpoints will be analyzed at the time of the primary analysis of OS. 
6.1.4 
Sample Size Re-estimation 
There are no planned sample size re-estimations. 
6.2 
Adjustments for Covariates 
It is planned that all statistical analyses will be stratified by geographical region 
(US/Non-US) and primary tumor location (GB/non-GB), in accordance with the 
stratification factors declared at randomization. 


 
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6.3 
Handling of Dropouts or Missing Data 
In general, missing data will remain missing and will not be included in analyses.   
Exceptions are described below.  
• 
Missing Baseline Data 
If a baseline (Day 1) value is not available and a screening value is available for the 
same parameter, then the last screening value will be used as baseline.  This value 
will also be used for calculations of changes from baseline. 
• 
Missing % Change from Baseline in Sum of Longest Diameters of Target Lesions 
(TLs) at Week 12 
An increase from baseline of 20% will be imputed for any subjects who die by any 
cause, or withdraw from the study due to symptomatic disease progression prior to 
Week 12+ 5 days. Any subjects who withdraw from the study due to radiological 
disease progression prior to Week 12 will be included in the analysis, and will be 
assigned a percentage change from baseline of 20%, or the value that was observed 
at the time of disease progression (whichever is larger). 
• 
Missing Best % Change from Baseline in Sum of Longest Diameters of TLs at any 
time 
For the waterfall plot of the best % change from baseline, subjects with measurable 
disease at baseline (see Section 4.3), for whom no post-baseline TL data are available, 
will have an increase from baseline of 20% imputed in the following circumstances: 
o The subject has died prior to week 12 (+ 5 days) 
o Progression has been detected based on NTLs or new lesions prior to week 
12 (+ 5 days) 
o Subject has withdrawn due to symptomatic progression prior to week 12 (+ 
5 days) 
6.4 
Monitoring and Interim Analyses 
6.4.1 
Monitoring 
The study will be monitored to ensure that the study is conducted and documented 
properly according to the protocol, good clinical practice (GCP), and all applicable 
regulatory requirements. 
6.4.2 
Interim Analysis 
Data from the open-label Safety lead-in will be reviewed on an ongoing basis, and a 
Data Safety Monitoring Board (DSMB) meeting will occur once the first 12 subjects 
have completed one cycle of treatment (with a minimum 85% compliance over the first 
14 days). The purpose of the initial DSMB meeting is to review the safety and 
tolerability data prior to commencement of Part 1 of the study. 
 


 
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There are no interim analyses planned during Part 1 or 2. The primary analysis of Part 
1 will be the later of 3 months after Last Subject In (LSI) or when 70% of the subjects 
(84 subjects) have experienced a PFS event. At this time, a database lock will be 
performed and the primary analysis of all primary and secondary endpoints will be 
performed. The data cut-off for Part 2 will be following the 247th OS event. Whilst Part 
2 is ongoing, further efficacy and safety data may continue to be accrued for Part 1 
subjects. For example, further OS events occurring after the primary analysis of Part 
1 will continue to be collected and databased. 
The database for both parts of the study will be locked at the data cut-off for the Part 
2 analyses.  
Data for any subjects who continue to receive treatment beyond this point will be 
reported as a further addendum to the CSR. 
6.5 
Multiple Testing Strategy 
6.5.1 
Part 1 
Part 1 is designed with co-primary endpoints, ORR and PFS. In order to maintain an 
overall, one-sided 10% type I error rate for Part 1, a Hochberg procedure will be used, 
such that the trial will be deemed to have met its primary objective if either endpoint is 
significant at the one-sided 5% level, or if both endpoints are significant at the one-
sided 10% significance level. If the trial meets its primary objective as described above, 
all secondary efficacy endpoints will also be tested at the one-sided 10% significance 
level to better understand the clinical benefit offered by varlitinib treatment. 
Furthermore, if the primary objective of the study is met, as described above, statistical 
significance at the two-sided 5% level will be tested to support marketing approval. For 
this assessment , the following approach to type I error control will be applied: 
• 
The overall type I error rate for marketing approval will be controlled at the two-
sided 5% level, using a Hochberg procedure 
• 
Using this approach, statistical significance may be claimed if either ORR or 
PFS is significant at the two-sided 2.5% significance level or if both ORR and 
PFS are significant at the two-sided 5% significance level.  
If statistical significance is demonstrated using the approach described above, the 
secondary endpoints OS and DCR will also be assessed at the two-sided 5% 
significance level, in order  to further describe the nature of the benefits offered by 
varlitinib treatment, to support marketing authorisation.   
For the purpose of supporting marketing approval, all hypothesis testing at significance 
levels higher than 5% will be considered exploratory. 
6.5.2 
Part 2 
In order to describe the nature of the benefits of varlitinib treatment, OS, ORR, PFS 
and DCR will all be tested at a 2-sided significance level of 5%. 


 
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However, in order to strongly control the type I error at the two-sided 5% level, the 
following hierarchical testing order is defined for the Part 2 efficacy endpoints: OS – 
ORR – PFS – DCR. 
6.6 
Examination of Subgroups 
For ORR (Part 1), PFS (Part 1) and OS (Part 2), sub-group analyses will be performed 
to investigate the consistency of the treatment effect across expected prognostic 
factors, and possible predictive factors. The sub-groups to be explored are the 
stratification factors region (US/Non-US) and primary tumor location (GB/Non-GB), 
plus the following factors: 
• 
Gender (Male vs. Female) 
• 
Race (Asian/Caucasian/Other) 
• 
Baseline ECOG Status 
• 
Extent of Disease (Locally Advanced/Metastatic) 
• 
Age (<60/>=60) 
• 
Baseline HER2 expression (positive defined as +++ or above by IHC, otherwise 
negative)  
• 
Any HER positivity (positive defined as + or higher by IHC for HER1, HER2, HER3 
or HER4, otherwise negative) 
These sub-group analyses will be performed using the primary analysis population, 
and considered supportive of the primary analyses, thus no adjustment to the 
significance level will be made.  
Sub-group analyses will not routinely be performed for the sensitivity analysis 
populations, unless the main sensitivity analysis results do not concur with the primary 
analysis, and further investigation is required. 
6.7 
Stratification Factors 
As described in Section 2.2, for Parts 1 and 2, the randomization scheme will be 
stratified by region (US/Non-US) and primary tumor location (GB/Non-GB). It is 
planned that all formal statistical analyses will be stratified by the same two factors, 
using the values declared at randomization. 
In the event that any individual stratum is very small, and contains limited information 
(i.e. events or responders), certain stratified analysis techniques may result in the 
entire stratum’s data being “omitted” from the fitted model. Furthermore, even when 
the primary analysis can be fitted, if the information within the stratum is limited, the 
treatment by stratum interaction tests are unlikely to be meaningful, and the planned 
sub-group analyses may also become problematic. 
If there are fewer than 8 patients in any of the 4 strata, the number of events (PFS and 
OS) and responders (ORR and DCR) within the affected stratum will be reviewed, prior 
to study unblinding. If at the blind review stage there is deemed to be insufficient 
information within the stratum to make the planned stratified analysis meaningful, 
geographical region will be “dropped” as a stratification factor from the statistical 
analyses, and the primary analyses would remain stratified by primary tumor location 
(GB/non-GB). The reason for removing geographical region rather than primary tumor 


 
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location as a stratification factor, is that it is anticipated that the percentage of GB:non-
GB patients will be closer to 50:50, therefore geographical region is the stratification 
factor most likely to be driving the small stratum. 
In this scenario, geographical location (US/non-US) would be added to the list of 
factors to be explored as part of the planned sub-group analyses. As noted above, any 
decision to exclude geographical region as a stratification factor in the analysis would 
be made prior to study unblinding, and would be fully documented in the study file. 
7. 
Methods of Analysis 
7.1 
Objective Response Rate 
All RECIST-based data will be listed, and the BoR and ORR will be summarized by 
treatment group. For those subjects with a BOR of PD, the summary will include sub-
categories to distinguish between PD as defined by the RECIST criteria, and early 
deaths that have been assigned to the PD category (see Section 3.1.1). A listing of 
early deaths will also be provided.  
As described in Section 3.1.1, and in accordance with RECIST v1.1, response 
confirmation is not required in order for a subject to be classified as a responder for 
the assessment of ORR. For Part 1 only, descriptive statistics will also be produced 
for BoR and ORR, based on confirmed responses only using the FAS set. For this 
summary table, to be classified as a responder, the subject would need to have at least 
two assessments where the visit response is PR or CR, without any intermediate 
assessments indicative of progression. 
There will be no formal analyses of efficacy data from the Safety lead-in. For Parts 1 
and 2, the primary analysis will test for the superiority of varlitinib-containing treatment 
arm relative to the placebo-containing arm. 
Objective Response Rate will be analyzed using a stratified exact binomial test (Mehta 
et al, Emerson) which extends Fisher’s Exact test to more than one strata. The analysis 
will be stratified by region (US/Non-US) and primary tumor location (Gall Bladder/Non-
GB). The 2-sided p-value will be obtained by doubling the 1-sided p-values.  
The conditional maximum likelihood estimate of the odds ratio will be presented 
together with its exact 2-sided 95% confidence limit, which excludes one if and only if 
the stratified exact binomial test is significant at a 2-sided 5% level. For Part 1 only, 
corresponding significance levels and confidence intervals will be calculated using 
tests performed at a 1-sided 10% level. The one-sided P-value will also be presented. 
To test for heterogeneity across strata, the exact test of Zelen will be performed by 
testing whether the treatment effect differs between the 4 strata included in the primary 
analysis. 
For Part 1 only, subgroup analyses will be conducted comparing ORR between 
treatments in the subgroups of the FAS set defined by the stratification factors Region 
(US/Non-US) and primary tumor location (GB/Non-GB), plus the following factors: 


 
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• 
Gender (Male vs. Female) 
• 
Race (Asian/Caucasian/Other) 
• 
Baseline ECOG Status 
• 
Extent of Disease (Locally Advanced/Metastatic) 
• 
Age (<60/>=60) 
• 
Baseline HER2 expression (positive defined as +++ or above by IHC, otherwise 
negative)  
• 
Any HER positivity (positive defined as + or higher by IHC for HER1, HER2, 
HER3 or HER4, otherwise negative) 
Other baseline variables may also be included if there is clinical justification or an 
imbalance is observed across the treatment arms.  
For Part 1, for each sub-group, the odds ratio and corresponding 80% confidence 
interval will be presented on a forest plot including the odds ratio and 80% CI from the 
overall population. Additionally, if the primary analysis of ORR is significant at the two-
sided 5% level in the overall population, the forest plot will be replicated using 95% 
confidence intervals. 
No adjustment to the significance level for testing will be made since all these analyses 
will be considered supportive of the primary analysis of ORR. 
Subjects whose data contributed to the Part 1 analysis will not contribute to the Part 2 
analysis. 
For Part 1, the primary analysis of ORR based on ICR will be performed using the FAS 
set, and two sensitivity analyses will be performed using the EFR and PP sets. Note 
that the subgroup analyses will not be repeated for the sensitivity analyses. ORR 
based on site assessments is a secondary endpoint and will be analyzed using the 
FAS set. No sub-group analyses are planned for this secondary endpoint. 
For Part 2, the primary analysis of ORR will be performed using the FAS set, based 
on the site assessments of radiological data. No subgroup analyses are planned for 
ORR in Part 2. 
7.2 
Progression-Free Survival 
In Parts 1 and 2, the primary analysis will test for the superiority of the 
varlitinib-containing treatment arm relative to the placebo-containing arm, as assessed 
by PFS.   
In Part 1, the data cut-off for the primary analysis of PFS will be the later of 12 weeks 
after LSI and 84th documented PFS event. The primary analysis of PFS will be based 
on data from the ICR. An analysis of PFS based on site assessments will be used to 
assess the sensitivity of the primary analysis to informative censoring. See Section 
7.2.1.2. 
In Part 2, PFS will be analyzed at the time of the primary analysis of OS. The Part 2 
PFS analysis will be based on the site assessments of radiological data. 
In both study parts, PFS will be analyzed using a stratified log-rank test using the 
Breslow method to handle ties (Breslow, 1974). The stratification factors are 


 
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geographical region (US/Non-US) and primary tumor location (GB/Non-GB). The 
results will be presented in terms of the HR (with a HR <1 favoring the varlitinib-
containing arm) and associated two-sided 95% confidence interval (CI) and two-sided 
p-value. For Part 1 only, the 80% confidence interval and one-sided p-value will also 
be presented. The HR and its CI can be estimated from the log-rank as follows (Berry 
et al 1991, Collett, 2003, Sellke and Siegmund 1983): 
 
Kaplan-Meier (KM) plots of PFS, with tick marks to identify censored observations, will 
be presented by treatment group. Summaries of the number and percentage of 
subjects experiencing a PFS event, and the type of event (RECIST 1.1 progression or 
death) will be provided along with median PFS for each treatment. 
The assumption of proportionality will be assessed. 
For Part 1 only, subgroup analyses will be conducted comparing PFS between 
treatments in the subgroups of the full analysis set defined by the stratification factors 
Region (US/Non-US) and primary tumor location (GB/Non-GB), plus the following 
factors: 
• 
Gender (Male vs. Female) 
• 
Race (Asian/Caucasian/Other) 
• 
Baseline ECOG Status 
• 
Extent of Disease (Locally Advanced/Metastatic) 
• 
Age (<60/>=60) 
• 
Baseline HER2 expression (positive defined as +++ or above by IHC, otherwise 
negative)  
• 
Any HER positivity (positive defined as + or higher by IHC for HER1, HER2, 
HER3 or HER4, otherwise negative) 
Other baseline variables may also be assessed if there is clinical justification. For each 
subgroup, the HRs (varlitinib: placebo) and associated CIs will be calculated from a 
log rank test within each individual subgroup.  These will be presented on a forest plot 
including the HR and 80% CI from the overall population. Additionally, if the primary 
analysis of PFS is significant at the two-sided 5% level in the FAS, the forest plot will 
be replicated using 95% confidence intervals. 
The purpose of the subgroup analyses is to assess the consistency of treatment effect 
across expected and possible prognostic and predictive factors. No adjustment to the 
significance level for testing will be made since all these analyses will be considered 
supportive of the primary analysis of PFS. 


 
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For both Part 1 and Part 2, Cox proportional hazards modeling will be employed to 
assess the effect of covariates on the HR estimate. Before embarking on more detailed 
modeling, an initial model will be constructed, containing treatment and the two 
stratification factors alone, to ensure any output from the Cox modeling is likely to be 
consistent with the results of the stratified log-rank test. 
The presence of quantitative interactions will be assessed formally by means of an 
overall global interaction test. This will be performed in the full analysis set by 
comparing the fit of a Cox proportional hazards model including treatment, all 
covariates, and all covariate-by treatment interaction terms, with one that excludes the 
interaction terms and will be assessed at the 2-sided 10% significance level. If the fit 
of the model is not significantly improved then it will be concluded that overall the 
treatment effect is consistent across the subgroups. 
If the global interaction test is found to be statistically significant, an attempt to 
determine the cause and type of interaction will be made. Stepwise backwards 
selection will be performed on the saturated model, whereby (using a 10% 2-sided 
level throughout) the least significant interaction terms are removed one-by-one and 
any newly significant interactions re-included until a final model is reached where all 
included interactions are significant and all excluded interactions are non-significant. 
Throughout this process all main effects will be included in the model regardless of 
whether the corresponding interaction term is still present. This approach will identify 
the factors that independently alter the treatment effect and prevent identification of 
multiple correlated interactions. 
Any quantitative interactions identified using this procedure will then be tested to rule 
out any qualitative interaction using the approach of Gail and Simon 1985. 
For both parts, the primary analysis of PFS will be based on the programmatically 
derived PFS using all scans regardless of whether they were scheduled or not.  
The primary analysis will be performed on the FAS.  
Subjects whose data contributed to the Part 1 analysis will not also contribute to the 
Part 2 analysis. 
7.2.1 
Sensitivity Analyses for PFS – Part 1 only 
The following sensitivity analyses will be performed to investigate the impact of 
potential sources of bias in the primary assessment of PFS. 
7.2.1.1 Assessment of Major Deviations 
To assess the impact of major protocol deviations on the primary analysis of PFS, a 
sensitivity analysis will be performed using the PP analysis set. PFS based on the PP 
set will be analyzed using a stratified log-rank rest, using the methods described for 
the primary analysis of PFS in Section 7.2. Note, sub-group analyses will not be 
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7.2.1.2 Assessment of Informative Censoring 
For Part 1, the primary analysis of PFS is based on an ICR of radiological data. 
Informative censoring can occur if site believe that a subject has progressed and 
perform no further radiological assessments in that subject, but the ICR disagree, thus 
the subject becomes censored at the last available radiological assessment for the 
ICR assessment of PFS. 
To investigate the sensitivity of the primary analysis to this source of bias, a sensitivity 
analysis will be performed using PFS based on the site assessment of the radiological 
data. PFS based on site assessments will be analyzed using a stratified log-rank rest, 
using the methods described for the primary analysis of PFS in Section 7.2. Note, the 
sub-group analyses will not be performed for the sensitivity analysis. 
7.2.1.3 Evaluation-Time Bias Assessment 
Bias can be introduced if one treatment arm is assessed more frequently than the 
other.  
For both Parts 1 and Part 2, sensitivity analyses will be performed to assess possible 
evaluation-time bias that may be introduced if scans are not performed at the protocol-
scheduled timepoints. The midpoint between the time of progression and the previous 
evaluable RECIST assessment will be analyzed using a stratified log-rank test, as 
described in Section 7.2. This approach has been shown to be robust to even highly 
asymmetric assessment schedules (Sun and Chen 2010). Note that the sub-group 
analyses will not be performed for the sensitivity analysis. 
7.2.1.4 Attrition-Bias Assessment 
Attrition bias will be assessed by repeating the primary PFS analysis except that the 
actual PFS event times, rather than the censored times, of subjects who progressed 
or died in the absence of progression immediately following two, or more, non-
evaluable tumor assessments will be included. In addition, subjects who take 
subsequent therapy prior to progression or death will be censored at their last 
evaluable assessment prior to taking the subsequent therapy. This analysis will be 
performed using the methods described in Section 7.2, supported by a Kaplan-Meier 
plot of the time to censoring where the censoring indicator of the primary PFS analysis 
is reversed. Note that the sub-group analyses will not be performed for the sensitivity 
analysis. 
7.3 
Overall Survival 
For Parts 1 and 2, the analysis of OS will test for the superiority of varlitinib-containing 
treatment arm relative to the placebo-containing arm.  
For Part 1, OS will be analyzed at the time of the primary analysis of ORR and PFS. 
For Part 2, the primary analysis of OS will be performed after the 247th documented 
OS event.  


 
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OS will be analyzed using the methods described in Section 7.2 for the primary 
analysis of PFS. For Part 2 only, sub-group analyses, as described in Section 7.2, will 
also be performed. 
Subjects whose data contributed to the Part 1 analysis will not contribute to the Part 2 
analysis. 
7.4 
Duration of Response 
The DoR will not be formally analyzed. DoR will be listed and presented using Kaplan-
Meier curves. Descriptive statistics, based on the KM estimates, will be presented by 
treatment group. For Part 1, DoR will be based on data from the ICR. For Part 2, DoR 
will be based on site assessments. 
7.5 
Disease Control Rate 
Disease Control Rate will be analyzed using a stratified exact binomial test (Mehta et 
al, Emerson) which extends Fisher’s Exact test to more than one strata. The analysis 
will be stratified by region (US/Non-US) and primary tumor location (Gall Bladder/Non-
GB).   The 2-sided p-value will be obtained by doubling the 1-sided p-values.  
The conditional maximum likelihood estimate of the odds ratio will be presented 
together with its exact 2-sided 95% confidence limit, which excludes one if and only if 
the stratified exact binomial test is significant a 2-sided 5% level.    For Part 1 only, 
corresponding significance levels and confidence intervals will be calculated using 
tests performed at a 1-sided 10% level. The one-sided p-value will also be presented. 
To test for heterogeneity across strata, the exact test of Zelen will be performed testing 
whether the treatment effect differs between the 4 strata included in the primary 
analysis. 
The primary analysis of DCR will be based on the FAS set. For Part 1 and 2, a 
sensitivity analysis will also be performed using the EFR. 
7.6 
Tumor Size 
For all study parts, tumor size will be presented graphically using waterfall plots for 
each treatment arm, presenting each subject’s Week 12 percentage change in tumor 
size as a separate bar with the bars ordered from the largest increase to the largest 
decrease.  Reference lines at the +20% and –30% change in tumor size levels will be 
added to the plots, which correspond with the definitions of disease progression and 
PR, respectively.  In these waterfall plots, the subjects whose Week 12 percentage 
change in tumor size is based on an imputation will be clearly identified. For Parts 1 
and 2, the two treatment arms will be plotted separately, but presented side-by-side 
on a single page. 
Waterfall plots of the best percentage change from baseline will also be presented, as 
described above for the Week 12 percentage change from baseline.  
The percentage change from baseline in tumor size at Week 12 (%ΔTSWk12) is a 
secondary endpoint for Part 1. In line with the exploratory objectives of the trial, the 


 
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statistical analysis of tumor size in Part 1 will be also be used to help evaluate the role 
of HER family expression levels as predictors of benefit to varlitinib.  If a relationship 
is found between biomarker(s) expression and clinical outcomes in Part 1 of the study, 
the biomarker(s) could be prospectively evaluated in Part 2 of the study. 
These analyses will be exploratory, and may be driven by the data observed, and 
specifically the prevalence of the HER family sub-groups of interest. However, the 
analysis principles to be followed are outlined below. 
1. ASLAN will create and document a list of the key biomarkers of interest, based 
upon the biological plausibility of predictivity for clinical outcomes. The list will 
be limited to those biomarkers, or combinations of biomarkers for which a 
scientific hypothesis exists. These will represent the biomarkers that will be 
used to assess the listed exploratory objectives, providing that there is 
sufficient prevalence of that biomarker in the trial population. 
2. For each biomarker of interest, each subject’s baseline biomarker status will 
be independently evaluated blinded to study treatment and clinical outcome 
3. For each biomarker sub-group, or combination of biomarkers identified on the 
prospectively defined list (step 1), if at least 15 subjects in the EFR population 
are determined to be expressors, then the role of that biomarker as a predictor 
of clinical outcome (tumor size) will be evaluated as described below. 
For each biomarker of interest (or combination of biomarkers), the absolute values at 
baseline and Week 12, along with the percentage change from baseline target lesion 
size at Week 12 will be summarized using descriptive statistics and presented by 
treatment arm and baseline biomarker status.  
The number and percentage of subjects in each treatment arm whose Week 12 data 
is imputed will also be presented (split by biomarker sub-group).   
The effect of varlitinib on percentage change in tumor size will be estimated from an 
analysis of covariance (ANCOVA) model fitting the Week 12 percentage change from 
baseline as the response variable, and treatment, geographical location (US/Non-US), 
primary tumor location (GB/Non-GB), baseline biomarker status (positive or negative), 
the interaction treatment x baseline biomarker status, baseline tumor size, and the time 
from the baseline scan to randomization as covariates.   
The significance of the interaction term will be evaluated at the one-sided 10% level, 
to determine whether there is evidence of a treatment biomarker interaction. 
Regardless of the significance of the interaction term, the number of subjects, 
unadjusted mean and adjusted least squares (LS) means for each treatment arm will 
be presented for each level of biomarker status factor (positive or negative), together 
with the difference in adjusted LS means between treatment arms for each level of the 
biomarker status factor, and corresponding p-value and 80% and 95% confidence 
intervals for the difference.  
If the interaction term is not significant at the one-sided 10% level, the number of 
subjects, unadjusted mean and adjusted least squares (LS) means for each treatment 
arm will also be presented together with the difference in adjusted LS means between 
treatment arms and corresponding p-value and 80% and 95% confidence intervals for 
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If, at blind review, it is judged the data do not adequately follow a normal distribution 
assumption, then a log-transformation may be used.  Specifically, in place of percent 
change in Week 12 value the ANCOVA model will use loge (Week 12/baseline).  In this 
situation the ratio of the geometric LS means corresponding confidence interval and 
p-value will be presented.   
As a sensitivity analysis a nonparametric analysis will be performed.  The p-value from 
the ANCOVA model will be presented together with the Hodges Lehmann estimate of 
the median difference and corresponding 80% confidence interval which will be 
derived.  The median percentage change and range will be presented for each 
treatment arm, together with the number of subjects and percentage of subjects in 
each treatment arm whose Week 12 data is imputed in the nonparametric analysis.  
For all biomarkers of interest (step 1), waterfall plots color-coded by baseline 
biomarker status will be produced. 
7.7 
Assessment of Safety and Tolerability  
All safety data will be assessed for the safety population.  
7.7.1 
Assessment of Adverse Events 
All AE data will be listed along with information regarding initial study dose, dose at 
onset, onset time, duration, severity, and relationship to study treatment.  
Treatment emergent AEs (TEAEs) are defined as AEs with an onset date on or after 
the start of treatment. The following summaries will be produced, by treatment group 
and overall for all TEAEs:  
• 
An overview table of the incidence of TEAEs, grade 3+ TEAEs, SAEs, TEAEs 
leading to treatment discontinuation and TEAEs leading to death, by treatment arm 
and overall. For each summary category, the results will be shown overall 
(regardless of causality), and for the incidence of causally related TEAEs. For 
example, the overall incidence of TEAEs will be presented, as well as the incidence 
of TEAEs related to randomized therapy, the incidence of TEAEs related to 
capecitabine and the incidence TEAEs related to both randomized therapy and 
capecitabine. 
• 
Summary of TEAEs by system organ class (SOC) and preferred term: Both the 
number and percentage of subjects in each category (subject-level summary) and 
the number of episodes (episode-level summary). This summary table will be 
repeated for TEAEs attributed as causally related to randomized therapy (varlitinib 
or placebo)  
• 
Summary of TEAEs occurring in at least 10% of subjects, sorted in descending 
order of frequency (i.e. most frequent event shown first). The order of frequency 
will be determined by the most frequent preferred term across both arms, 
regardless of CTC grade. For each event, the results will be presented for all CTC 
grades, and also split by grade 1-2, and grade 3+. 
• 
Summary of TEAEs attributed as causally related to randomized therapy occurring 
in at least 10% of subjects, sorted in descending order of frequency (i.e. most 
frequent event shown first). The order of frequency will be determined by the most 


 
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frequent preferred term across both arms. For each event, the results will be 
presented for all CTC grades, and also split by grade 1-2, and grade 3+. 
• 
Summary of CTC grade 3 and above TEAEs sorted in descending order of 
frequency (i.e. most frequent event shown first). The order of frequency will be 
determined by the most frequent preferred term across both arms. 
• 
A summary or CTC grade 3 and above TEAEs attributed as causally related to 
randomized therapy sorted in descending order of frequency (i.e. most frequent 
event shown first). The order of frequency will be determined by the most frequent 
preferred term across both arms. 
• 
Summary of SAEs by preferred term  
• 
Summary of SAEs attributed as causally related to randomized therapy, sorted by 
preferred term 
Additionally, the following will be listed:  
• 
AEs with outcome of death along with the date of onset, study day, dose at onset, 
treatment status at onset (pre-treatment, ongoing or post-treatment) and 
investigator’s assessment of severity and relationship to study drug  
• 
All SAEs along with the date of onset, study day, dose at onset, treatment status 
at onset (pre-treatment, ongoing or post-treatment), date of resolution (if AE is 
resolved), investigator’s assessment of severity and relationship to study drug 
• 
AEs leading to discontinuation of study medication, listed along with the date of 
onset, study day, dose at onset, treatment status at onset (pre-treatment, ongoing 
or post-treatment) and investigator’s assessment of severity and relationship to 
study drug  
If an AE is reported more than once during the study period the greatest severity and 
the worst-case attribution will be presented in summary tables. Any AEs commencing 
>28 days after discontinuation of study treatment will not be included in the tabulations 
of AE data.  
7.7.2 
Clinical Laboratory Data 
All clinical laboratory data (clinical chemistry, hematology and urinalysis data), vital 
signs and ECG data will be listed. In addition, all data measured on a continuous scale 
(except respiration rate and pulse) will be displayed graphically as described below:  
For the Safety lead-in:  
• 
Subject profile plots of laboratory data over time, including reference lines at the 
LLN and ULN. Any dose reductions will be indicated on the plots using a change 
in line-type. 
• 
Subject profile plots of the change from baseline over time, including a horizontal 
reference line at zero. Any dose reductions will be indicated on the plots using a 
change in line-type. 
For Parts 1 and 2:  
• 
Box plots over time, by treatment, including reference lines at the LLN and ULN  
• 
Box plots of the change from baseline over time, by treatment, including a 
horizontal reference line at zero  


 
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To enable assessment of the potential for drug-induced liver injury, for all study parts 
the following outputs will be produced: 
• 
A scatter plot of maximum on-treatment alanine aminotransferase (ALT) versus 
maximum on-treatment total bilirubin (x-axis), both expressed as multiples of the 
upper limit of normal (ULN), including reference lines at 3×ULN for ALT, and 
2×ULN for total bilirubin. For each subject, the maximum ALT and maximum total 
bilirubin may occur at different visits  
• 
A scatter plot of maximum on-treatment aspartate aminotransferase (AST) versus 
maximum on-treatment total bilirubin (x-axis), both expressed as multiples of the 
upper limit of normal (ULN), including reference lines at 3×ULN for AST, and 
2×ULN for total bilirubin.  For each subject, the maximum AST and maximum total 
bilirubin may occur at different visits. 
In the event that the scatter plots of ALT or AST against bilirubin identify any potential 
Hy’s law cases (subjects with either both ALT > 3 x ULN and total bilirubin > 2 x ULN, 
or both AST > 3 x ULN and total bilirubin > 2 x ULN), profile plots over time will be 
produced for these subject’s liver function tests (ALT, AST, ALP and total bilirubin), 
expressed in multiples of the ULN, showing all four FLT parameters on the same plot. 
7.7.3 
ECG Data 
For all study parts, ECG data will be summarized as described below: 
• 
For each parameter, absolute values and the change from baseline at each 
scheduled assessment will be summarized by treatment group using 
descriptive statistics including number of observations, mean, standard 
deviation, minimum, median and maximum values. 
For both the Safety lead-in and Part 1, the following will be summarized: 
• 
The proportion of patients obtaining treatment-emergent absolute QTcF values 
> 450 ms and ≤ 480 ms; > 480 ms and < 500 ms; and > 500 msec 
• 
The proportion of patients obtaining a QTcF increase from baseline values ≥30 
and <60 ms; and ≥60 ms 
• 
The proportion of patients obtaining a QRS change from baseline > 25% 
resulting in QRS > 120 ms 
• 
The proportion of patients obtaining a PR interval change from baseline >25% 
reaching a value >220 ms 
• 
The proportion of patients obtaining a > 25% decrease from baseline in heart 
rate, resulting in a heart rate < 50 beats per minute (bpm) or a >25% increase 
from baseline in heart rate resulting in a heart rate > 100 bpm 
 
For Part 1, the above categorical data summaries will be presented by treatment arm.  
All outliers will be summarized for each treatment group on the basis of incidence rates.  
A subject will be counted only once for a particular outlier event if the subject 
experiences more than one episode of that event. 
 
T-wave morphology will also be analyzed and will be listed and summarized using 
descriptive statistics, focusing on change from baseline, i.e., treatment emergent 
changes. 


 
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7.7.4 
Physical Examination 
Physical examination data will be listed.  
7.7.5 
Exposure, Dose Intensity and General Tolerability 
To further assess the tolerability of varlitinib 300 mg BID in combination with 
capecitabine, the dose intensity and treatment exposure of both the randomized 
therapy and capecitabine, as defined in Section 3.2.2, will be listed and summarized 
by treatment arm. Exposure summaries will be produced overall (across all cycles) and 
dose intensity will be presented by cycle for the first 3 cycles, and overall. 
 
For Part 1, swimmer plots of the time on treatment will be presented for all subjects in 
the FAS. The bars on these plots will be ordered as follows: 
 
CR subjects at the top, PR subjects next, SD next, PD next and NE subjects at the 
bottom. Within each category they will be sorted from longest treatment duration to 
shortest treatment duration. Subjects whose time on treatment is censored will be 
indicated.  
 
This plot will be repeated to account for dose modifications and interruptions. 
For Part 2, swimmer plots of time on treatment will be produced for responding subjects 
only. 
7.8 
Disposition of Subjects 
Subject disposition, including but not limited to, the date of informed consent, 
randomization details (Parts 1 and 2 only), date of first dose (Safety lead-in only) and 
reasons for discontinuation from randomized therapy (Parts 1 and 2) or study 
treatment (Safety lead-in), will be listed and summarized by treatment group. 
7.9 
Demographics and Baseline Characteristics 
Demographic and baseline characteristic data will be presented based on the FAS.  
 
Baseline demographic data, including, but not limited to: 
• 
age 
• 
gender 
• 
weight 
• 
height 
• 
race 
• 
geographical location 
• 
primary tumor location (intra-hepatic bile duct, extra-hepatic bile duct, hilar, gall 
bladder, ampulla of vater or other)  
• 
ethnicity 
• 
baseline HER1, HER2, HER3 and HER4 status 
 
will be listed and summarized using appropriate descriptive statistics. 


 
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7.10 
Medical History and Prior and Concomitant Medications  
Relevant medical history and prior treatment for BTC will be listed. For Parts 1 and 2, 
prior therapies will also be summarized by treatment group, type of therapy (local/, 
surgery, or systemic therapy), reason for therapy (adjuvant, neoadjuvant or metastatic 
therapy) and best response.  
 
All medications received following the start of treatment (including those that were 
ongoing prior to first dose) will be listed.  
 
7.11 
Pharmacokinetic Data 
Safety Lead-in part: 
 
Pharmacokinetic 
parameters 
in 
plasma 
will 
be 
derived 
using 
standard 
non-compartmental methods with WinNonlin® Professional Version 7.3 or higher 
(Pharsight Corp., Mountain View, California, US) or SAS® Version 9.2 or higher (SAS 
Institute, Inc., Cary, North Carolina, US). Based on previous population PK analyses, 
a one compartment with delayed first-order absorption and first-order elimination, and 
auto-inhibition on parameter CL/F will be selected as the base model. Actual elapsed 
time from dosing will be used for final plasma PK parameter calculations. 
 
Part 1 and Part 2: 
 
The bioanalytical analysis of the plasma concentration data for varlitinib will be 
performed at CMIC Pharmaceuticals Japan. Pharmacokinetic analyses will be 
conducted according to CMIC Standard Operating Procedures (SOPs) for PK analyses 
unless otherwise specified.  
In Parts 1 and 2 of the study, Population PK analyses to describe the PK in the 2nd line 
BTC population, and PK/PD analyses to explore the potential of varlitinib to prolong 
the QTc interval, will be performed by nonlinear mixed effects model (NLME) using 
NONMEM version 7.3 (ICON plc, Ellicott City, MD, USA).  
R version 3.3.3 or later (R Foundation for Statistical Computing, Vienna, Austria. 
URL http://www.R-project.org/) or SAS® Version 9.2 or higher (SAS Institute, Inc., 
Cary, North Carolina, United States) will be used for data preparation, visualization 
and inspection of the raw data and/or post-processing of NONMEM outputs. PsN 4.4.8 
(Lindbom et al) may be used as aids in model assessment and for some automated 
modeling and simulation procedures.  
Actual dates and time of samples and doses will be used for final analyses. 
7.11.1 
Concentration Values  
All concentration values below the lower limit of quantification (LLQ) and samples with 
no reportable value occurring prior to dosing will be replaced by “0”. For tabulation, 
graphical representation and calculation of summary statistics, all samples <LLQ or 
with no reportable value observed after drug administration will be treated as missing.  


 
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7.11.2 
Calculation of the Actual Sampling Times  
For all sampling times, the actual sampling times will be calculated as the difference 
between the sample collection actual clock time and the actual clock time of the oral 
administration of the tablet. 
 
Therefore:  
Actual clock time of sample collection = actual clock time of dosing + difference  
 
The actual sampling times expressed in hours and rounded off to 3 decimal digits will 
be used to calculate the PK parameters, except for pre-dose samples, which will 
always be reported as zero (0.000), regardless of the time difference.  
 
7.11.3 
Pharmacokinetic Analysis  
For the Safety lead-in summary statistics for varlitinib will be tabulated for the PK 
parameters detailed in Section 3.3 by study day. The mean, standard deviation (std), 
coefficient of variation (%CV), geometric mean, %CV geometric coefficient of variation, 
median, minimum, and maximum will be presented for PK parameters detailed in 
Section 3.3. Median, minimum, and maximum will be presented for tmax.  
 
Profile plots will be provided on both linear and log scale, showing the subject data.  
 
For Part 1 and 2 
 
Using appropriate PK software depending on whether comprehensive PK sampling 
or sparse PK sampling is obtained in practice, the PK data will be used to derive PK 
parameters such as, but not restricted to, Cmax, AUC, and t1/2 for varlitinib. 
 
The final PK analyses will be the responsibility of the CRO. Pharmacokinetic 
analyses will be conducted according to CRO Standard Operating Procedures 
(SOPs) for PK analyses unless otherwise specified. The actual PK sampling times 
will be used in the PK calculations.  
 
The varlitinib concentration-time profiles, along with the derived PK variables, will be 
listed for each patient per dose and dosing day and summarized appropriately. 
Population PK models may be used to derive the PK parameters and will aim to 
characterize variability in the population by investigating the influence of covariates 
such as weight, age, smoking status and/or concomitant medications. In addition, if 
the data are suitable, potential relationships between plasma varlitinib and efficacy or 
safety endpoints will be investigated using a graphical approach and/or appropriate 
PK/PD modeling techniques. 
7.11.4 
PK/PD Analyses with special consideration of effects on QT 
7.11.4.1 General Principles 
The final ECG assessments (including interval measurements) will be made by the 
Core ECG laboratory. The Part 1 electrocardiographic Core ECG Laboratory 
assessments constitute the study’s primary assessment of ECG/QTc. Any analysis of 
ECG data from the Safety lead-in is considered exploratory. 


 
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Due to the non-randomized, open label design of the Safety lead-in, data from the 
Safety lead-in will be presented separately from data from Part 1 of the study. 
Furthermore, local ECG/QT outputs (not the central ECG report) will be made available 
to the DSMB for consideration when determining whether the study should progress 
to Part 1. 
7.11.4.2 Methods of Analysis 
Safety Lead-in 
Data from the Safety lead-in will be used to explore possible relationships between the 
varlitinib plasma concentrations and changes from baseline in QTcF via exposure-
response modeling of the QTcF and the concentrations of varlitinib, capecitabine, and 
their major metabolites.  
To support the interpretation of these analyses, the following graphical displays will be 
produced: 
• 
Time-matched scatter plots of varlitinib plasma concentrations vs. change from 
baseline in QTcF.  
• 
Time-matched scatter plots of capecitabine plasma concentrations vs. change 
from baseline in QTcF.  
• 
Time-matched scatter plots of plasma concentrations for concentrations 5-FU 
(active metabolite of capecitabine) vs. change from baseline in QTcF.  
• 
In case that major circulating metabolites of capecitabine (5’-DFCR, 5’-DFUR 
and FBAL) will be determined, time-matched scatter plots of plasma 
concentrations for major metabolites (>10% AUCparent) vs. change from 
baseline in QTcF will be also conducted. 
 
Part 1 
 
For Part 1, a multi-step approach will be applied to evaluate the effect of capecitabine 
alone and varlitinib in combination with capecitabine on the ECG parameters at 
different time points post-dose. The comparisons will be done between ECG values at 
each time point post-dose and baseline and between treatment arms with and without 
varlitinib for each time point individually. The evaluation of the cardiodynamic effects 
of capecitabine and varlitinib may be explored using exposure-response modeling if 
there appears to be a meaningful effect of varlitinib when added to capecitabine on the 
ECG parameters including QTcF.   
 
The statistical stepwise approach to be used to separate the cardiodynamic effect of 
varlitinib from normal circadian fluctuation in the ECG values and from the effect of 
capecitabine is described below: 
 
1. ANOVA mixed effects comparison of the absolute values of ECG parameters at 
each time point vs baseline using treatment as a fixed effect in order to evaluate 
the contribution of circadian fluctuation and to determine how treatment differences 
contribute to the changes. The ECG parameter values will be log-transformed and 
the resulting output will include the geometric mean ratio for test vs reference with 
the corresponding confidence interval and p-value. Interaction term, time point x 
treatment, will be also evaluated if the data allow. 


 
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2. ANOVA comparison of the absolute values of ECG parameters as well as change 
from baseline (ΔECG) between treatments for each post-dose time point assessed 
separately in order to separate the varlitinib effect from that of capecitabine. The 
ECG parameter values will be log-transformed and the resulting output will include 
the geometric mean ratio for test vs reference with the corresponding confidence 
interval and p-value. ΔECG will be tested as untransformed and log-transformed 
parameters to avoid bias from discarding 0 ΔECG values from the comparisons. 
3. Exposure-Response Analysis:  Linear mixed effect model between ΔQTcF and 
time matched concentrations of varlitinib and other potential metabolites if 
measured and as appropriate.  Other ECG variable may be similarly analyzed if 
appropriate and other models use, if appropriate. 
3.1. ΔQTcF will be calculated as the difference between each time point value and 
the average baseline value for each arm.  
3.2. ΔΔQTcF will be calculated for each patient in the combination arm individually 
as the difference between the ΔQTcF value for the arm with combination 
varlitinib/capecitabine treatment and the average value of all patients in the 
capecitabine alone arm matching time point. Other ECG parameters may also 
be used in the analysis including QTcB, heart rate, etc to provide supporting 
information. 
3.3. Base linear mixed effect model will include patients as a random effect 
3.4. The total dose of capecitabine may be included as a fixed effect in the model 
to account for differences in total doses received by subjects with different 
body surface area. 
4. Linear mixed effect model between ΔQTcF parameters and time matched 
concentrations of capecitabine and 5-FU (metabolite of capecitabine) and other 
potential metabolites of varlitinib and capecitabine, if measured.  
4.1. ΔQTcF will be calculated for all patients in both arms as the difference between 
each time point value and the average baseline value. 
4.2. Base linear mixed effect model will include patients as a random effect and 
treatment (capecitabine alone or in combination with varlitinib) as a fixed 
effect; the total capecitabine dose may also be used as a fixed effect. 
5. Different covariates may be included in the complex models in addition to the base 
model as fixed effects such as time point in order to ensure the model feasibility 
and to evaluate covariates influential to ECG parameters. 
 
The results of the fitted models will be presented using statistical parameters such as 
the geometric mean ratios and corresponding confidence intervals (for ANOVA) and 
estimates of the slope, and associated confidence interval for the linear mixed effect 
models. 
 
In addition, graphic exploration of the exposure-ECG relationship may be performed: 
  
• 
Residual plots to predict results 
• 
Double Y plots with time on the X axis and time matched values of PK 
concentrations for varlitinib and capecitabine on the Y1 axis, ΔECG on the 
Y2 axis to determine the possibility of hysteresis between drug 
concentration and cardiodynamic effects 
• 
Regression/scatter plots with time matched concentrations of varlitinib and 
capecitabine on the X axis and ΔECG on the Y axis 


 
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• 
Regression/scatter plots with varlitinib or capecitabine non-compartmental 
PK parameters of Cmax, Ctrough, AUCtau and others on the X axis and 
maximum ΔECG on the Y axis 
• 
Forest plots for different categories in ECG changes vs mean (SD) non-
compartmental PK parameters for varlitinib or capecitabine on the X axis 
 
7.11.5 
Biomarker Analysis 
For Parts 1 and 2, all biomarkers assessed via IHC will be listed and summarized by 
treatment arm, using appropriate descriptive statistics.  If a relationship is found 
between biomarker(s) expression and clinical outcomes in Part 1 of the study 
(exploratory endpoint), the biomarker(s) could be prospectively evaluated in Part 2 of 
the study. 
Biomarkers assessed via PCR/Sequencing, for example the mutational status of 
genes, such as KRAS, NRAS, BRAF, EGFR and other genetic factors that may affect 
response to therapy, will not be reported in the CSR and are not covered in this SAP. 
8. 
Changes in the Conduct of the Study or Planned Analysis 
Following completion of the safety lead-in, Protocol V4.0 incorporated changes to the 
study inclusion/exclusion criteria. These changes were made based on the advice from 
the study investigators, to ensure that the trial population reflected a true 2nd line BTC 
population, and excluded primary refractory patients and other patients deemed 
unlikely to benefit from any further treatment. Following these changes to the study 
population, the major deviation definition (Section 5.1) and consequently the per 
protocol analysis set definition (Section 4.4) in SAP v3.0 were also updated to reflect 
these changes. 
The original protocol and SAP included stratified randomization and analyses, based 
on the primary tumor location (GB or non-GB ) and geographical location (US or non-
US). When strata are small and contain limited or no “events” (PFS or OS) or 
responders (ORR and DCR), certain statistical techniques exclude all data within the 
affected stratum from the fitted model. To ensure that the primary analyses are 
meaningful and that data from all patients in the FAS contribute to the statistical 
analyses, Section 6.2 of SAP v3.0 has been amended to describe the conditions under 
which a stratification variable, e.g. geographical location, may not be included as a 
stratification factor in the statistical analyses. As outlined in Section 6.2, any decisions 
to remove a stratification factor from the statistical analyses will be reached and 
documented prior to unblinding. 
PFS and ORR have always been, and remain, co-primary endpoints in the study. In 
the previous protocol and SAP, a Hochberg procedure was proposed for testing at the 
one-sided 10% level, whereas hierarchical testing was proposed to support marketing 
approval at the two-sided 5% significance level. In SAP v3.0, a Hochberg procedure is 
also proposed to maintain an overall two-sided 5% type I error rate, as required for 
marketing approval. This change is a result of the data from the ongoing ASLAN001-
007 trial in first line BTC, in which durable disease stabilization has been reported. 


 
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9. 
REFERENCES 
Berry G, Kitchin RM, Mock PA.  A comparison of two simple hazard ratio estimators 
based on the logrank test.  Statistics in Medicine 1991; 10:749-755 
Breslow, NE. Covariance Analysis of Censored Survival Data. Biometrics 1974; 30:89–
99. 
Collett D. Modelling Survival Data in Medical Research. 2nd ed. Boca Raton (FL): 
Chapman & Hall/CRC; 2003. 
Eisenhauer EA et al. New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1). European Journal of Cancer 2009:45:228-247 
Emerson JD.   Combining estimates of the odds ratio: the state of the art.  Statistical 
Methods in Medical Research 1994;3:157-178 
Gail M, Simon R. Testing for qualitative interactions between treatment effects and 
subject subsets. Biometrics 1985;41:361-72. 
Hochberg, Y. A Sharper Bonferroni procedure for multiple tests of significance. 
Biometrika  1988;75: 800-802. 
Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN) - A Perl module for 
NONMEM related programming. Comput Methods Programs Biomed 2004; 
75:85±94. https://doi.org/10.1016/j. cmpb.2003.11.003. 
 
Mehta CR, Patel NR, Gray R.   Computing an exact confidence interval for the common 
odds ratio in several contingency tables.   Journal of the American Statistical 
Association 1985;80:969-973 
Sellke, T. and Siegmund, D. Sequential analysis of the proportional hazards model. 
Biometrika 70: 315-326, 1983 
Zelen M. The analysis of several 2x2 contingency tables.   Biometrika  1971;58:129-
137 
 
 
 
 


 
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10. 
LIST OF TABLES, FIGURES AND LISTINGS 
10.1 
Tables 
Unless otherwise stated, tables will be all repeated for safety run-in, part 1 and part 2. 
Table 
Number 
Table Title 
14.1.1 
Subject Disposition and Withdrawals – All Subjects 
14.1.2 
Analysis Populations – All Subjects 
14.1.3.1 
Major Protocol Deviations – Full Analysis Set (Parts 1 and 2) 
14.1.3.2 
Important Protocol Deviations – Full Analysis Set (Parts 1 and 2) 
14.1.3.3 
Stratification Levels – Full Analysis Set (Parts 1 and 2) 
14.1.4 
Demographic Characteristics – Full Analysis Set 
14.1.5 
Prior First Line Therapies for BTC – Full Analysis Set (Parts 1 and 
2) 
14.1.6 
Treatments for Early Stage Disease including Surgical and Adjuvant 
Treatments – Full Analysis Set (Parts 1 and 2) 
14.2.1.1 
Summary of Objective Response Rate – FAS Population 
14.2.1.2 
Primary Statistical Analysis of Objective Response Rate – FAS 
Population (Parts 1 and 2) 
14.2.1.3 
Summary of Objective Response Rate by Subgroup – FAS 
Population (Parts 1 and 2) 
14.2.1.4 
Statistical Analysis of Objective Response Rate by Subgroup – FAS 
Population (Parts 1 and 2) 
14.2.1.6 
Summary of Objective Response Rate to Support Per Protocol 
Sensitivity Analysis – PP Population (Part 1) 
14.2.1.7 
Per Protocol Sensitivity Analysis of Objective Response Rate – PP 
Population (Part 1) 
14.2.1.8 
Summary of Objective Response Rate to Support EFR Sensitivity 
Analysis – EFR Population (Part 1) 
14.2.1.9 
EFR Sensitivity Analysis of Objective Response Rate – EFR 
Population (Parts 1) 


 
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Table 
Number 
Table Title 
14.2.1.10 
Summary of Objective Response Rate based on Site Assessments 
– FAS Population (Part 1) 
14.2.1.11 
Statistical Analysis of Objective Response Rate based on Site 
Assessments – FAS Population (Part 1) 
14.2.1.12 
Summary of Confirmed Objective Response Rate – FAS Population 
(Part 1) 
14.2.2.1 
Summary Statistics for Progression – FAS Population 
14.2.2.2 
Progression Status at Data Cut-Off – FAS Population 
14.2.2.3 
Primary Analysis of Progression-Free Survival – FAS Population 
(Parts 1 and 2) 
14.2.2.5 
Subgroup Analysis of Progression-Free Survival – FAS Population 
(Part 1) 
14.2.2.7 
Summary Statistics for Progression to Support Per-Protocol 
Sensitivity Analysis – PP Population (Part 1) 
14.2.2.8 
Progression Status at Data Cut-Off to Support Per-Protocol 
Sensitivity Analysis– PP Population (Part 1) 
14.2.2.9 
Per Protocol Sensitivity Analysis of Progression-Free Survival – PP 
Population (Part 1) 
14.2.2.11 
Summary Statistics for Progression to Support Sensitivity Analysis 
Based on Site Assessment – FAS Population (Part 1) 
14.2.2.12 
Progression Status at Data Cut-Off to Support Sensitivity Based on 
Site Assessment – FAS Population (Part 1) 
14.2.2.13 
Sensitivity Analysis of Progression-Free Survival Based on Site 
Assessment – FAS Population (Part 1) 
14.2.2.14 
Sensitivity Analysis of Progression-Free Survival – Evaluation-Time 
Bias Assessment – FAS Population (Part 1) 
14.2.2.15 
Sensitivity Analysis of Progression-Free Survival – Attrition Bias 
Assessment – FAS Population (Part 1) 
14.2.3.1 
Summary Statistics for Overall Survival – FAS Population 
14.2.3.2 
Survival Status at Data Cut-Off – FAS Population 
14.2.3.3 
Statistical Analysis of Overall Survival – FAS Population (Parts 1 
and 2) 


 
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Table 
Number 
Table Title 
14.2.3.5 
Subgroup Analysis of Overall Survival – FAS Population (Part 2) 
14.2.4.1 
Summary Statistics for Duration of Response – FAS Population 
14.2.4.3 
Summary Statistics for Duration of Response – PP Population (Part 
1 only) 
14.2.5.1 
Summary of Disease Control Rate – FAS Population 
14.2.5.2 
Statistical Analysis of Disease Control Rate – FAS Population 
(Parts 1 and 2) 
14.2.5.3 
Summary of Disease Control Rate to Support Per Protocol 
Sensitivity Analysis – PP Population (Part 1) 
14.2.5.4 
Per Protocol Sensitivity Analysis of Disease Control Rate – PP 
Population (Part 1) 
14.2.5.5 
Summary of Disease Control Rate to Support EFR Sensitivity 
Analysis – EFR Population (Part 1) 
14.2.5.6 
EFR Sensitivity Analysis of Disease Control Rate – EFR Population 
(Part 1) 
14.2.6.1 
Summary of Tumor Size at Baseline and Week 12 – EFR 
Population 
14.2.6.3 
Analysis of Covariance of Percentage Change from Baseline in 
Tumor Size at Week 12 – EFR Population 
14.2.6.4 
Non-Parametric Sensitivity Analysis of Percentage Change from 
Baseline in Tumor Size at Week 12 – EFR Population 
14.2.6.6 
Summary of Tumor Size at Baseline and Week 12 by Subgroup – 
EFR Population 
14.2.6.8 
Analysis of Covariance of Percentage Change from Baseline in 
Tumor Size at Week 12 by Subgroup – EFR Population 
14.2.6.9 
Non-Parametric Sensitivity Analysis of Percentage Change from 
Baseline in Tumor Size at Week 12 by Subgroup – EFR Population 
14.2.7.1 
Summary of Plasma Concentrations - Varlitinib – PK Population 
14.2.7.2 
Summary of Plasma Concentrations - Capecitabine – PK 
Population (Parts 1 and 2) 


 
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Table 
Number 
Table Title 
14.2.7.3 
Summary of Plasma Pharmacokinetic Parameters – Varlitinib -   PK 
Population 
14.2.7.4 
Summary of Plasma Pharmacokinetic Parameters – Capecitabine  -  
PK Population (Parts 1 and 2) 
14.2.8.1 
Summary of IHC Biomarkers – FAS Population (Parts 1 and 2) 
14.2.8.2 
Shift Table of IHC Biomarkers from Baseline to Week 6 – FAS 
Population (Parts 1 and 2) 
14.3.1.1 
Summary Statistics for Exposure – Safety Population 
14.3.1.2 
Summary Statistics for Dose Intensity – Safety Population 
14.3.2.1 
Overview of TEAEs – Safety Population 
14.3.2.2 
Incidence of TEAEs by System Organ Class and Preferred Term – 
Subject and Episode Level – Safety Population 
14.3.2.3 
Incidence of Causally Related TEAEs by System Organ Class and 
Preferred Term – Subject and Episode Level – Safety Population 
14.3.2.4 
Incidence of most frequent (>10%) TEAEs by Preferred Term – 
Safety Population 
14.3.2.5 
Incidence of most frequent (>10%) Causally Related TEAEs by 
Preferred Term – Safety Population 
14.3.2.6 
Incidence of TEAEs CTCAE Grade 3 or Higher by System Organ 
Class and Preferred Term – Safety Population 
14.3.2.7 
Incidence of Causally Related TEAEs CTCAE Grade 3 or Higher by 
System Organ Class and Preferred Term – Safety Population 
14.3.2.8 
Incidence of serious TEAEs by System Organ Class and Preferred 
Term – Safety Population 
14.3.2.9 
Incidence of Serious Causally Related TEAEs by System Organ 
Class and Preferred Term – Safety Population 
14.3.3 
Summary of Deaths – Safety Population 
14.3.4.16 
Categorical Summary of Haematology Parameters – Safety 
Population (Parts 1 and 2) 
14.3.4.17 
Categorical Summary of Clinical Chemistry Parameters – Safety 
Population (Parts 1 and 2) 


 
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Table 
Number 
Table Title 
14.3.4.18 
Categorical Summary of Urinalysis Parameters – Safety Population 
(Parts 1 and 2) 
14.3.6.1 
Absolute Values and Change from baseline in ECG Data – Safety 
Population 
14.3.6.2 
Categorical ECG Data Summaries – Safety Population 
14.3.6.3 
ECG Overall Evaluation by Visit – Safety Population 
14.3.6.5 
Comparison of ECG parameters at all visits to baseline by 
treatment – Safety Population 
14.3.6.6 
Comparison of ECG parameters at all visits between treatments – 
Safety Population 
14.3.6.7 
Comparison of ECG parameters at all visits between treatments – 
PK Population 
 
10.2 
Listings 
Unless otherwise stated, listings will be all repeated for safety run-in, part 1 and part 
2. 
Listing 
Number 
Listing Title 
16.2.1 
Discontinuation Information – Safety Population 
16.2.2.1 
Inclusion/Exclusion Criteria Eligibility – All Subjects 
16.2.2.2 
Randomization – All Subjects (Parts 1 and 2) 
16.2.2.3 
Screening Failure Data – All Subjects 
16.2.3.1 
Major Protocol Deviations – Full Analysis Set 
16.2.3.2 
Important Deviations – Full Analysis Set 
16.2.3.3 
Analysis Populations – All Subjects 
16.2.3.4 
Stratification Information - FAS 
16.2.4.1 
Demographic Characteristics – Safety Population 
16.2.4.2 
Medical History – Safety Population 


 
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Listing 
Number 
Listing Title 
16.2.4.3 
Baseline Disease Characteristics – Safety Population 
16.2.4.4 
Prior and Concomitant Medications – Safety Population 
16.2.4.5 
Prior Anti-Cancer Therapies – Safety Population 
16.2.4.6 
Local Anti-Cancer Therapies – Safety Population 
16.2.4.7 
Substance Use – Safety Population 
16.2.4.8 
Primary Tumour Diagnosis – Safety Population 
16.2.4.9 
Tissue Collection – Safety Population 
16.2.4.10 
Biopsy Collection – Safety Population 
16.2.4.11 
Therapeutic or Diagnostic Procedures – Safety Population 
16.2.4.12 
Meal Record – Safety Population 
16.2.4.13 
Emergency Unblinding – Safety Population 
16.2.5.1 
Study Drug Administration – Safety Population 
16.2.5.2 
Capecitabine Administration – Safety Population 
16.2.5.3 
Study Drug Exposure and Dose Intensity – Safety Population 
16.2.5.4 
Capecitabine Exposure and Dose Intensity – Safety Population 
16.2.5.5 
Study Drug Dispensing– Safety Population 
16.2.5.6 
Study Drug Compliance (Varlitinib / Placebo) – Safety Population 
16.2.5.7 
Study Drug Compliance (Capecitabine) – Safety Population 
16.2.6.1.1 
Varlitinib Plasma Concentrations – Safety Population 
16.2.6.1.2 
Capecitabine Plasma Concentrations – Safety Population 
16.2.6.1.3 
Varlitinib Plasma Pharmacokinetic Parameters – PK Population 
16.2.6.1.4 
Capecitabine Plasma Pharmacokinetic Parameters – PK 
Population 
16.2.6.2.1 
Target Lesion Assessments (ICR) – FAS Population 
16.2.6.2.2 
Non-Target Lesion Assessments (ICR) – FAS Population 


 
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Listing 
Number 
Listing Title 
16.2.6.2.3 
Best Overall Response and Objective Response Rate (ICR) - FAS 
Population 
16.2.6.2.4 
Target Lesion Assessments (Site Assessments) – FAS Population 
16.2.6.2.5 
Non-Target Lesion Assessments (Site Assessments) – FAS 
Population 
16.2.6.2.6 
Best Overall Response and Objective Response Rate (Site 
Assessments) - FAS Population 
16.2.6.2.7 
Early Deaths Considered as Progression Events – FAS Population 
16.2.6.2.8 
Progression-Free Survival – FAS Population 
16.2.6.2.9 
Overall Survival – Safety Population 
16.2.6.2.10 
Duration of Response  – All Responding Subjects 
16.2.6.2.11 
IHC Biomarker Data – Safety Population 
16.2.7.1 
Adverse Events – Safety Population 
16.2.7.2 
Adverse Events Leading to Discontinuation of Study Medication – 
Safety Population 
16.2.7.3 
Serious Adverse Events – Safety Population 
16.2.7.4 
Adverse Events Leading to Death – Safety Population 
16.2.7.5 
Deaths – Safety Population 
16.2.8.1 
Haematology Parameters – Safety Population 
16.2.8.2 
Clinical Chemistry Parameters – Safety Population 
16.2.8.3 
Urinalysis Parameters – Safety Population 
16.2.8.4 
Coagulation Parameters – Safety Population 
16.2.8.5 
Serology Parameters – Safety Population 
16.2.8.6 
Pregnancy Test Results – Safety Population 
16.2.8.7 
CA19 and CEA Results - Safety Population 
16.2.8.8 
Urine Microscopy Parameters – Safety Population 


 
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Listing 
Number 
Listing Title 
16.2.9.1 
ECG Assessment– Safety Population 
16.2.9.2 
Patients with ECG Elevations – Safety Population 
16.2.9.3 
Vital Signs – Safety Population 
16.2.9.3 
Physical Examinations – Safety Population 
16.2.9.4 
ECOG Assessment – Safety Population 
 
10.3 
Figures 
Unless otherwise stated, figures will be all repeated for safety run-in, part 1 and part 
2. 
Figure Number Figure Title 
14.2.1.5 
Forest Plot of Objective Response Rate by Subgroup – FAS 
Population (Parts 1 and 2) 
14.2.2.4 
Kaplan-Meier Plot of Progression-Free Survival – FAS Population 
(Parts 1 and 2) 
14.2.2.6 
Forest Plot of Progression-Free Survival by Subgroup – FAS 
Population (Parts 1 and 2) 
14.2.2.10 
Kaplan-Meier Plot of Progression-Free Survival – PP Population 
(Part 1) 
14.2.2.17 
Kaplan-Meier Plot of Progression-Free Survival – Attrition-Bias 
Assessment – FAS Population (Parts 1 and 2) 
14.2.3 
Kaplan-Meier Plot of Overall Survival – FAS Population (Parts 1 
and 2) 
14.2.3.6 
Forest Plot of Overall Survival by Subgroup – FAS Population 
(Parts 1 and 2) 
14.2.4.2 
Kaplan-Meier Plot of Duration of Response – FAS Population 
(Parts 1 and 2) 
14.2.4.4 
Kaplan-Meier Plot of Duration of Response – PP Population (Part 
1) 
14.2.6.2 
Waterfall Plot of the Percentage Change From Baseline in Tumor 
Size at Week 12 – EFR Population 


 
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Figure Number Figure Title 
14.2.6.5 
Waterfall Plot of the Best Percentage Change from Baseline in 
Tumor Size – EFR Population 
14.2.6.7 
Waterfall Plot of Percentage Change from Baseline in Tumor Size 
at Week 12 by Subgroup – EFR Population 
14.2.6.10 
Waterfall Plot of Best Percentage Change from Baseline in Tumor 
Size by Subgroup – EFR Population 
14.2.7.5 
Profile Plots of Plasma Concentrations on a Linear Scale – 
Varlitinib - PK Population 
14.2.7.6 
Profile Plots of Plasma Concentrations on a Log Scale – Varlitinib 
- PK Population 
14.2.7.7 
Mean Profile Plots of Plasma Concentrations on a Linear Scale - 
Capecitabine – PK Population 
14.2.7.8 
Mean Profile Plots of Plasma Concentrations on a Log Scale - 
Capecitabine – PK Population 
14.2.8.9 
Scatter Plots of Plasma Concentration Against Change from 
Baseline in QTcF on a Linear Scale – Varlitinib – PK Population 
14.2.8.10 
Scatter Plots of Plasma Concentration Against Change from 
Baseline in QTcF on a Linear Scale – Capecitabine – PK 
Population 
14.2.8.11 
Scatter Plots of Plasma Concentration Against Change from 
Baseline in QTcF on a Linear Scale – Varlitinib Metabolites – PK 
Population 
14.2.8.12 
Scatter Plots of Plasma Concentration Against Change from 
Baseline in QTcF on a Linear Scale – Capecitabine Metabolites – 
PK Population 
14.3.1.3 
Swimmer Plot of Time on Treatment by Response Category – 
FAS Population (Part 1) 
14.3.1.4 
Swimmer Plot of Time on Treatment by Response Category, 
Accounting for Dose Modifications and Interruptions – FAS 
Population (Part 1) 
14.3.1.5 
Swimmer Plot of Time on Treatment by Response Category – 
Responding Subjects - FAS Population (Part 2) 
14.3.1.6 
Swimmer Plot of Time on Treatment by Response Category, 
Accounting 
for 
Dose 
Modifications 
and 
Interruptions 
– 
Responding Subjects - FAS Population (Part 2) 


 
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Figure Number Figure Title 
14.3.4.1 
Profile Plots of Haematology Parameters – Safety Population 
(Safety Lead-in) 
14.3.4.2 
Profile Plots of Clinical Chemistry Parameters – Safety Population 
(Safety Lead-in) 
14.3.4.3 
Profile Plots of Urinalysis Parameters – Safety Population (Safety 
Lead-in) 
14.3.4.4 
Profile Plots of Change from Baseline in Haematology 
Parameters – Safety Population (Safety Lead-in) 
14.3.4.5 
Profile Plots of Change from Baseline in Clinical Chemistry 
Parameters – Safety Population (Safety Lead-in) 
14.3.4.6 
Profile Plots of Change from Baseline in Urinalysis Parameters – 
Safety Population (Safety Lead-in) 
14.3.4.7 
Box Plots of Haematology Parameters – Safety Population (Parts 
1 and 2) 
14.3.4.8 
Box Plots of Clinical Chemistry Parameters – Safety Population 
(Parts 1 and 2) 
14.3.4.9 
Box Plots of Urinalysis Parameters – Safety Population (Parts 1 
and 2) 
14.3.4.10 
Box Plots of Change From Baseline in Haematology Parameters 
– Safety Population (Parts 1 and 2) 
14.3.4.11 
Box Plots of Change from Baseline in Clinical Chemistry 
Parameters – Safety Population (Parts 1 and 2) 
14.3.4.12 
Box Plots of Change from Baseline in Urinalysis Parameters – 
Safety Population (Parts 1 and 2) 
14.3.4.13 
Scatter Plots of Maximum ALT vs Maximum Total Bilirubin – 
Safety Population 
14.3.4.14 
Scatter Plots of Maximum AST vs Maximum Total Bilirubin – 
Safety Population 
14.2.4.15.x 
Hys Law Plot for Subject XXXXX – Safety Population 
14.3.5.1 
Profile Plots of Vital Signs Parameters – Safety Population 
(Safety Lead-in) 
14.3.5.2 
Profile Plots of Change from Baseline in Vital Signs Parameters 
– Safety Population (Safety Lead-in) 


 
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Figure Number Figure Title 
14.3.5.3 
Box Plots of Vital Signs Parameters – Safety Population (Parts 1 
and 2) 
14.3.5.4 
Box Plots of Change From Baseline in Vital Signs Parameters – 
Safety Population (Parts 1 and 2) 
14.3.6.5 
Profile Plots of ECG Parameters – Safety Population (Safety 
Lead-in) 
14.3.6.6 
Profile Plots of Change from Baseline in ECG Parameters – 
Safety Population (Safety Lead-in) 
14.3.6.7 
Box Plots of ECG Parameters – Safety Population (Parts 1 and 
2) 
14.3.6.8 
Box Plots of Change From Baseline in ECG Parameters – Safety 
Population (Parts 1 and 2) 
14.3.6.9 
Scatter Plots of Time Matched Plasma Concentrations Against 
Change from Baseline in QTcF on a Linear Scale – Varlitinib; PK 
Population 
14.3.6.10 
Scatter Plots of Plasma Concentrations Against Change from 
Baseline in QTcF on a Linear Scale - Capecitabine; PK 
Population 
14.3.6.11 
Scatter Plots of Plasma Concentrations Against Change from 
Baseline in QTcF on a Linear Scale – Varlitinib Metabolites; PK 
Population 
14.3.6.12 
Scatter Plots of Plasma Concentrations Against Change from 
Baseline in QTcF on a Linear Scale – Capecitabine Metabolites; 
PK Population