Varlitinib in Combination With Capecitabine for Advanced or Metastatic Biliary Tract Cancer (TreeTopp)
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ClinicalTrials.gov Identifier: NCT03093870 |
Recruitment Status :
Active, not recruiting
First Posted : March 28, 2017
Last Update Posted : January 2, 2019
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Condition or disease | Intervention/treatment | Phase |
---|---|---|
Biliary Tract Cancer | Drug: Varlitinib Drug: Capecitabine Drug: Placebo (for Varlitinib) | Phase 2 Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 490 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | Treatment: protocol designed to evaluate one or more interventions for treating a disease, syndrome or condition |
Masking: | Double (Participant, Investigator) |
Primary Purpose: | Treatment |
Official 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 |
Actual Study Start Date : | July 4, 2017 |
Estimated Primary Completion Date : | July 2019 |
Estimated Study Completion Date : | December 2022 |

Arm | Intervention/treatment |
---|---|
Experimental: Varlitinib and Capecitabine |
Drug: Varlitinib
Varlitinib:300mg, oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death.
Other Names:
Drug: Capecitabine 1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. |
Placebo Comparator: Placebo and Capecitabine |
Drug: Capecitabine
1000mg/m2, oral tablets, twice daily for 2 weeks followed by a 1-week rest period in 3-week cycles. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death. Drug: Placebo (for Varlitinib) oral tablets, twice daily. Number of cycles: until disease progression, unacceptable toxicity, withdrawal of consent, or death |
- Incidence of Adverse events (AE) - safety lead-in [ Time Frame: Through 28-days post last study medication administration ]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)
- Objective response rate (ORR) - part 1 [ Time Frame: the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: ORR defined as the proportion of subjects with a best objective response (BOR) of complete response (CR) or partial response (PR), as assessed by an Independent Central Review(ICR) defined by the RECIST v1.1 criteria
- Progression-free survival (PFS) - part 1 [ Time Frame: The later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: Progression-free survival (PFS), defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression). Progression is defined in accordance with the RECIST v1.1 criteria and will be derived programmatically based on data from the ICR of radiological data.
- Overall survival (OS) - part 2 [ Time Frame: When 247 OS events have occurred. With median OS times of 8.6 months and 6 months for respective arms, 247 OS is estimated to occur after approximately 31 months. ]Part 2; Overall survival (OS) Defined as the time from randomization until death by any cause
- Pharmacokinetics: Maximum plasma concentration (Cmax) - safety lead in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: time to Cmax(tmax) - safety lead in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: plasma concentration before next dose (Ctrough) - safety lead in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: area under the plasma concentration-time curve from 0 to 12 hours (AUC0- τ) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: half-life (t1/2) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: apparent clearance (Cl/F) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: apparent volume of distribution (Vz/F) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: apparent volume of distribution at the steady state (Vss/F) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: where τ = 12 hours (dosing interval) [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 8/Day 1) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 8 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: accumulation ratio of Cmax RacCmax (Day 8/Day 1) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 8 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: accumulation ratio of AUC0- τ (RacAUC0- τ) (Day 14/Day 1) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 14 ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Pharmacokinetics: accumulation ratio of Cmax RacCmax (Day 14/Day 1) - safety lead-in [ Time Frame: Pharmacokinetic measurements will be taken on Day 14. ]Safety lead in: Pharmacokinetics of varlitinib, capecitabine, and 5-FU (active metabolite of capecitabine)
- Electrocardiogram - safety lead-in and part 1 [ Time Frame: Electrocardiogram measurements will be taken during the study. The analysis will be performed the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Safety lead in: Electrocardiogram measurements
- Objective response rate (ORR) - safety lead-in [ Time Frame: CT/MRI every 6 weeks from Cycle 1 Day 1. The database for the Safety lead-in will be locked at the time of the Part 1 analyses which is the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event ]Safety lead in: ORR defined as the proportion of subjects with a best objective response (BOR) of complete response (CR) or partial response (PR), as defined by the RECIST v1.1 criteria
- Duration of response (DoR) - safety lead-in [ Time Frame: CT/MRI every 6 weeks from Cycle 1 Day 1. The database for the Safety lead-in will be locked at the time of the Part 1 analyses which is the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event ]Safety lead in: DoR is 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.
- Disease control rate (DCR) - safety lead-in [ Time Frame: CT/MRI every 6 weeks from Cycle 1 Day 1. The database for the Safety lead-in will be locked at the time of the Part 1 analyses which is the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event ]Safety lead in: DCR is defined as stable disease for a minimum of twelve weeks (± 5 days) from starting treatment, as defined by RECIST v1.1 criteria. 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.
- Overall Survival OS - Part 1 [ Time Frame: the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: OS defined as the time from randomization until death by any cause
- Duration of response (DoR) - Part 1 [ Time Frame: the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: DoR 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.
- Disease control rate (DCR) - Part 1 [ Time Frame: the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: DCR is defined as stable disease for a minimum of twelve weeks (± 5 days) from starting treatment, as defined by RECIST v1.1 criteria. 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.
- Objective response rate ORR - Part 1 [ Time Frame: the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: ORR as based on site review of radiological data
- Tumor size - Part 1 [ Time Frame: the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: Tumor size Defined as the percentage change from baseline in the sum of target lesions at Week 12 ((%ΔTSWk12)
- Incidence of Adverse Events (AEs) - Part 1 [ Time Frame: Through 28-days post last study medication administration ]Part 1: 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)
- Pharmacokinetics - Part 1, the PK data will be used to derive PK parameters such as, but not restricted to, Cmax, AUC, and t1/2 for varlitinib. [ Time Frame: Pharmacokinetic measurements will be taken on Day 1, Day 8, and end of study. The analysis will be performed the later of 3 months after last subject in or when 70% of the subjects (84 subjects) have experienced a PFS event in Part 1 ]Part 1: Pharmacokinetics samples will be obtained for the PK evaluation of varlitinib (and any relevant circulating metabolites).Population PK evaluation in Part 1 and Part 2 of the study will be performed by nonlinear mixed effects model (NLME). Actual elapsed time from dosing will be used for final plasma PK parameter calculations.
- Objective response rate (ORR) - Part 2 [ Time Frame: CT/MRI every 6 weeks from Cycle 1 Day 1. The data cut off(DCO) is when 247 OS events have occurred. With median OS times of 8.6 months and 6 months for respective arms, 247 OS is estimated to occur after approximately 31 months. ]Part 2: based on site review of radiological data
- Duration of response (DoR) - Part 2 [ Time Frame: CT/MRI every 6 weeks from Cycle 1 Day 1. The DCO is when 247 OS events have occurred. With median OS times of 8.6 months and 6 months for respective arms, 247 OS is estimated to occur after approximately 31 months. ]Part 2: based on site review of radiological datacontributing 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
- Disease control rate (DCR) - Part 2 [ Time Frame: CT/MRI every 6 weeks from Cycle 1 Day 1. The DCO is when 247 OS events have occurred. With median OS times of 8.6 months and 6 months for respective arms, 247 OS is estimated to occur after approximately 31 months. ]Part 2: based on site review of radiological dataabsence 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. DCR will be evaluated for the subset of the FAS with measurable disease at baseline (the EFR set).
- Progression-free survival (PFS) - Part 2 [ Time Frame: The DCO is when 247 OS events have occurred. With median OS times of 8.6 months and 6 months for respective arms, 247 OS is estimated to occur after approximately 31 months. ]Part 2: based on site assessment
- Incidence of Adverse Events (AEs) - Part 2 [ Time Frame: The DCO is when 247 OS events have occurred. With median OS times of 8.6 months and 6 months for respective arms, 247 OS is estimated to occur after approximately 31 months. ]Part 2: 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)
- Sparse Pharmacokinetics - Part 2, the PK data will be used to derive PK parameters such as, but not restricted to, Cmax, AUC, and t1/2 for varlitinib. [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1. The DCO is when 247 OS events have occurred, estimated to occur 31 months after the first patient in for part 2 ]Part 2: 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.Population PK evaluation in Part 1 and Part 2 of the study will be performed by nonlinear mixed effects model (NLME). Actual elapsed time from dosing will be used for final plasma PK parameter calculations.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | Child, Adult, Older Adult |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Subjects will be eligible for the study if they:
- Are of or older than the legal age in the respective countries at the time when written informed consent is obtained
- Have histologically or cytologically confirmed advanced (unresectable) or metastatic biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma (CCA), gallbladder cancer and carcinoma of Ampulla of Vater. This includes clinical diagnosis of biliary tract cancer with histological confirmation of adenocarcinoma.
- Have received and failed one and only one prior line of systemic treatment for advanced or metastatic disease with radiologic evidence of disease progression. This prior line of systemic treatment must also contain gemcitabine
- Have received at least 6 doses of gemcitabine containing treatment in first line (Adjuvant therapy is not regarded as 1st line therapy)
- Have radiographically measurable disease based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 as assessed by Independent Central Review (ICR) (For Part 1)
- Have no evidence of biliary duct obstruction, unless obstruction is controlled by local treatment or, in whom the biliary tree can be decompressed by endoscopic or percutaneous stenting with subsequent reduction in bilirubin to below or equal to 1.5 × upper level of normal (ULN)
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Are able to understand and willing to sign the informed consent form
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Have adequate organ and hematological function:
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Hematological function, as follows:
- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
- Platelet count ≥ 100 × 109/L
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Renal functions, as follows:
• Estimated glomerular filtration rate or creatinine clearance > 50 mL/min/1.73m2
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Hepatic function, as follows:
- Albumin ≥ 3 g/dL
- Total bilirubin ≤ 1.5 × ULN
- Aspartate aminotransferase and alanine aminotransferase ≤ 5 × ULN
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Exclusion Criteria:
Subjects will be ineligible for the study if they:
- Are currently on or have received anti-cancer therapy within the past 3 weeks before receiving the first dose of study medication
- Are currently on or have received radiation or local treatment within the past 3 weeks for the target lesion(s) before receiving the first dose of study medication
- Have evidence of multiple (≥ 2) peritoneal metastases or ascites at baseline as assessed by ICR (For Part 1). (Ascites which can be attributed by non-malignant causes is not excluded. Minimal ascites, which does not require paracentesis is permitted.)
- Have had major surgical procedures within 14 days prior to first dose of study medication
- Have a known metastatic brain lesion(s), including asymptomatic and well controlled lesion(s)
- Have malabsorption syndrome, diseases significantly affecting gastrointestinal function, resection of the stomach or small bowel, or difficulty in swallowing and retaining oral medications which in the opinion of the Investigator could jeopardize the validity of the study results
- Have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, diabetes, hypertension, or psychiatric illness/social situations that would limit compliance with study requirements
- Have any history of other malignancy unless in remission for more than 1 year (non-melanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with curative intent is not exclusionary)
- Are female patients who are pregnant or breast feeding
- Have been previously treated with varlitinib or have been previously treated with capecitabine as first line therapy for advanced or metastatic disease. For patients who have previously received capecitabine as a radiosensitizer or as part of their adjuvant therapy and their disease has relapsed for more than 6 months after their last dose of capecitabine adjuvant therapy, their capecitabine therapy will not be considered as a line of systemic chemotherapy for metastatic/advanced disease, and thus they can participate in the study
- Have received any investigational drug (or have used an investigational device) within the last 14 days before receiving the first dose of study medication
- Have unresolved or unstable serious toxicity (≥ common terminology criteria for adverse events [CTCAE] 4.03 Grade 2), with the exception of anemia, asthenia, and alopecia, from prior administration of another investigational drug and/or prior cancer treatment
- Have a known positive test for human immunodeficiency virus, hepatitis C (treatment naïve or after treatment without sustained virologic response), or hepatitis B infection with hepatitis B virus deoxyribonucleic acid exceeding 2000 IU/mL
- Have a known history of drug addiction within last 1 year which, in the opinion of the Investigator, could increase the risk of non-compliance to investigational product
- Need continuous treatment with proton pump inhibitors during the study period
- Have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis, or have a history of interstitial lung disease or current interstitial lung disease
- Have any history or presence of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic or psychiatric disease or any other condition which in the opinion of the Investigator could jeopardize the safety of the patient or the validity of the study results
- Have a baseline corrected QT interval (Fridericia's formula) (QTcF) > 450 ms or patients with known long QT syndrome; torsade de pointes; symptomatic ventricular tachycardia; an unstable cardiac syndrome in the past 3 months before screening visit; > class 2 New York Heart Association heart failure; or > class 2 angina pectoris; or receiving quinidine, procainamide, disopyramide, amiodarone, dronedarone, arsenic, dofetilide, sotalol, or methadone. Please also see prohibited medication/therapy (Section 5.4.10.1)

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03093870

Responsible Party: | Aslan Pharmaceuticals |
ClinicalTrials.gov Identifier: | NCT03093870 |
Other Study ID Numbers: |
ASLAN001-009 |
First Posted: | March 28, 2017 Key Record Dates |
Last Update Posted: | January 2, 2019 |
Last Verified: | December 2018 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Neoplasms Biliary Tract Neoplasms Bile Duct Neoplasms Gallbladder Neoplasms |
Biliary Tract Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms Biliary Tract Diseases Digestive System Diseases |
Capecitabine Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents |