Varlitinib in Combination With Capecitabine for Advanced or Metastatic Biliary Tract Cancer (TreeTopp)

• Sponsor: Aslan Pharmaceuticals
• Information provided by (Responsible Party): Aslan Pharmaceuticals

Study Description

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

Condition or disease	Intervention/treatment	Phase
Biliary Tract Cancer	Drug: Varlitinib; Drug: Capecitabine; Drug: Placebo (for Varlitinib)	Phase 2; Phase 3

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.

Study Design

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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

Arms and Interventions

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: ASLAN001; ARRY-334543; QBT01; 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

Outcome Measures

Primary Outcome Measures :

1. 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)
2. 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
3. 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.
4. 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

Secondary Outcome Measures :

1. 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)
2. 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)
3. 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)
4. 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)
5. 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)
6. 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)
7. 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)
8. 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)
9. 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)
10. 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)
11. 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)
12. 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)
13. 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)
14. 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
15. 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
16. 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.
17. 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.
18. 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
19. 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.
20. 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.
21. 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
22. 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)
23. 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)
24. 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.
25. 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
26. 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
27. 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).
28. 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
29. 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)
30. 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.

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Older Adult
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Subjects 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:

   1. Hematological function, as follows:

      • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
      • Platelet count ≥ 100 × 109/L

   2. Renal functions, as follows:

      • Estimated glomerular filtration rate or creatinine clearance > 50 mL/min/1.73m2

   3. Hepatic function, as follows:

      • Albumin ≥ 3 g/dL
      • Total bilirubin ≤ 1.5 × ULN
      • Aspartate aminotransferase and alanine aminotransferase ≤ 5 × ULN

Exclusion Criteria:

Subjects will be ineligible for the study if they:

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 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)

Contacts and Locations

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Sponsors and Collaborators

Aslan Pharmaceuticals

More Information

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Responsible Party:	Aslan Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT03093870 History of Changes
Other Study ID Numbers:	ASLAN001-009
First Posted:	March 28, 2017
Last Update Posted:	January 1, 2019
Last Verified:	December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Aslan Pharmaceuticals:

Neoplasms; Biliary Tract Neoplasms; Bile Duct Neoplasms; Gallbladder Neoplasms

Additional relevant MeSH terms:

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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