| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic biliary tract cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic biliary tract cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055111 |
| E.1.2 | Term | Biliary cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 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). |
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| E.2.2 | Secondary objectives of the trial |
Safety lead-in:
1. To evaluate the pharmacokinetics (PK) of varlitinib and capecitabine (and its metabolites) when given as 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 and Part 2:
1. To evaluate the efficacy of varlitinib in combination with capecitabine, as measured by OS, DoR, DCR, and tumor size 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 via sparse PK sampling and population PK analyses |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
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 radiographically measurable disease based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1
5. 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 1.5 × upper level of normal (ULN)
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Are able to understand and willing to sign the informed consent form
8. 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:
• Total bilirubin ≤ 1.5 × ULN
• Aspartate aminotransferase and alanine aminotransferase ≤ 5 × ULN |
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| E.4 | Principal 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 had major surgical procedures within 14 days prior to study entry
4. Have a known metastatic brain lesion(s), including asymptomatic and well controlled lesion(s)
5. 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
6. 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
7. 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)
8. Are female patients who are pregnant or breast feeding
9. Have been previously treated with varlitinib or have been previously treated with capecitabine as first line therapy for advanced or metastatic disease
10. Have received any investigational drug (or have used an investigational device) within the last 14 days before receiving the first dose of study medication
11. 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
12. Have a known positive test for human immunodeficiency virus, active hepatitis C, or hepatitis B infection with hepatitis B virus deoxyribonucleic acid exceeding 2000 IU/mL
13. Have a known history of drug addiction within last 1 year, on the basis that there could be a higher risk of non-compliance to investigational product
14. Need continuous treatment with proton pump inhibitors during the study period
15. 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
16. 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
17. 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 receiving quinidine, procainamide, disopyramide, amiodarone, dronedarone, arsenic, dofetilide, sotalol, or methadone. Please also see prohibited medication/therapy (Section 5.4.10.1) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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:
• 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 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety Lead-in:
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
Part 1:
every 3 weeks for Cycle 1D1 to Cycle 3D1, every 6 weeks from Cycle 4D1 to disease progression
Part 2:
every 3 weeks for Cycle 1D1 to Cycle 3D1, every 6 weeks from Cycle 4D1 to disease progression |
|
| E.5.2 | Secondary end point(s) |
Safety lead-in:
• Pharmacokinetics endpoints: The PK of varlitinib 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 be only 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)
• Electrocardiogram endpoints: QT/QTc values will be evaluated using exposure-response modeling at selected time points (pre-dose, 1, 2, 3, 4, 5, 6, 8.5, and 12 hours post dose) on Day 1 and Day 8. PK samples will be drawn immediately (<5 min) for evaluation of varlitinib and capecitabine (and relevant metabolites). In addition, the following endpoints will be evaluated from triplicate readings following standardized ECG recording techniques:
• QT/QTc changes from baseline per time point
• 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
- 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)
• PK Endpoints
- A population PK study with sparse sampling will be included in the Part 1 of the study to assess explore exposure-response relationships for varlitinib (and any relevant circulating metabolites) for measures of efficacy, safety, and pharmacological responses.
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, ECG parameters, 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety lead-in:
Safety: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 14, and every 3 weeks from Cycle 2 Day 1 onwards.
PK: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 14
ECG: Cycle 1 Day 1, Cycle 1 Day 8
Part 1 and Part 2:
Efficacy - every 3 weeks for Cycle 1D1 to Cycle 3D1, every 6 weeks from Cycle 4D1 to disease progression.
ECG - Screening, Safety follow-up, Cycle 1 Day 1: 45 minutes pre-dose, 5 minutes pre-dose, 1-3 h, 3-5 h and 5-8 h post dose. Cycle 2 Day 1: 45 minutes pre-dose, 5 minutes pre-dose, 1-3 h, 3-5 h and 5-8 h post dose.
PK - Cycle 1 Day 1, Cycle 2 Day 1: pre-dose, 1-3 h, 3-5 h and 5-8 h post dose.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| China |
| Hong Kong |
| Hungary |
| Japan |
| Korea, Republic of |
| Poland |
| Singapore |
| Spain |
| Taiwan |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of study is defined as the date of the last visit of the last patient |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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