Background
Methods and study design
Study objectives
Primary objective
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PFS rate at 4 months, defined as the proportion of patients with non-progressive disease 4 months after randomization by intention-to-treat analysis
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Overall progression-free survival
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3-years overall survival
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Disease control rate according to RECIST 1.1 [17] after 2 months
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Objective tumor response rate (ORR) according to RECIST 1.1 [17]
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Toxicity/safety according to CTCAE-criteria version 4.03 (≥ Grade 3/4)
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Patient-related outcome/quality of life/time to definitive deterioration (TUDD) to be assessed with the following tools: EORTC QLQ-BIL21, QLQ-C30 and HADS-D
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Tumor resectability in accordance with a retrospective central surgical board compared to local surgical review
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Radiological response according to RECIST 1.1 [17] and volumetry determined by a retrospective central radiological review
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Exploratory biomarkers analysis (cfDNA exome sequencing, transcriptome, miRNA-arrays prior to and after start of treatment, and on progression).
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Establishment of predictive/prognostic biomarker profiles for advanced BTC
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Tumor evolution under chemotherapy
Patient selection and randomization
Main inclusion and exclusion criteria
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Histologically confirmed, non-resectable, locally advanced or metastatic adenocarcinoma of the intrahepatic or extrahepatic biliary tract (not papillary cancer or gallbladder cancer)
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Non-resectability has to be stated by the local multidisciplinary tumor board
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Measurable or assessable disease according to RECIST 1.1 [17]
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ECOG performance status 0–1
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Age ≥ 18 years at time of study entry
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Life expectancy of more than 3 months
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If applicable, adequately treated biliary tract obstruction before study entry with total bilirubin concentration ≤ 2 x ULN
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Adequate blood count, liver-enzymes, and renal function:
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◦ AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal
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◦ Serum Creatinine ≤1.5 x institutional ULN and a calculated glomerular filtration rate ≥ 30 mL per minute
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◦ Patients not receiving therapeutic anticoagulation must have an INR < 1.5 ULN and PTT < 1.5 ULN within 7 days prior to randomization
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No prior palliative chemotherapy for biliary tract cancer
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No adjuvant treatment within 6 months prior to study entry
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Written informed consent including participation in translational research
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Clinically significant cardiovascular disease (incl. Myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) within 6 months before enrollment
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Prior (< 3 years) or concurrent malignancy (other than biliary-tract cancer) which either progresses or requires active treatment. Exceptions are: basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a or T1b prostate carcinoma, or superficial urinary bladder tumor [Ta, Tis and T1].
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Known Gilbert-Meulengracht syndrome
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Known chronic hypoacusis, tinnitus or vertigo
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Previous enrollment or randomization in the present study (does not include screening failure).
Staging assessments
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Medical history and demographics including dates and description of initial diagnosis of advanced biliary tract cancer and relevant concurrent illness
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Complete physical examination including: weight, height, BSA, vital signs (blood pressure, heart rate, respiratory rate and oral body temperature)
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Residual symptoms/toxicities from previous therapies should be recorded according to the NCI Common Toxicity Criteria
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ECOG Performance Status
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Review of prior/concomitant medications
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Tumor assessment according to RECIST 1.1 [17] done by local investigator in the context of standard care (contrast enhanced multislice CT of the abdomen or abdominal MRI and an enhanced multislice thoracic CT scan)
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EORTC QLQ-BIL21, QLQ-C30 and HADS-D questionnaire
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Nutritional risk score
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12-lead ECG
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Hematological tests, Clinical chemistry
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Serum Tumor Marker (Ca 19–9, CEA)
Treatment
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Nanoliposomal-irinotecan 80 mg/m2 as 1.5 h infusion
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5-fluorouracil 2400 mg/m2 as 46 h infusion
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Leucovorin 400 mg/m2 as 0.5 h infusion
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Cycle q2w ± 5 days
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Cisplatin 25 mg/m2 as 1 h infusion on day 1 and day 8
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Gemcitabine 1000 mg/m2 as 0.5 h infusion on day 1 and day 8
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Cycle q3w ± 5 days
Follow-up
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Assessment of survival status
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Anti-cancer treatments must be recorded during follow up
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Reporting of all adverse events (AEs) and severe adverse events (SAEs) within 4 weeks after the end of treatment (EoT) visit
Sample size calculation and statistical analysis
Quality of life assessment and time to definitive deterioration
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At baseline, within 7 days prior to randomization
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Before the beginning of each cycle of systemic therapy
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At end of treatment visit
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Quality of life assessment should be performed even when chemotherapy cannot be given at the beginning of a cycle e.g. due to toxicity reasons.