E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
proximal bile duct cancer |
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MedDRA Classification |
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 |
To investigate, if adjuvant gemcitabine chemotherapy is feasible in ≥ 85 % of patients after liver transplantation. |
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E.2.2 | Secondary objectives of the trial |
To obtain preleminary data on recurrence- and survival rates after liver transplantation for hilar cholangiocarcinoma using strict selection criteria and either adjuvant or no adjuvant chemotherapy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Listing for liver transplantation
• diagnosis of hilar cholangiocarcinoma with or without primary sclerosing cholangitis (PSC): i.e. histological diagnosis of cholangiocarcinoma (obtained via ERC) or dominant stenosis plus cytological diagnosis of severe dysplasia or two subsequent cytological results of severe dysplasia or carcinoma whereby the second has been obtained after 2 weeks of antibiotic treatment to exclude inflammatory changes • tumor not curatively resectable as judged by one local experienced hepatobiliary surgeon (> 50 liver resections for hilar cholangiocarcinoma) • on-line review (protective website) of defined patient data and acceptance for priority listing by an Eurotransplant expert panel consisting of two experts recruited from the Eurotransplant Liver Allocation Committee; in case of split decision addition of a third expert for definite decision on priority listing with an respective matchMELD. • obligatory staging laparotomy before priority listing (see SOP staging laparotomy) • age between 18 and 65 years • negative pregnancy test • informed consent before study specific procedures are performed (i.e. at the time of randomization for chemotherapy, all other procedures are clinical routine procedures in the management of these patients)
for randomization adj. chemotherapy vs. observation:
• liver transplantation within three months after listing for liver transplantation • histologically proven proximal bile duct cancer • curative resection of the tumor (R0) • in case of previously unknown hilar lymph node metastases nearby the tumor region in the final pathological report: stratification in the treatment groups • no previous photodynamic therapy, radiation, chemotherapy, brachytherapy or combinations of these procedures • CT scan of the chest not older than 8 weeks before randomization showing no detectable distant metastases • possibility to start adjuvant chemotherapy between 4 and 8 weeks (but not later than 10 weeks) after liver transplantation • sufficient bone marrow function (WBC > 3.5/nl, platelets > 80/nl, hemoglobin > 8 g/dl) • sufficient renal function (creatinin clearance ≥ 30 ml/min) • sufficient liver function (bilirubin < 3 mg/dl) • if female either be postmenopausal, surgically sterile or have a negative pregnancy test as part of the screening investigations. Women of childbearing potential also must agree to use an acceptable highly effective contraception method of birth control (defined as pearl index < 1), if necessary also for partners of test persons or complete abstinence of intercourse (from the date of liver transplantation until 2 months after end of adjuvant chemotherapy). if male must agree to use an acceptable method of birth control, as determined by the investigator, from the date of liver transplantation until 2 months after end of adjuvant chemotherapy • all patients must be informed of the nature of the study and provide written informed consent before any study specific procedures are performed |
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E.4 | Principal exclusion criteria |
Contraindications for liver transplantation:
• locally very advanced, irresectable tumor infiltrating adjacent other organs, the main trunk of the hepatic artery • a visible tumor mass on CT or MRI scan larger than 3 cm in diameter • highly elevated CA 19-9 levels (> 1000 U/ml) • tumors suspicious for gallbladder cancer • known lymph node or distant metastasis (determined mandatory by CT scan and laparoscopy, further investigations if deemed necessary, PET scan is strongly recommended) • patients undergoing multi-organ transplantation or have undergone previous solid organ or bone marrow transplantation • previous or intended photodynamic therapy, radiation, chemotherapy, brachytherapy or combinations of these procedures • previous tumor biopsy (except via ERC) systematic lymphadenectomy (except SOP defined staging laparotomy), surgical preparation at the region of the hepatoduodenal ligament (except cholecystectomy for other reasons) or previous completed or attempted surgery for hilar cholangiocarcinoma • patients with known hypersensibility for gemcitabine • pregnancy or breastfeeding • patients unwilling to consent to saving and propagation of pseudonymized medical data for study reasons • general contraindications for liver transplantation • subjects who are legally detained in an official institute • HIV infection (based on testing performed during the transplant-evaluation or within 6 months before)
for randomization (adj. chemotherapy vs. observation):
• patients with biliary sepsis, intrahepatic abscesses or other complications (e.g. severe liver dysfunction) contraindicating adjuvant chemotherapy • contraindications against study medication (including auxiliary substances) • pregnancy or breastfeeding • induction therapy with antibodies as primary immunosuppression after liver transplantation (rejection treatment with antibodies is not a contraindication) • therapy with mTOR-inhibitors (sirolimus, everolimus) • any clinically significant medical or surgical condition, that in the investigator`s opinion would preclude adjuvant chemotherapy • participitation in other clinical trials
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints: • percentage of patients completing the 24 weeks course of adjuvant chemotherapy
Secondary endpoints: • recurrence free survival at 12 months • overall survival at 3 and 5 years • complication rate (protocol defined high grade toxicities grade 3/4) • number of patients, which could not be randomized (due to perioperative complications, no detectable bile duct cancer in the explanted liver or other reasons)
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 29 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
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study duration and till year 5 follow-up |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |