E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
incidental gallbladder carcinoma (IGBC) or biliary tract cancer (BTC) (intrahepatic cholangiocarcinoma (ICC)/ extrahepatic cholangiocarcinoma (ECC)) |
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E.1.1.1 | Medical condition in easily understood language |
gallbladder carcinoma or 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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025734 |
E.1.2 | Term | Malignant neoplasm of biliary tract, part unspecified |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 27.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008593 |
E.1.2 | Term | Cholangiocarcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028982 |
E.1.2 | Term | Neoplasm biliary tract |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10004675 |
E.1.2 | Term | Biliary tract and gallbladder therapeutic procedures |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 | 10017614 |
E.1.2 | Term | Gallbladder cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061962 |
E.1.2 | Term | Gallbladder operation |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
to investigate whether induction chemotherapy followed by radical re-resection (and - if possible - postoperative chemotherapy) in incidental gallbladder carcinoma (IGBC) or in front radical resection in biliary tract cancer (BTC) (intrahepatic cholangiocarcinoma (ICC)/ extrahepatic cholangiocarcinoma (ECC)) prolongs overall survival compared to immediate radical surgery alone with or without adjuvant chemotherapy (investigator’s choice) in patients with IGBC, or BTC (ICC/ECC) |
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E.2.2 | Secondary objectives of the trial |
• Quality of life (EORTC QLQ-C30) • PFS rates at 3 and 5 years • OS rates at 3 and 5 years • Progression free survival (PFS) • R0- resection rate • Toxicity, graded using CTC adverse events criteria version CTCAE V 5.0 • perioperative morbidity and mortality (30 days and 90 days mortality/morbidity) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Incidental gallbladder carcinoma (IGBC), gallbladder carcinoma (GBC) () or Biliary tract cancer (BTC) (intrahepatic, hilar or distal Cholangiocarcinoma (CCA)) scheduled for complete resection (mixed tumor entities with hepatocellular carcinoma are excluded). 2. No prior partial or complete tumor resection for BTC (intrahepatic, hilar or distal CCA), and for IGBC/GBC prior Cholecystectomy is allowed. 3. Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax, bone scan or MRI (if bone metastases are suspected due to clinical signs). Exclusion of the infiltration of any adjacent organs or structures by CT or MRI, indicating an unresectable situation. 4. ECOG performance status of 0, 1, or 2. 5. Estimated life expectancy > 3 months. 6. Female and male patients ≥18 years. 7. Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures 8. No previous or preceding cytotoxic or targeted therapy for BTC or IGBC/GBC. 9. No previous malignancy within two years or concomitant malignancy, except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer 10. No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last three months, significant arrhythmia). 11. Absence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent. 12. No serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial. 13. A) Females of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 7 months after the last study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (has not had ≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
B) Males must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year during the treatment period and for at least 6 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Men with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy. 14. No pregnancy or lactation. 15. Adequate hematologic function: ANC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥ 9 g/dl or ≥ 5.59 mmol/L; prior transfusions for patients with low hemoglobin are allowed 16. Adequate liver function as measured by serum transaminases (AST and ALT) ≤ 5 x ULN and bilirubin ≤ 3 x ULN. 17. Adequate renal function, i.e. serum creatinine ≤ 1.5 x institutional ULN, a calculated glomerular filtration rate ≥ 30 mL/min. 18. Adequate coagulation functions as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin/ phenprocoumon must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to randomization. 19. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy (patients on long-term antibiotics are eligible provided signs of active infection have been resolved). 20. No concurrent treatment with other experimental drugs or other anti-cancer therapy, treatment in a clinical trial within 30 days or five half-lives (whichever is longer) prior to randomization. 21. Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women <1 year after the onset of menopause |
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E.4 | Principal exclusion criteria |
1. Known hypersensitivity against gemcitabine or cisplatin 2. Other known contraindications to gemcitabine or cisplatin 3. Clinically significant valvular defect 4. Past or current history of other malignancies not curatively treated and without evidence of disease for more than two years, except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer 5. Locally unresectable tumor or metastatic disease: - Radiological evidence suggesting inability to resect with curative intent whilst maintaining adequate vascular inflow and outflow, and sufficient future liver remnant - Radiological evidence of direct invasion into adjacent organs - Radiological evidence of extrahepatic metastatic disease 6. Other severe internal disease or acute infection 7. Chronic inflammatory bowel disease 8. Receiving chronic antiplatelet therapy, including aspirin (Once-daily aspirin use (maximum dose 325 mg/day) is permitted), nonsteroidal anti-inflammatory drugs (including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. 9. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) during 3 months prior to randomization. 10. Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or ascites. 11. On-treatment participation in another clinical study 30 days or five half-lives (whichever is longer) prior to inclusion and during the study 12. Pregnant or breast feeding patient, or patient is planning to become pregnant within 7 months after the end of treatment. 13. Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4) 14. Any other concurrent antineoplastic treatment including irradiation |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival will be measured as time from randomization to death of any cause. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall survival will be measured as time from randomization to death of any cause. |
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E.5.2 | Secondary end point(s) |
• Quality of life (EORTC QLQ-C30) • PFS rates at 3 and 5 years • OS rates at 3 and 5 years • Progression free survival (PFS) • R0- resection rate • Toxicity, graded using CTC adverse events criteria version CTCAE V 5.0 • perioperative morbidity and mortality (30 days and 90 days mortality/morbidity)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 50 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 72 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 72 |