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Fully-informed written consent and locally required authorization (European Union [EU]: General Data Privacy Regulation (GDPR)) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations |
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Age ≥ 18 years |
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Histologically documented diagnosis of locally-advanced OR limited metasized intrahepatic BTC not amenable to curative treatment (tumor resection or ablation), specified as |
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Tumor being confined to the liver or |
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In case of presence of extrahepatic lesions, metastasis must be stable AND of limited extent AND patient must have a potential benefit from study participation in comparison to standard of care systemic therapy per local tumor board evaluation |
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Limited extent is defined in this protocol as presence of |
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EITHER ≤3 malignant extrahepatic lymph nodes (short axis diameter ≥3cm) |
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OR metastatic lesions in one organ other than liver (if only single lesion is present diameter MUST be < 3cm; if up to 3 lesions in one organ each lesion MUST be ≤ 1cm) |
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Presence of peritoneal or brain metastatsis excludes patients from study participation (see exclusion criterion #4) |
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Tumor tissue (block or at least 4 slides) is available for translational |
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research |
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Patients with prior chemotherapy can be enrolled if ONE of the following criteria is |
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met |
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Capecitabin or gemcitabine+cisplatin in the adjuvant setting |
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Experienced progressive disease under gemcitabine+cisplatin therapy in the advanced setting |
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Stable disease after 3 months of gemcitabine+cisplatin treatment |
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Has been considered candidate for standard-of-care Y-90 SIRT therapy per Investigator |
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decision and after prior consultation with the tumor board if available at |
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site and does not display contraindications against SIRT |
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Contraindications against SIRT would be |
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hepatic tumor load > 50% |
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any Gastrointestinal deposition that cannot be corrected via angiographic techniques |
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irreversibly elevated serum bilirubin |
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renal insufficiency |
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increased pulmonary shunt fraction being able to deliver > 16.5 mCi to the lungs |
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gastrointestinal ulceration |
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hepatic dysfunction |
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biliary complications |
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portal hypertension |
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vascular injury and lymphopenia |
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Performance status (PS) ≤ 1 (ECOG scale) |
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Body weight >30 kg |
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At least one measurable site of disease as defined by RECIST 1.1 criteria |
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Adequate bone marrow and renal function |
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Adequate hepatic function (with stenting for any obstruction, if required) |
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Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial |
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Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause |
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The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations |
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Must have a life expectancy of at least 12 weeks |
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If patient has concurrent Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection, meets the following criteria |
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Patients with HBV or HCV infection should be monitored for viral levels during study participation |
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Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should have HBV DNA < 100 IU/ml and should be managed per local treatment guidelines |
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Controlled (treated) hepatitis B subjects will be allowed if they started treatment at the |
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time point of enrollment into the study by the latest and treatment is continued during |
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study participation and for ≥ 6 months after end of study treatment |
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HCV patients with advanced BTC are mostly not treated for their HCV infection. However |
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patients treated for HCV are considered suitable for inclusion if antiviral therapy has |
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been completed ≥ 30 days prior to first administration of study drug |
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Presence of peritoneal carcinomatosis or brain metastases
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Concurrent enrolment in another clinical study, unless it is an observational
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(non-interventional) clinical study, or during the follow-up period of an
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interventional study
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Participation in another clinical study with an investigational product within 21 days
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prior to the first dose of the study treatment
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Prior immunotherapy or use of other investigational agents, including prior treatment
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with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1
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(PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4)
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antibody, therapeutic cancer vaccines
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Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the
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exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
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criteria
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Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal
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therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer
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related conditions (eg, hormone replacement therapy) is acceptable
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Prior radiotherapy treatment before the first dose of any study drug
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Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into
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the study; patients must have recovered from effects of any major surgery. Note: Local
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non-major surgery for palliative intent (e.g. surgery of isolated lesions
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per-cutaneous biliary drainage or biliary stenting) is acceptable
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Active or prior documented autoimmune or inflammatory disorders (including
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inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the
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exception of diverticulosis], celiac disease, systemic lupus erythematosus
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Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'
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disease, rheumatoid arthritis, hypophysitis, uveitis]
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Uncontrolled intercurrent illness, including but not limited to, ongoing or active
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infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
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angina pectoris, cardiac arrhythmia, , serious active, uncontrolled, gastrointestinal
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conditions associated with diarrhea, or psychiatric illness/social situations that
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would limit compliance with study requirement, substantially increase risk of
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incurring AEs or compromise the ability of the patient to give written informed
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consent
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History of non-infectious pneumonitis requiring steroids, or patients with Grade ≥ 2
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pneumonitis
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History of another primary malignancy except for
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Malignancy treated with curative intent and with no known active disease ≥ 5
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years before the first dose of IP and of low potential risk for recurrence
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Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
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of disease
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Adequately treated carcinoma in situ without evidence of disease
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History of leptomeningeal carcinomatosis
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Brain metastases or spinal cord compression. Patients with suspected brain metastases
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at screening should have a CT/ MRI of the brain prior to study entry
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History of active primary immunodeficiency
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History of allogenic organ transplantation
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Active infection including tuberculosis (clinical evaluation that includes clinical
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history, physical examination and radiographic findings, and TB testing in line with
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local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies) or
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active hepatitis B/hepatitis C co-infection
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Current or prior use of immunosuppressive medication within 14 days before the first
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dose of durvalumab or tremelimumab
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Female patients who are pregnant or breastfeeding or male or female patients of
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reproductive potential who are not willing to employ highly effective birth control
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from screening to 180 days after the last dose of durvalumab
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Known allergy or hypersensitivity to any of the IMPs or any of the constituents of the
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product
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Any co-existing medical condition that in the investigator's judgement will
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substantially increase the risk associated with the patient's participation in the
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study
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Patient who has been incarcerated or involuntarily institutionalized by court order or
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by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG
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Patients who are unable to consent because they do not understand the nature
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significance and implications of the clinical trial and therefore cannot form a
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rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG]
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Receipt of live attenuated vaccine within 30 days prior to the first administration of
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any of the IMPs and without need to receive any live attenuated vaccines during study
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conduct and for up to 30 days after end of Durvalumab treatment or 90 days after end
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of Tremelimumab treatment respectively
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