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    Summary
    EudraCT Number:2017-001375-22
    Sponsor's Protocol Code Number:1560-GITCG
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-05-03
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSweden - MPA
    A.2EudraCT number2017-001375-22
    A.3Full title of the trial
    EORTC ILOC study: Phase II of immunotherapy plus local tumor ablation (RFA or stereotactic radiotherapy) in patients with colorectal cancer liver metastases
    EORTC ILOC-studie: Fas II av immunterapi plus lokal tumörablation (RFA eller stereotaktisk strålbehandling) hos patienter med levermetastaser från kolorektal cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    EORTC ILOC study: Phase II of immunotherapy plus local tumor ablation (RFA or stereotactic radiotherapy) in patients with colorectal cancer liver metastases
    EORTC ILOC-studie: Fas II av immunterapi plus lokal tumörablation (RFA eller stereotaktisk strålbehandling) hos patienter med levermetastaser från kolorektal cancer
    A.3.2Name or abbreviated title of the trial where available
    ILOC
    A.4.1Sponsor's protocol code number1560-GITCG
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03101475
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorEuropean Organisation for the Research and Treatment of Cancer (EORTC)
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Organization for the Research and Treatment of Cancer (EORTC)
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportAstra Zeneca
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEuropean Organisation for the Research and Treatment of Cancer (EORTC)
    B.5.2Functional name of contact pointClinical Operations Department/RAU
    B.5.3 Address:
    B.5.3.1Street AddressAvenue E. Mounier 83 / 11
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number+3227741023
    B.5.5Fax number+3227727063
    B.5.6E-mailregulatory@eortc.org
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDurvalumab
    D.3.2Product code MEDI4736
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDurvalumab
    D.3.9.1CAS number 1428935-60-7
    D.3.9.2Current sponsor codeMEDI4736
    D.3.9.3Other descriptive nameDurvalumab
    D.3.9.4EV Substance CodeSUB175688
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTremelimumab
    D.3.2Product code MEDI1123
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTremelimumab
    D.3.9.1CAS number 745013-59-6
    D.3.9.2Current sponsor codeMEDI1123
    D.3.9.3Other descriptive nameTREMELIMUMAB
    D.3.9.4EV Substance CodeSUB37101
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Metastatic colorectal cancer with Incurable liver metastases
    Metastatisk kolorektal cancer med obotliga levermetastaser
    E.1.1.1Medical condition in easily understood language
    Metastatic colorectal cancer with Incurable liver metastases
    Metastatisk kolorektal cancer med obotliga levermetastaser
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10052362
    E.1.2Term Metastatic colorectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this proof of concept study will be to investigate whether the combined use of local tumor ablation/radiation plus immunomodulating drugs may induce a significant immune response in patient with incurable liver metastases from colorectal cancer (CRC) (+/- limited extrahepatic disease) being stable or in partial response after a course of first- or second-line therapy.
    The primary objective of the study is to show an overall response rate of lesions not treated by ablation/radiotherapy including the extrahepatic lesions (according to iRECIST criteria) higher than 10%. With the continuation of first line systemic treatment, no further responses are expected.
    Det primära målet med denna konceptvaliderings-studie är att undersöka huruvida kombinerad användning av lokal tumörablation eller strålbehandling plus immunmodulerande läkemedel kan medföra ett signifikant immunsvar, vid stabil eller partiell respons, efter fullföljd systemisk behandling, hos patient med obotlig levermetastasering från kolorektal cancer (KRC) (+/- begränsad extrahepatisk sjukdom).
    Studiens primära mål är att visa en total responsfrekvens (enligt iRECIST-kriterier), mer än 10 %, för lesioner som inte behandlats med ablation/strålbehandling inklusive extrahepatiska lesioner. Vid fortsatt första linjens systemisk behandling så förväntas ingen ytterligare respons.
    E.2.2Secondary objectives of the trial
    Secondary objectives are:
    •To establish the feasibility and safety of the combined treatment modalities;
    •To study the impact of the local technique (RFA/Radiotherapy) on the results;
    •To investigate biomarkers to predict response to the combined treatment.
    Sekundära mål är:
    •att fastställa möjlighet och säkerhet med de kombinerade behandlingsmodaliteterna
    •att studera vilken inverkan den lokala tekniken (RFA/strålbehandling) har på resultaten
    •att undersöka biomarkörer för att förutspå respons på kombinerad behandling.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Histologically confirmed CRC
    •Patients with CRC liver metastases, with/without extrahepatic disease,in which curative treatment is not possible by resection and or local ablation/radiotherapy
    •≥ 18 years of age at time of study entry
    •WHO performance status 0 to 1
    •Body weight >30kg
    •Measurable disease according to RECIST 1.1
    •Stable disease or partial remission by RECIST 1.1 criteria afterat least 3 months systemic therapy for CRC. Patients are eligible following first- or second-line treatment.
    Note: if patient receives maintenance treatment after the first line treatment, she/he remains eligible for this study
    •Complete responders or partial responders with a 80% or more decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions following last systemic therapy,taking as reference sum of diameters from baseline scan prior to initiation of systemic therapy are excluded as well as patients with almost complete cystic degeneration of liver metastases
    •Note: Interval between last dose of systemic treatment to first dose of study drugs must be of maximum 8weeks (in case bevacizumab was administered as part of the systemic treatment,a min 21days wash out period is required from last administration to planned local ablative treatment initiation)
    •Liver metastases amenable to ablation or stereotactic radiotherapy (SBRT) at completion of systemic therapy:
    •For SBRT: allowing a total ablated volume of at least 25 cm3 &a maximum of 40 cm3 with a max of 2lesions treated with SBRT
    •For RFA: allowing a total ablated volume of at least 25 cm3 &a maximum advised volume of 120 cm3
    •At least 2measurable liver metastases, or at least 1measurable liver metastasis and 1 measurable extrahepatic lesion should remain untreated by ablation or SBRT to allow response monitoring according to RECIST 1.1 & iRECIST
    •Limited extra hepatic disease is allowed, including up to 2extra hepatic metastatic sites,either lung, abdominal, pelvis, bone, or localized lymph node metastases. Each is counted separately as 1site. 2abdominal lesions will be counted as 1extra-hepatic site; 1lung & 1abdominal lesion will be counted as 2sites. Individual extrahepatic lesions should be ≤ 5 cm
    •Availability of tumor sample for biomarkers testing (MSI, PDL-1, etc) (archival tissue from primary tumor)
    •Adequate normal organ &marrow function before initial systemic treatment as well as baseline as defined below:
    •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
    •Platelet count ≥ 100 x 109/L (>100,000 per mm3)
    •Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in absence of hemolysis or hepatic pathology), who will be allowed only in consultation with physician
    •AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal
    •Creatinine ≤ 1.5 x institutional ULN or measured or calculated creatinine clearance >40 mL/min by the Cockcroft-Gault formula (Appendix E) •Hemoglobin ≥ 9.0 g/dL at baseline

    PLEASE SEE THE PROTOCOL FOR FURTHER INCLUSION CRITERIA
    • Histologiskt bekräftad KRC.
    • Patienter med KRC-relaterade levermetastaser (KRLM), med eller utan extrahepatisk sjukdom, där botande behandling inte är möjlig genom resektion och/eller lokal ablation/strålbehandling.
    • ≥ 18 års ålder vid inträde i studien.
    • WHO prestationsstatus 0 till 1.
    • Kroppsvikt > 30 kg.
    • Mätbar sjukdom enligt RECIST 1.1.
    • Stabil sjukdom eller delvis remission enligt kriterier från RECIST 1.1 efter minst 3 månader med systemisk behandling för CRC.Patienter är inkluderbara efter första eller andra linjens behandling. Observera att patient som erhåller underhållsbehandling efter första linjens terapi är möjlig att inkludera i studien.
    • Patienter med fullständig respons eller delvis respons med en 80 % eller större minskning av summan av mått (längsta diameter för tumörlesioner och kort axelmått för lymfkörtlar) av mållesioner efter last systemisk behandling, där summan av diametrar från baslinjeskanning före systemosk behandling används som referens, exkluderas liksom patienter med nästan komplett cystisk degeneration av levermetastaser.
    • Obs: Intervallet mellan sista dosen av systemisk behandling till registrering är maximalt 35 dagar (ifall bevacizumab administrerades som en del av första linjens behandling krävs en minst 21 dagar lång elimineringsperiod (wash out-period) från sista administrering till planerat påbörjande av lokal ablativ behandling).
    • Levermetastaser mottagliga för ablation eller stereotaktisk strålbehandling (SBRT) efter fullföljd första linjens behandling under 4–6 månader:
    • För SBRT: tillåter en total ablaterad volym på minst 25 cm3 och maximalt 40 cm3 där maximalt två lesioner behandlats med SBRT.
    • För RFA: tillåter en total ablaterad volym på minst 25 cm3 och maximal rekommenderad volym på 120 cm3.
    • Minst två mätbara levermetastaser, eller minst 1 mätbar levermetastas och 1 mätbar extrahepatisk leverlesion, bör förbli obehandlade med ablation eller SBRT för att tillåta responsmonitorering enligt RECIST 1.1 och iRECIST.
    • Begränsad extrahepatisk sjukdom är tillåten omfattande upp till 2 extrahepatiska metastaslokalisationer, antingen lung-, buk-,
    bäcken-, skelett- eller lokaliserade lymfkörtelmetastaser. Vardera kommer att räknas separat som en lokalisation. Alltså kommer två buklesioner att räknas som en extrahepatisk lokalisation och en lunglesion och en buklesion kommer att räknas som två lokalisationer. Individuella extrahepatiska lesioner skall vara ≤ 5 cm.
    • Tillgängliga tumörprover för biomarköranalyser (MSI, PDL-1 osv.) (arkiverad vävnad från primärtumör).
    • Adekvat normal organ- och märgfunktion före systemiska behandling såväl som vid baslinjen enligt nedanstående definition:
    • Totalt neutrofilantal (ANC, absolute neutrophil count) ≥ 1,5 x 109/l (> 1 500 per mm3).
    • Trombocyter ≥ 100 x 109/l (> 100 000 per mm3).
    • Serumbilirubin ≤ 1,5 x övre normalgräns (ULN, upper limit of normal) för kliniken. Detta gäller inte patienter med bekräftat Gilberts syndrom (ihållande eller återkommande hyperbilirubinemi som företrädesvis är okonjugerat i frånvaro av hemolys eller leverpatologi) som endast tillåts delta i samråd med patientens läkare.
    • ASAT (SGOT)/ALAT (SGPT) ≤ 5 x övre normalgräns för kliniken.
    • Kreatinin ≤ 1,5 x ULN för kliniken eller mätt eller beräknad kreatininclearance > 40 ml/min beräknad med Cockcroft-Gaults formel.
    • Hemoglobin ≥ 9,0 g/dl vid baslinjen.

    SE PROTOKOLL FÖR ÖVRIGA INKLUSIONSKRITERIER
    E.4Principal exclusion criteria
    •Patients with known brain metastases or history of leptomeningeal carcinomatosis
    •Hilar liver lesions close to central bile ducts to be treated by RFA
    •Prior treatment:
    •History of radiation therapy of the liver, upper abdomen or lower thorax
    •History of radioembolization of the liver
    •Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab and tremelimumab.
    •Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, a CTLA-4 including tremelimumab or other checkpoint inhibitors or other immune therapy during the last 12 months
    •Any unresolved toxicity NCI CTCAE v 4.0 Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
    •Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
    •Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
    •Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab and tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid, or steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
    •Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
    •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
    •History of allogeneic organ transplant
    •History of hypersensitivity to durvalumab, tremelimumab or any excipient
    •Uncontrolled intercurrent illness including, but not limited to:
    •Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
    •Active peptic ulcer disease or gastritis
    •Liver cirrhosis CHILD B+, C (Appendix I)
    •Active bleeding diatheses
    •History of primary immunodeficiency
    •Cardiac disorders:
    •Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia
    •Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia’s Correction
    •Female patients who are pregnant or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.
    •Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
    • Patienter med kända hjärnmetastaser eller anamnes på leptomeningeal carcinomatos.
    • Hiluslesioner i levern nära de centrala gallgångarna som ska behandlas med RFA.
    • Föregående behandling:
    Anamnes på strålbehandling av lever, övre del av buk eller nedre del av bröstkorg.
    Anamnes på radioembolisering av levern.
    Större kirurgiskt ingrepp (enligt prövarens definition) inom 28 dagar före den första dosen av durvalumab och tremelimumab.
    • Pågående eller tidigare användning av immunsupprimerande läkemedel inom 14 dagar före den första dosen av durvalumab och tremelimumab, med undantag av intranasala eller inhalerade kortikosteroider eller systemiska kortikosteroider i fysiologiska doser, som inte får överstiga 10 mg/dag av prednison, eller likvärdig kortikosteroid, eller steroider som förmedicinering för överkänslighetsreaktioner (t.ex. förmedicinering före CT-undersökning).
    • All kvarstående toxicitet NCI CTCAE v 4.0 grad ≥ 2 från tidigare anti-cancerbehandling med undantag för alopeci, vitiligo och de laboratorievärden som definieras i inklusionskriterierna.
    • Patienter med neuropati grad ≥ 2 kommer att utvärderas från fall till fall efter att studieläkaren konsulterats.
    • Patienter med irreversibel toxicitet som inte rimligtvis förväntas att förvärras av behandling med durvalumab eller tremelimumab kan inkluderas endast efter att studieläkaren konsulterats.
    • All tidigare behandling med en PD1- eller PD-L1-hämmare, inklusive durvalumab, en CTLA-4 inklusive tremelimumab eller annan kontrollpunktshämmare eller annan immunterapi under de senaste 12 månaderna.
    • Erhållen vaccination med levande försvagat vaccin inom 30 dagar före inträde i studien eller inom 30 dagar efter administrering av durvalumab.
    • Aktiva eller tidigare dokumenterade autoimmuna eller inflammatoriska sjukdomar (omfattande inflammatoriska lungsjukdomar, interstitiell lungsjukdom, inflammatorisk tarmsjukdom [t.ex. kolit eller Crohns sjukdom], divertikulit [med undantag för divertikulos], systemisk lupus erythematosus, sarkoidossyndrom eller Wegeners syndrom [granulomatos med polyangit, Graves sjukdom, reumatoid artrit, hypofysit, uveit osv.]).
    • Anamnes på allogen organtransplantation.
    • Anamnes på överkänslighet mot durvalumab, tremelimumab eller något hjälpämne.
    • Okontrollerad samtidigt förekommande sjukdom omfattande, men inte begränsat till:
    • Aktiv infektion inklusive tuberkulos (klinisk utvärdering som omfattar klinisk anamnes, kroppsundersökning och röntgenfynd samt TB-prov enligt lokala riktlinjer), hepatit B (känt positivt HBV-ytantigenresultat (HBsAg)), hepatit C eller humant immunbristvirus (positivt resultat för HIV-1/2-antikroppar). Patienter med tidigare eller utläkt HBV-infektion (definierad som att hepatit B-kärnantikroppar [anti-HBc] föreligger och frånvaro av HBsAg) är lämpade. Patienter som är positiva för hepatit C-antikroppar (HCV) är lämpade endast om polymeraskedjereaktion är negativ för HCV RNA.
    • Aktiv magsårssjukdom eller gastrit.
    • Levercirros CHILD B+, C.
    • Aktiv blödningsdiates.
    • Anamnes på primär immunbristsjukdom.
    • Hjärtsjukdom:
    • Symtomatisk hjärtsvikt, okontrollerad hypertoni, instabil angina pectoris, hjärtarytmi.
    • Genomsnittsvärde på QT-intervall för hjärtrytm (QTc) ≥ 470 ms beräknad från 3 elektrokardiogram (EKG) genom att använda Frediricias frekvenskorrigering.
    • Kvinnliga gravida patienter eller manliga eller kvinnliga fertila patienter som inte är villiga att använda effektiv preventivmedelsmetod från screening fram till 90 dagar efter den sista dosen av monoterapi med durvalumab eller 180 dagar efter den sista dosen av kombinationsbehandling med durvalumab + tremelimumab.
    • Alla psykologiska, familjerelaterade, sociologiska eller geografiska tillstånd som eventuellt kan hindra följsamhet med studieprotokollet och uppföljningsschemat. Sådana omständigheter ska diskuteras med patienten före registrering i studien.
    E.5 End points
    E.5.1Primary end point(s)
    •1 year (maximum) after the start of study treatment of the last enrolled patient
    •1 år (max) efter start av studie behandling av den sista inskrivna patienten
    E.5.1.1Timepoint(s) of evaluation of this end point
    •1 year (maximum) after the start of study treatment of the last enrolled patient
    •1 år (max) efter start av studie behandling av den sista inskrivna patienten
    E.5.2Secondary end point(s)
    •Best overall immune response (iBOR) rate of liver lesions not treated with local therapy according to iRECIST (with response confirmation)
    •Best overall response rate of lesions not treated by ablation/radiotherapy including or not the extrahepatic lesions according to RECIST v1.1 (with response confirmation)
    •Response duration according to iRECIST and to RECIST v1.1
    •Stable disease duration according to iRECIST and to RECIST v1.1
    (At the same time as primary endpoint)
    •Progression free survival according to iRECIST and RECIST v1.1
    •Overall survival
    •Long-term endpoints to be reported 30 months after the last patient has been enrolled (individual follow-up of 30 months minimum for each patient)
    Sekundära resultatmått:
    •Bästa totala immunresponsfrekvens (iBOR, best overall immune response) av leverlesioner som inte behandlats med lokal behandling enligt iRECIST (med bekräftelse av respons).
    •Bästa totala immunresponsfrekvens för lesioner som inte behandlats med ablation/strålbehandling omfattande eller inte omfattande extrahepatiska lesioner enligt RECIST v1.1 (med bekräftelse av respons).
    •Varaktighet av respons enligt iRECIST och RECIST v1.1.
    •Stabil varaktighet av sjukdom enligt iRECIST och RECIST v1.1.
    •Progressionsfri överlevnad enligt iRECIST och RECIST v1.1.
    •Total överlevnad.
    •Långsiktiga endpoints som ska rapporteras 30 månader efter det att den sista patienten inkluderats (minst 30 månaders uppföljning för varje patient)
    E.5.2.1Timepoint(s) of evaluation of this end point
    •180 dagar efter att alla patienter har avslutat protokollets behandlingar.
    •Ogynsamma händelser (biverkningar) (CTCAE v4.0 vanliga toxicitetskriterier (Common Toxicity Criteria)).
    •180 dagar efter alla patienter har slutat protokollbehandling
    •Ogynnsamma händelser (biverkningar) (CTCAE v4.0 vanliga toxicitetskriterier [Common Toxicity Criteria]).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    G8 screening assessment for patient ≥ 70 years within 21 days prior to registration
    G8-screeningsbedömning för patienten> 70 år inom 21 dagar före registrering
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    France
    Germany
    Netherlands
    Sweden
    Switzerland
    E.8.7Trial 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 occurs when all of the following criteria have been satisfied:
    1. 90 days after all patients have stopped protocol treatment
    2. The trial is mature for the analysis of the primary endpoint as defined in the protocol, if the study reaches its primary endpoint
    3. The database has been fully cleaned and frozen for this analysis
    Studien avslutas när följande kriterier uppfyllts:
    1. 90 dagar efter att alla patienter har avslutat sin behandlingen i enlighet med protokollet.
    2. Studien har nått en tidpunkt när analys av den primära endpointen är möjlig, om studien når den.
    3. Studiedatabasen har blivit komplett och avslutad för denna analys.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 42
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 61
    F.4.2.2In the whole clinical trial 70
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    According to the discretion of the treating physician
    Enligt den behandlande läkarens diskretion
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-02-22
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