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    Summary
    EudraCT Number:2017-003553-42
    Sponsor's Protocol Code Number:AIO-HEP-0217
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-01-03
    Trial 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 ConcernedGermany - PEI
    A.2EudraCT number2017-003553-42
    A.3Full title of the trial
    A Phase II single-arm, open-label study of transarterial chemoembolization (TACE) in combination with nivolumab performed for intermediate stage hepatocellular carcinoma (HCC)
    Eine offene, einarmige Phase-II-Studie zur transarteriellen Chemoembolisation (TACE) in Kombination mit Nivolumab bei hepatozellulärem Karzinom (HCC) im intermediären Stadium
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of transarterial chemoembolization (TACE) in combination with nivolumab for liver cell cancer
    Eine Studie zur transarteriellen Chemoembolisation (TACE) in Kombination mit Nivolumab bei Leberzellkrebs
    A.3.2Name or abbreviated title of the trial where available
    IMMUTACE
    A.4.1Sponsor's protocol code numberAIO-HEP-0217
    A.5.4Other Identifiers
    Name:BMS study numberNumber:CA209-9KK
    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 SponsorAIO-Studien-gGmbH
    B.1.3.4CountryGermany
    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 supportBristol-Myers Squibb GmbH & Co. KGaA
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAIO-Studien-gGmbH
    B.5.2Functional name of contact pointAIO-Studien-gGmbH
    B.5.3 Address:
    B.5.3.1Street AddressKuno-Fischer-Strasse 8
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code14057
    B.5.3.4CountryGermany
    B.5.4Telephone number004930814534431
    B.5.5Fax number004930322932926
    B.5.6E-mailinfo@aio-studien-ggmbh.de
    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 Yes
    D.2.1.1.1Trade name Opdivo®
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameNivolumab
    D.3.2Product code L01XC17
    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 INNNivolumab
    D.3.9.1CAS number 946414-94-4
    D.3.9.3Other descriptive nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    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
    intermediate stage hepatocellular carcinoma (HCC)
    hepatozelluläres Karzinom (HCC) im intermediären Stadium
    E.1.1.1Medical condition in easily understood language
    intermediate stage liver cell cancer
    Leberzellkrebs im mittleren Stadium
    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 10019828
    E.1.2Term Hepatocellular carcinoma non-resectable
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10049010
    E.1.2Term Carcinoma hepatocellular
    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 PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10077738
    E.1.2Term Hepatocellular carcinoma metastatic
    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 aim of the study is the assessement of the clinical activity of the anti-programmed-death-1 antibody (anti-PD-1) nivolumab in combination with transarterial chemoembolization (TACE) in patients with multinodular, intermediate stage hepatocellular carcinoma (HCC) as first line therapy.
    E.2.2Secondary objectives of the trial
    Secondary objectives of this study are:
    1.) to assess efficacy by PFS, TTP, TTFS, duration of response and OS
    2.) safety and tolerability of nivolumab in combination with TACE in patients with intermediate stage HCC.
    3.) Quality of Life analysis
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent including participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
    2. Age ≥ 18 years at time of study entry
    3. Multinodular or large, solitary HCC, not eligible for resection or local ablation, Tumor burden below 50% of liver volume
    4. Histologically confirmed diagnosis of HCC.
    5. At least one measurable site of disease as defined by modified RECIST (mRECIST) criteria with spiral CT scan or MRI.
    6. Child-Pugh A, Performance status (PS) ≤ 2 (ECOG scale)
    7. Subjects with chronic HBV infection must have HBV DNA viral load < 100 IU/mL at screening. In addition, they must be on antiviral therapy per regional standard of care guidelines prior to initiation of study therapy
    8. Life expectancy of at least 12 weeks.
    9. Adequate blood count, liver-enzymes, and renal function:
    - Haemoglobin ≥ 8.5 g/dL, absolute neutrophil count ≥ 1,500 /L, platelets ≥70 x10^3/L;
    - Total bilirubin ≤ 3x upper normal limit;
    - AST (SGOT), ALT (SGPT) ≤ 5 x upper normal limit;
    - International normalized ratio (INR) ≤1.25;
    - Albumin ≥ 31 g/dL;
    - Serum Creatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 30 mL/min (if using the Cockcroft-Gault formula)
    10. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
    11. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment, adherence to contraceptive measures, scheduled visits and examinations including follow up.
    E.4Principal exclusion criteria
    1. Diffuse HCC or presence of vascular invasion or extrahepatic spread with the following exceptions
    - Invasion of a segmental portal or hepatic veins
    - Limited extrahepatic metastases with one organ system manifestations, e.g. lymphnodal, pulmonary, ossary metastases. For lymphonodal metastases maximum three metastases, max. 2 cm in the longest diameter, and for all other metastases only solitary metastases, max. 2 cm in the longest diameter, are allowed
    2. Patients on a liver transplantation list or with advanced liver disease as defined below
    - Encephalopathy
    - Untreatable ascites
    3. Any contraindications for hepatic embolization procedures
    - Known hepatofugal blood flow
    - Known porto-systemic shunt
    - Impaired clotting test (platelet count <70 x103/L, INR >1.25)
    - Renal failure/ insufficiency requiring hemo-or peritoneal dialysis
    - Known severe atheromatosis
    - Total thrombosis or total invasion of the main branch of the portal vein
    4. History of cardiac disease
    - Congestive heart failure > NYHA class 2
    - Active coronary artery disease (myocardial infarction ≥6 months prior to study entry is allowed)
    - Cardiac arrhythmias (>Grade 2 NCI-CTCAE Version 4.03) which are poorly controlled with anti-arrhythmic therapy or requiring pace maker
    - Uncontrolled hypertension
    - Clinically significant gastrointestinal bleeding within 4 weeks prior to start of study treatment (TACE + nivolumab)
    5. Thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug with the exception of thrombosis of a segmental portal vein
    6. Prior systemic anti-cancer therapy OR endocrine- OR immunotherapy
    7. Prior treatment with TACE
    8. RFA and resection administered less then 4 weeks
    9. Radiotherapy administered less then 4 weeks
    10. Major surgery within 4 weeks of starting the study treatment OR subjects who have not recovered from effects of major surgery
    11. Patients with second primary cancer, except adequately treated basal skin cancer or carcinoma in-situ of the cervix
    12. Immunocompromised patients, e.g. patients who are known HIV
    13. Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer
    14. Previous treatment in the present study
    15. Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results, including but not limited to
    - history of interstitial lung disease
    - HBV and HCV coinfection
    - known acute or chronic pancreatitis
    - active tuberculosis
    - any other active infection requiring systemic therapy
    - history of allogeneic tissue/solid organ transplant
    - diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of nivolumab-monotherapy treatment
    - active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
    - Live vaccine within 30 days prior to the first dose of nivolumab treatment or during study treatment
    - History or clinical evidence of CNS metastases
    16. Medication that is known to interfere with any of the agents applied in the trial
    17. Has known hypersensitivity to nivolumab or any of the constituents of the products
    18. Any other efficacious cancer treatment except protocol specified treatment at study start
    19. Patient has received any other investigational product within 28 days of study entry
    20. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD‑L1, anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
    21. Female subjects who are pregnant, breast-feeding or male/female patients of reproductive potential who are not employing an effective method of birth control. Negative pregnancy test (serum β-HCG) at screening
    22. Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent
    23. Patient who has been incarcerated or involuntarily institutionalized by court order
    24. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts
    E.5 End points
    E.5.1Primary end point(s)
    ORR according to modified RECIST for HCC
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of study (EoS)
    E.5.2Secondary end point(s)
    • tumor response according to RECIST 1.1
    • PFS
    • TTP
    • Time to Failure of Strategy (TTFS):
    - Progression according to mRECIST for HCC with the exception of new intrahepatic lesions, which are assessed to be treatable with one additional locoregional therapy (TACE, RFA/ MWA or resection). Progression following one additional locoregional treatment of such lesions according to mRECIST would be equivalent to failure of strategy.
    • Duration of response
    • Duration of treatment
    • OS
    • QoL (EORTC QLQC30 and HCC-18)
    • AEs/SAEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of study (EoS)
    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
    Quality of Life (QoL)
    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.8.3 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.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 (EoS) is defined as the time point when the last patient has completed a 6 month follow-up period
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months42
    E.8.9.1In the Member State concerned days
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 state49
    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)
    None. Patients will be treated according to standard-of-care at the discretion of the investigator.
    Keine. Die Patienten werden nach Studienende entsprechend dem medizinischen Standard nach dem Ermessen des Arztes behandelt.
    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 Decision2018-03-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-12-10
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