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    Summary
    EudraCT Number:2016-004758-13
    Sponsor's Protocol Code Number:CA209-934
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-09-25
    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 number2016-004758-13
    A.3Full title of the trial
    Multicenter randomized controlled study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy
    (IMSTAR HN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Multicenter randomized controlled study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy
    (IMSTAR HN)
    Eine randomisiert kontrollierte Studie mit Nivolumab allein oder in Kombination mit Ipilimumab als Immuntherapie im Vergleich zur Standardnachsorge bei chirurgisch resezierten Kopf-Hals Tumoren nach adjuvanter Therapie (IMSTAR HN)
    A.4.1Sponsor's protocol code numberCA209-934
    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 SponsorUniversity Medical Center Hamburg-Eppendorf
    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 organisationUniversity Medical Center Hamburg-Eppendorf, Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde
    B.5.2Functional name of contact pointStudy Coordinator
    B.5.3 Address:
    B.5.3.1Street AddressMartinistrasse 52
    B.5.3.2Town/ cityHamburg
    B.5.3.3Post code20246
    B.5.3.4CountryGermany
    B.5.4Telephone number00494074105236
    B.5.5Fax number00494074105631
    B.5.6E-mailcj.busch@uke.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 (100 mg/10 ml)
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 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 Yes
    D.2.1.1.1Trade name YERVOY
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 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
    Locally advanced, resectable HNSCC (head and neck squamous cell carcinoma)
    Lokal fortgeschrittenes, resektables HNSCC
    E.1.1.1Medical condition in easily understood language
    Surgically treatable, locally advanced head and neck squamous cell carcinoma
    Primär operables lokal fortgeschrittenes Plattenepithelkarzinomen des Kopf-Hals-Bereiches
    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 PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    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
    To evaluate the efficacy and safety in terms of disease free survival (DFS) at 3 years of nivolumab alone or in combination with ipilimumab as adjuvant immunotherapy after adjuvant radio(chemo)therapy in locally advanced resected HNSCC.
    Zur Bewertung der Effektivität und Sicherheit bezüglich des krankheitsfreien Überlebens (DFS) nach 3 Jahren mit Nivolumab allein oder in Kombination mit Ipilimumab als Immuntherapie nach adjuvanter Radio(chemo)therapie bei lokal fortgeschrittenen resektierten HNSCC.
    E.2.2Secondary objectives of the trial
    • Local regional control (LRC)
    • Distant metastasis free survival (DMFS)
    • Overall survival (OS)
    • acute toxicity and late morbidity
    • Quality of life (QoL)
    • Survival depending on PD-L1 Status
    • Comparison of nivolumab alone group vs control and nivolumab & ipilimumab group vs control in terms of DFS
    • Lokoregionäre Kontrolle (LRC)
    • Fernmetastasen-freies Überleben (DMFS)
    • Gesamtüberleben (OS)
    • Akute Toxizität und späte Morbidität
    • Lebensqualität (QoL)
    • Überleben abhängig vom PD-L1 Status
    • Vergleich der Gruppe mit Nivolumab allein versus der Kontrolle und Vergleich der Gruppe mit Nivolumab & Ipilimumab versus der Kontrolle in Bezug auf DFS
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically proven SCC of the oropharynx, oral cavity, hypopharyngx, and larynx
    • clinical stage III-IVB (T1, N2-3; T2, N2-3; T3, N0-3; T4a, N0-3)
    • oropharyngeal cancer HPV-negative
    • Primary tumor and neck metastasis must be resectable
    • Written and signed informed consent
    • ECOG PS 0/1
    • Age ≥ 18
    • Curative treatment intent
    • Adequate bone marrow function: leucocytes > 3.0 x 109/L, neutrophils ≥1500/μL, platelets ≥ 100 x103/μL, hemoglobin > 9.5 g/dL
    • Adequate liver function: Bilirubin < 2.0 g/dL, SGOT, SGPT, < 3 x ULN
    • Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min
    • If of childbearing potential, willingness to use effective contraceptive method for the study duration and 2 months post-dosing.
    • Histologisch nachgewiesene SCC des Oropharynx, Mundhöhle, Hypopharynx und Larynx
    • Klinisches Stadium III-IVB (T1, N2-3; T2, N2-3; T3, N0-3; T4a, N0-3)
    • Oropharynxkarzinom HPV-negativ
    • Primär-Tumor und Hals-Metastasen müssen rese-zierbar sein
    • Unterschriebene schriftliche Einverständniserklärung
    • ECOG PS 0/1
    • Alter ≥ 18 Jahre
    • Kurative Behandlung vorgesehen
    • Adäquate Knochenmarksfunktion: Leukozyten > 3,0 x 109/L, Neutrophile ≥1500/μL, Blutplättchen ≥ 100 x103/μL, Hämoglobin > 9,5 g/dL
    • Adäquate Leberfunktion: Bilirubin < 2,0 g/dL, SGOT, SGPT, < 3 x ULN
    • Serum-Kreatinin ≤ 1,5 x ULN oder Kreatinin-Clearance (CrCl) ≥ 40 mL/min
    • Gebärfähige Frauen: Bereitschaft eine zuverlässige Verhütungsmethode anzuwenden und diese während der Studie und 2 Monate nach der letzten Dosis fortzuführen.
    E.4Principal exclusion criteria
    • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis
    • Prior therapy with anti-PD-1, anti-PD-L1, anti-CTLA and other antibodies targeting checkpoint pathways
    • Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study screening
    • Previous treatment with chemotherapy, radiotherapy, EGFR-targeting agents or surgery exceeding biopsy in head and neck
    • Subjects with a condition requiring systematic treatment either corticosteroids or other immunsuppressive medications within 4 weeks of randomization
    • Prior invasive malignancy except controlled skin cancer or carcinoma in situ of cervix
    • Unknown primary (CUP), nasopharyngeal or salivary gland cancer
    • Metastatic disease
    • Allergies and Adverse Drug Reaction concerning study drug components and any monoclonal antibodies
    • Patients with positive hepatitis B or hepatitis C indicating acute or chronic infection
    • Patients with known human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    • Serious co-morbidity, e.g. high-grade carotis stenosis, congestive heart failure NYHA grade 3 and 4, liver cirrhosis CHILD C
    • Hemoglobin level <9.5g/dl within 10 days before randomization
    • Pregnancy or lactation
    • Women of child-bearing potential with unclear contraception
    • Social situations that limit compliance with study requirements or patients with an unstable condition (e.g., psychiatric disorder, a recent history of drug or alcohol abuse, interfering with study compliance, within 6 months prior to screening) or otherwise thought to be unreliable or incapable of complying with the requirements of the protocol
    • Patients institutionalized by official means or court order
    • Deficient dental preservation status or not accomplished wound healing
    • Akute oder zuvor dokumentierte Autoimmun- oder Entzündungserkrankungen (einschließlich chronisch-entzündlichen Darmerkrankungen [„inflammatory bowel disease“ z.B. Kolitis, Morbus Crohn], Divertiku-litis)
    • Vorherige Therapie mit Anti-PD-1, Anti-PD-L1, Anti-CTLA und andere Antiköper, die im Checkpoint-Signalweg eingreifen
    • Gleichzeitige Behandlung mit anderen experimentel-len Medikamenten oder Teilnahme an anderen klini-schen Studien mit Prüfpräparaten innerhalb 30 Tage vor dem Studienscreening
    • Vorherige Behandlung mit Chemotherapie, Radiothe-rapie, auf EGFR wirkende Agentien oder Operatio-nen außer Biopsien im Kopf- und Halsbereich
    • Patienten, die eine systematische Behandlung mit Kortikosteroiden oder andere immunsuppressive Medikation innerhalb 4 Wochen nach Randomisie-rung benötigen
    • Vorherige invasive Malignität ausgenommen kontrol-lierter Hautkrebs oder Karzinoma in situ der Zervix
    • Unbekannter Primärtumor (CUP), nasopharyngealer oder Speicheldrüsen-Krebs
    • Fernmetastasen
    • Allergien oder Adverse Drug Reaction bezüglich Komponenten des Prüfpräparat oder bei monoklona-len Antikörpern
    • Patienten mit akuter oder chronischer Hepatits B oder Hepatitis C Infektion
    • Patienten mit einer bekannten Infektion mit dem Hu-manes Immundefizienz-Virus (HIV) oder bekanntem erworbenes Immunschwächesyndrom (AIDS)
    • Schwerwiegende Co-Morbidität, z.B. hochgradige Carotis-Stenose, Herzinsuffizienz NYHA Grad 3 und 4, Leberzirrhose CHILD C
    • Hämoglobin-Gehalt < 9,5 g/dl innerhalb 10 Tage vor Randomisierung
    • Schwangerschaft oder stillende Frauen
    • Frauen im gebärfähigen Alter mit unklarer Verhütung
    • Soziale Situation, die die Compliance mit den Stu-dienerfordernissen limitiert oder Patienten in labilem Zustand (z.B. psychische Erkrankung, aktueller Dro-gen- oder Alkoholmissbrauch, interferierend mit der Compliance der Studie, innerhalb 6 Monate vor dem Screening) oder andere Bedenken nicht zuverlässig oder nicht in der Lage zu sein den Erfordernissen des Prüfplans zu entsprechen
    • Patienten, die durch offizielle oder Gerichts-Beschlüsse institutionalisiert sind
    • Mangelnde Zahnerhaltung oder nicht erfolgte Wund-heilung
    E.5 End points
    E.5.1Primary end point(s)
    Disease free survival (DFS):
    Defined as time from randomization to date of first observed either histologically proven recurrence (local, locoregional or distant), or death from any cause whatever occurs first. Second malignancy will not be counted as event in the DFS analysis.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The time of reaching the primary endpoint DFS (and secondary survival endpoints LRC, DMFS, OS) will be censored at study end for event-free patients.
    E.5.2Secondary end point(s)
    • Local regional control (LRC)
    • Distant metastasis free survival (DMFS)
    • Overall survival (OS)
    • Therapy-associated toxicity
    • Quality of Life (QoL)
    E.5.2.1Timepoint(s) of evaluation of this end point
    At study end or:
    Therapy-associated toxicity: During therapy (acute) and 1 and 2 years after randomization
    Quality of Life (QoL) at 1 and 2 years after randomization
    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 No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3.1Comparator description
    Standard treatment with surgical resection of primary tumor and radio(-chemo)therapy
    E.8.2.4Number of treatment arms in the trial2
    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
    3 years after last patient’s end of treatment
    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 months71
    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: 276
    F.1.3Elderly (>=65 years) Information not present in EudraCT
    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 state276
    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
    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 Decision2018-01-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-22
    P. End of Trial
    P.End of Trial StatusOngoing
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