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    Summary
    EudraCT Number:2016-001456-21
    Sponsor's Protocol Code Number:B9991016
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-22
    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 ConcernedUK - MHRA
    A.2EudraCT number2016-001456-21
    A.3Full title of the trial
    A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF AVELUMAB IN COMBINATION WITH STANDARD OF CARE CHEMORADIOTHERAPY (CISPLATIN PLUS DEFINITIVE RADIATION THERAPY) VERSUS STANDARD OF CARE CHEMORADIOTHERAPY IN THE FRONT LINE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A CLINICAL STUDY OF INVESTIGATIONAL DRUG AVELUMAB IN COMBINATION WITH STANDARD CHEMORADIOTHERAPY, VERSUS STANDARD CHEMORADIOTHERAPY ALONE, IN THE TREATMENT OF PATIENTS WITH A SPECIFIC TYPE OF HEAD AND NECK CANCER
    A.3.2Name or abbreviated title of the trial where available
    JAVELIN HEAD AND NECK 100
    A.4.1Sponsor's protocol code numberB9991016
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02952586
    A.5.4Other Identifiers
    Name:US INDNumber:IND 130,328
    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 SponsorPfizer Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc., 235 East 42nd Street, New York, NY 10017
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+1800718 1021
    B.5.5Fax number+1303739 1119
    B.5.6E-mailclinicaltrials.govcallcenter@pfizer.com
    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 Bavencio
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Europe Limited
    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 nameAvelumab
    D.3.2Product code MSB0010718C
    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 INNAVELUMAB
    D.3.9.3Other descriptive nameMSB0010718C
    D.3.9.4EV Substance CodeSUB180078
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK (SCCHN)
    E.1.1.1Medical condition in easily understood language
    Cancer of the head and neck
    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 demonstrate that treatment with avelumab in combination with SOC CRT is superior to SOC CRT alone in prolonging PFS in front-line patients with high risk (as defined in Inclusion Criterion 2 [Section 4.1] of the protocol), locally advanced SCCHN who are candidates for definitive CRT with cisplatin
    E.2.2Secondary objectives of the trial
    - To compare the OS of avelumab in combination with SOC CRT vs SOC CRT alone.
    - To evaluate the anti-tumor activity of avelumab in combination with SOC CRT and SOC CRT alone.
    - To evaluate the overall safety and tolerability profile of avelumab in combination with SOC CRT and SOC CRT alone.
    - To evaluate the PK of avelumab.
    - To evaluate the PK of cisplatin (total and free).
    - To assess avelumab ADAs.
    - To evaluate the effect of avelumab in combination with SOC CRT and SOC CRT alone on patient-reported outcomes (PROs) of disease-related symptoms and healthrelated quality of life.
    - To evaluate candidate immune-related predictive biomarkers of sensitivity or insensitivity to treatment with avelumab in combination with SOC CRT in pre-treatment tumor samples (eg, PD-L1 expression).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx with tissue available.
    2. High-risk disease as defined by American Joint Committee on Cancer [AJCC] Guidelines 7th Edition:
    - HPV-negative disease, Stage III, IVa, IVb per tumor/nodes/metastasis (TNM) guidelines for head and neck sites; or
    - Non-oropharyngeal HPV-positive disease, Stage III, IVa, IVb per TNM guidelines for head and neck sites; or
    - HPV-positive oropharyngeal disease T4 OR N2c OR N3 per TNM guidelines for head and neck sites.
    where HPV status will be determined per institutional standard using p16 immunohistochemistry (IHC).
    3. No prior therapy for advanced stage SCCHN; eligible for definitive CRT with curative intent.
    4. Available tumor samples for submission or willing to undergo further tumor biopsies:
    - Availability of a formalin-fixed paraffin-embedded (FFPE) tumor tissue block from primary tumor or nodal biopsy. If an FFPE tissue block cannot be provided, 15 unstained slides (10 minimum) will be acceptable.
    5. Age ≥18 years (≥20 years in Japan).
    6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
    7. Adequate bone marrow function, including:
    - Absolute Neutrophil Count (ANC) ≥1,800/μL or ≥1.8 x 109/L.
    - Platelets ≥100,000/μL or ≥100 x 109/L.- Hemoglobin ≥9 g/dL (may have been transfused).
    8. Adequate renal function, including:
    - Estimated creatinine clearance ≥50 mL/min as calculated using the Cockcroft-Gault (CG) equation OR:
    - a creatinine clearance of at least 60 ml/min if this value is described in the contraindications for cisplatin as per country’s local labeling.
    9. Adequate liver function, including:
    - Total serum bilirubin ≤1.5 x upper limit of normal (ULN).
    - Aspartate and alanine aminotransferase (AST and ALT) ≤2.5 x ULN.
    10. Pregnancy test (for patients of childbearing potential) negative at screening.
    11. Male patients able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use two methods of contraception (at least one of which is considered to be highly effective as defined in section 4.3 of the protocol) throughout the study and for at least 6 months after the last dose of cisplatin and 30 days after the last dose of avelumab/placebo (whichever is later).
    Female patients who are not of childbearing potential (ie, meet at least one of the following criteria):
    - have undergone a documented hysterectomy and/or bilateral oophorectomy;
    - have medically confirmed ovarian failure;
    - have achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause. Status may be confirmed by a serum follicle-stimulating hormone (FSH) level consistent with the post-menopausal state.
    12. Evidence of a signed and dated informed consent document indicating that the patient (or a legally acceptable representative, as allowed by local guideline/practice) has been informed of all pertinent aspects of the study.
    13. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
    E.4Principal exclusion criteria
    1. Prior immunotherapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti CTLA 4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co stimulation or immune checkpoint pathways.
    2. Major surgery ≤4 weeks prior to randomization.
    3. Prior malignancy (other than the current Head and Neck cancer or in situ disease) requiring tumor-directed therapy within the last 2 years prior to enrollment, or concurrent malignancy associated with clinical instability. Exceptions for disease within the 2 years are superficial esophageal cancer (TIS or T1a) fully resected by endoscopy, prostate cancer (Gleason score ≤6) either curatively treated or deemed to not require treatment, ductal in situ carcinoma of the breast that has completed curative treatment, adequately treated basal cell or squamous cell skin cancer.
    4. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
    5. Any of the following in the 6 months prior to randomization: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary embolism.
    6. Active infection requiring systemic therapy.
    7. Known prior severe hypersensitivity to investigational products or any component in the formulations, including known severe hypersensitivity reactions to mAbs, cisplatin, or platinum-related compounds (NCI CTCAE v4.03 Grade ≥ 3).
    8. Use of immunosuppressive medication at time of randomization, except the following:
    a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);
    b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent;
    c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
    9. Prior organ transplantation including allogenic stem-cell transplantation.
    10. Diagnosis of prior immunodeficiency or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
    11. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA [ribonucleic acid] if anti-HCV antibody screening test positive).
    12. Vaccination within 4 weeks prior to randomization except for administration of inactivated vaccines.
    13. Current use of or anticipated need for treatment with other anti-cancer drugs.
    14. Pregnant female patients, breastfeeding female patients, and male patients able to father children and female patients of childbearing potential who are unwilling or unable to use 2 methods of contraception (at least one of which is considered to be highly effective) as outlined in the protocol for the duration of the study and for at least 6 months after the last dose of cisplatin and 30 days after the last dose of avelumab/placebo (whichever is later).
    15. Other severe acute or chronic medical conditions including: immune colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
    16. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees directly involved in the conduct of the study.
    17. Participation in other interventional studies involving investigational drug(s) within 4 weeks prior to randomization.
    E.5 End points
    E.5.1Primary end point(s)
    PFS per modified RECIST v1.1 (see Appendix 3 of the protocol for specific modifications, including pathologic confirmation) by investigator assessment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    As per protocol
    E.5.2Secondary end point(s)
    - OS.
    - Antitumor activity: Pathologic complete response in any resected specimens, neck dissection.
    - Antitumor activity: Locoregional failure, objective response, distant metastatic failure, and duration of response, per modified RECIST v1.1 by investigator assessment.
    - Safety: Adverse events and laboratory abnormalities as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; vital signs (blood pressure, pulse rate).
    - Pharmacokinetics:
    - Cmax and Ctrough for avelumab;
    - Area under the concentration-time curve extrapolated to infinity (AUCinf),Cmax, clearance (CL), time to maximum plasma concentration (Tmax), elimination half-life (t1/2), and volume of distribution (Vz) for cisplatin (total
    and free), as data permit.
    - Immunogenicity: ADA (neutralizing antibody) against avelumab.
    - Patient-Reported Outcomes: Disease-related symptoms and Health-Related Quality of Life as measured by the National Cancer Comprehensive Network (NCCN) Head and Neck Symptom Index-22 items (FHNSI-22), and the EuroQoL Group 5- Dimension 5- Level Self-Report Questionnaire (EQ-5D-5L).
    - Biomarkers: Tumor tissue biomarkers includi
    E.5.2.1Timepoint(s) of evaluation of this end point
    As per protocol
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA115
    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
    Australia
    Austria
    Belgium
    Canada
    China
    France
    Germany
    Greece
    Hungary
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Netherlands
    Poland
    Portugal
    Russian Federation
    Spain
    Switzerland
    Taiwan
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days14
    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: 500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 140
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 235
    F.4.2.2In the whole clinical trial 640
    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)
    No difference from normal treatment of this condition
    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 Decision2017-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-06-19
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