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    Summary
    EudraCT Number:2015-003262-86
    Sponsor's Protocol Code Number:B9991001
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-05-04
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2015-003262-86
    A.3Full title of the trial
    A PHASE 3, MULTICENTER, MULTINATIONAL, RANDOMIZED, OPEN-LABEL,
    PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) PLUS BEST
    SUPPORTIVE CARE VERSUS BEST SUPPORTIVE CARE ALONE AS A
    MAINTENANCE TREATMENT IN PATIENTS WITH LOCALLY ADVANCED OR
    METASTATIC UROTHELIAL CANCER WHOSE DISEASE DID NOT PROGRESS
    AFTER COMPLETION OF FIRST-LINE PLATINUM-CONTAINING
    CHEMOTHERAPY
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Avelumab in Patients with Bladder Cancer that did Not Worsen Following Completion of First-Line Chemotherapy
    A.3.2Name or abbreviated title of the trial where available
    JAVELIN Bladder 100
    A.4.1Sponsor's protocol code numberB9991001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02603432
    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.
    B.4.2CountryUnited States
    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 Centre
    B.5.3 Address:
    B.5.3.1Street Address66 Hudson Boulevard East
    B.5.3.2Town/ cityNew York, NY
    B.5.3.3Post code10001
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1800718 1021
    B.5.6E-mailClinicalTrials.gov_Inquiries@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 Europe B.V
    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 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.3.9.2Current sponsor codeMSB0010718C
    D.3.9.3Other descriptive nameAnti-PD-L1
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Locally advanced or metastatic urothelial cancer
    E.1.1.1Medical condition in easily understood language
    Locally advanced or metastatic bladder cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10046714
    E.1.2Term Urothelial carcinoma bladder
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The study is a Phase 3 to demonstrate the benefit of maintenance treatment with avelumab plus Best Standard Care (BSC) vs. BSC alone in prolonging overall survival (OS) in patients with unresectable locally advanced or metastatic urothelial cancer (UC) whose disease did not progress on or following completion of first-line platinum-containing chemotherapy in each co-primary UC patient population: 1) patients determined to have PD-L1-positive tumors (including infiltrating immune cells) by a verified GMP PD-L1 IHC test, and 2) all randomized patients.
    E.2.2Secondary objectives of the trial
    To compare the progression-free survival (PFS) of avelumab plus BSC vs. BSC alone in each of the co-primary UC patient populations treated with avelumab;
    To evaluate the anti-tumor activity of avelumab plus BSC and BSC alone according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in each of the co-primary UC patient populations treated with avelumab;
    To evaluate the overall safety profile of avelumab plus BSC and BSC alone;
    To evaluate the PK of avelumab in each of the co-primary UC patient populations treated with avelumab;
    To assess the immunogenicity of avelumab in each of the co-primary UC patient populations treated with avelumab;
    To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab in pre-treatment tumor tissue in each of the co-primary UC patient populations treated with avelumab;
    To evaluate the effect of avelumab plus BSC and BSC alone on patient-reported outcomes (PROs) in each of the co-primary UC patient populations.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological diagnosis of confirmed, unresectable locally advanced or metastatic transitional cell carcinoma of the urothelium. Patients with
    documented Stage IV disease (per American Joint Committee on
    cancer/International Union for Cancer Control Tumor Node Metastasis
    (TNM) system 7th edition) at the start of first-line chemotherapy and
    measurable disease prior to the start of first-line chemotherapy by
    RECIST v1.1.
    2. Prior first-line chemotherapy must have consisted of at least 4 cycles
    and no more than 6 cycles of gemcitabine + cisplatin and/or gemcitabine
    + carboplatin. No other chemotherapy regimens are allowed in this
    study. The last dose of first-line chemotherapy must have been received
    no less than 4 weeks, and no more than 10 weeks, prior to
    randomization;
    3. Patients without progressive disease as per RECIST v1.1 guidelines
    (ie, with an ongoing CR, PR, or SD) following completion of 4 to 6 cycles
    of first-line chemotherapy. Eligibility based on this criterion will be
    determined by investigator review of pre-chemotherapy and postchemotherapy
    radiological assessments (CT/MRI scans);
    4. Provision of a recent formalin-fixed, paraffin-embedded (FFPE) tumor
    tissue block (subsection thereof) from the most recent primary or
    metastatic tumor biopsy or resection obtained prior to treatment with
    first line chemotherapy but within 24 months prior to randomization,
    with no intervening systemic anti-cancer therapy. If a FFPE tissue block
    cannot be provided, 15 freshly cut unstained slides (10 minimum) will be
    acceptable. Tumor tissue from cytologic sampling (eg, fine needle
    aspiration, including FFPE cell pellet material) or bone metastases are
    not acceptable and should not be submitted;
    5. 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;
    6. Patients who are willing and able to comply with scheduled visits,
    treatment plans, laboratory tests, and other study procedures;
    7. Age above 18 years;
    8. Estimated life expectancy of at least 3 months;
    9. Eastern Cooperative Oncology Group (ECOG) performance status (PS)
    0 or 1;
    10. Adequate bone marrow, renal and liver function;
    11. Negative serum pregnancy test at screening (for females of
    childbearing potential);
    12. Female patients able to have children must agree to use a highly
    effective method of contraception throughout the study and for at least
    30 days after the last dose of assigned treatment.
    E.4Principal exclusion criteria
    1. Patients whose disease progressed by RECIST v1.1 on or after firstline
    chemotherapy for urothelial cancer;
    2. Prior adjuvant or neoadjuvant systemic therapy within 12 months of
    randomization;
    3. Prior immunotherapy with IL-2, IFN-α, or an anti-PD-1, anti-PD-L1,
    anti-PD-L2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or
    any other antibody or drug specifically targeting T-cell co-stimulation or
    immune checkpoint pathways;
    4. Major surgery within 4 weeks or major radiation therapy within 2
    weeks prior to randomization. Prior palliative radiotherapy is permitted,
    provided it has been completed at least 48 hours prior to patient
    randomization;
    5. Patients with known symptomatic central nervous system (CNS)
    metastases requiring steroids. Patients with previously diagnosed CNS
    metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to
    randomization, have discontinued corticosteroid treatment for these
    metastases for at least 4 weeks, and are neurologically stable;
    6. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1;
    however, alopecia, sensory neuropathy Grade <= 2 is acceptable, or
    other Grade <=2 adverse eventsnot constituting a safety risk based on
    the investigator's judgment are acceptable;
    7. Diagnosis of any other malignancy within 5 years prior to
    randomization, except for adequately treated basal cell or squamous cell
    skin cancer, or carcinoma in situ of the breast or of the cervix, or lowgrade
    (Gleason 6 or below) prostate cancer on surveillance without any
    plans for treatment intervention (eg, surgery, radiation, or castration),
    or prostate cancer that has been adequately treated with prostatectomy
    or radiotherapy and currently with no evidence of disease or symptoms;
    8. Participation in other studies involving investigational drug(s) within
    4 weeks prior to randomization. Observational studies are permitted;
    9. 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;
    10. Clinically significant (ie, active) cardiovascular disease: cerebral
    vascular accident/stroke (< 6 months prior to enrollment), myocardial
    infarction (< 6 months prior to enrollment), unstable angina, congestive
    heart failure, or serious cardiac arrhythmia requiring medication;
    11. Active infection requiring systemic therapy;
    12. Known severe hypersensitivity reactions to monoclonal antibodies
    (Grade >= 3), any history of anaphylaxis, or uncontrolled asthma;
    13. Known prior or suspected hypersensitivity to study drugs or any
    component in their formulations;
    14. Current or prior use of immunosuppressive medication within 7 days
    prior to randomization;
    15. Diagnosis of prior immunodeficiency or organ transplant requiring
    immunosuppressive therapy;
    16. Positive test for human immunodeficiency virus (HIV) infection or
    known acquired immunodeficiency syndrome (AIDS);
    17. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at
    screening;
    18. Vaccination within 4 weeks of the first dose of study treatment and
    while on trial is prohibited except for administration of inactivate
    vaccines (for example, inactivated influenza vaccines);
    19. 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;
    20. Pregnant female patients; breastfeeding female patients and female
    patients of childbearing potential who are unwilling or unable to use a
    highly effective method of contraception as outlined in the protocol for
    the duration of the study and for at least 30 days after the last dose of
    investigational product;
    21. Other severe acute or chronic medical conditions including but not
    limited to colitis, inflammatory bowel disease, pneumonitis, and
    pulmonary fibrosis; 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the overall survival (OS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline up to approximately 24 months.
    Disease progression will be assessed through radiological tumor assessments conducted at baseline, at 8 weeks after randomization, then every 8 weeks for up to 1 year from randomization, and every 12 weeks thereafter until documented disease progression regardless of initiation of subsequent anti-cancer therapy.
    E.5.2Secondary end point(s)
    1. Progression-free survival (PFS) based on BICR assessment per
    RECIST v1.1;
    2. Investigator-assessed Progression-Free Survival (PFS). Objective
    Response (OR), Time to Tumor Response (TTR), Duration of Response
    (DR), and Disease Control (DC), as assessed per RECIST v1.1 by BICR
    and investigator.
    3. Safety: Adverse events (AEs) and laboratory abnormalities as graded
    by National Cancer Institute (NCI) Common Terminology Criteria for
    Adverse Events (CTCAE) v.4.03; vital signs (blood pressure, pulse rate).
    4. Pharmacokinetics (PK): maximum concentrations (Cmax) and trough
    concentrations (Ctrough) for avelumab.
    5. Immunogenicity: Anti-drug antibodies (ADA; neutralizing antibody
    [Nab]) against avelumab.
    6. Biomarkers: Tumor tissue biomarkers including, but not limited to,
    PD-L1 expression and tumor-infiltrating CD8+ T lymphocytes.
    7. Patient-Reported Outcomes: patient-reported bladder cancer
    symptom, functioning, global quality of life (QOL), and Time to
    Deterioration (TTD) using the NCCN-FACT FB1SI-18; and health status
    using the EQ-5D-5L.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Baseline up to approximately 24 months.
    2. Baseline up to approximately 24 months
    3. Recorded at each visit and every 30 days for 3 months after the end of treatment
    4. Pre-dose and at the end of infusion on Day 1 and Day 15 of Cycles 1 – 3, and then pre-dose and at the end of infusion on Day 1 of Cycle 5, 7, 9, 11 and 13
    5. Pre-dose on Day 1 and Day 15 of Cycles 1 – 3, and then on Day 1 of Cycle 5, 7, 9, 11 and 13
    6. Prior to Cycle 1 Day 1, and on Day 1 of Cycles 2, 3, and 5 (all pre-dose). An additional sample timepoint will include pre-dose on Cycle 1 Day 15 for Arm A patients
    7. On Day 1 of each cycle
    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 Yes
    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 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
    Best Supportive Care (BSC)
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA120
    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
    Argentina
    Australia
    Brazil
    Canada
    India
    Israel
    Japan
    Mexico
    New Zealand
    United States
    Belgium
    Czechia
    Denmark
    France
    Greece
    Hungary
    Italy
    Netherlands
    Norway
    Poland
    Portugal
    Spain
    Sweden
    Hong Kong
    Korea, Republic of
    Taiwan
    United Kingdom
    Romania
    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 trial in a Member State of the European Union (EU) is defined as the time at which it is deemed that a sufficient number of patients have been recruited and completed the study as stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application in the Member State.

    End of Trial in all other participating countries is defined as Last Patient Last Visit.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months9
    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: 187
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 481
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Legally acceptable representative, as allowed by local guideline/practice
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 400
    F.4.2.2In the whole clinical trial 668
    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)
    At completion of subject's participation, it is under the Investigator's responsibility to prescribe the most appropriate treatment and provide adequate follow-up for the subject. At the end of the study, patients who are still experiencing clinical benefit, the patient may be eligible for continued treatment with avelumab.
    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 Decision2016-05-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-04-06
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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