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    Summary
    EudraCT Number:2015-003262-86
    Sponsor's Protocol Code Number:B9991001
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-03-30
    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 ConcernedNetherlands - Competent Authority
    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, 235 East 42nd Street, New York, NY 10017
    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 Address235 E 42nd Street
    B.5.3.2Town/ cityNew York, NY
    B.5.3.3Post code100017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1800718 1021
    B.5.5Fax number+1800739 1119
    B.5.6E-mailClinicalTrials.govCallCentre@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 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 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 recieved 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 an investigator review of pre-chemotherapy and post-chemotherapy 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 suitable tissue sample is not otherwise available. 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 sumbitted;
    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. Male and female patients able to have children must agree to use 2 highly effective methods of contraception throughout the study and for at least 60 days after the last dose of assigned treatment.
    E.4Principal exclusion criteria
    1. Patients whose disease progressed by RECIST v1.1 on or after first-line 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 (<= 10 fractions) to metastatic lesion(s) 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 Grad <= 2 adverse events not constituting a safety risk based on the investigator's judgement 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 low-grade (Gleason 6 or below) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration), or prostate cancer that had been adequatley treated with prostatectomy or radiotherapy and currentley 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. Clinicaly significant (ie, active) cardiovascualr disease; cerebral vascular accident/stroke (<6 monts prior to enrolment), myocardial infarction (<6months prior to enrolment), unstable angina, congestive heart failure, or serious cardiac arrytmia 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, or known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness;
    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) 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; male patients able to father children, and female patients of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in the protocol for the duration of the study and for at least 60 days after the last dose of investigational product;
    21. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, and 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: Incidence of 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 concerned4
    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
    Belgium
    Brazil
    Canada
    Czech Republic
    Denmark
    France
    Hong Kong
    Hungary
    India
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    New Zealand
    Norway
    Portugal
    Spain
    Sweden
    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
    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 years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days16
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days25
    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 state20
    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 Decision2016-03-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-06
    P. End of Trial
    P.End of Trial StatusOngoing
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