Clinical Trials Register

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.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2015-003262-86

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

JAVELIN Bladder 100

A.4.1

Sponsor's protocol code number

B9991001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02603432

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Centre
B.5.3	Address:
B.5.3.1	Street Address	66 Hudson Boulevard East
B.5.3.2	Town/ city	New York, NY
B.5.3.3	Post code	10001
B.5.3.4	Country	United States
B.5.4	Telephone number	+1800718 1021
B.5.6	E-mail	ClinicalTrials.gov_Inquiries@pfizer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Bavencio
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Europe B.V
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Avelumab
D.3.2	Product code	MSB0010718C
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AVELUMAB
D.3.9.2	Current sponsor code	MSB0010718C
D.3.9.3	Other descriptive name	Anti-PD-L1
D.3.9.4	EV Substance Code	SUB180078
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Locally advanced or metastatic urothelial cancer

E.1.1.1

Medical condition in easily understood language

Locally advanced or metastatic bladder cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10046714
E.1.2	Term	Urothelial carcinoma bladder
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

E.3

Principal 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.4

Principal 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.5.1

Primary end point(s)

The primary endpoint is the overall survival (OS)

E.5.1.1

Timepoint(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.5.2

Secondary 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.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Best Supportive Care (BSC)

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

120

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If 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.8.7

Trial 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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

187

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

481

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Legally acceptable representative, as allowed by local guideline/practice

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

400

F.4.2.2

In 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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-05-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-04-06

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