Clinical Trials Register

Summary
EudraCT Number:	2017-004512-19
Sponsor's Protocol Code Number:	UC-0160/1717
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-02-15
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

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A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2017-004512-19

A.3

Full title of the trial

An open label, randomized, phase III trial, evaluating efficacy of Atezolizumab in addition to one year BCG (Bacillus CaLmette-Guerin) bladder instillation in BCG-naive patients with high-risk non-muscle invasive Bladder cANcer.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.3.2

Name or abbreviated title of the trial where available

ALBAN

A.4.1

Sponsor's protocol code number

UC-0160/1717

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	Unicancer
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Laboratoire ROCHE
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	UNICANCER
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	101, rue de Tolbiac
B.5.3.2	Town/ city	Paris cedex 13
B.5.3.3	Post code	75654
B.5.3.4	Country	France
B.5.4	Telephone number	331 85 34 31 12
B.5.5	Fax number	33185 34 33 79
B.5.6	E-mail	m-chausson@unicancer.fr

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	TECENTRIQ
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION GmbH
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	Atezolizumab
D.3.2	Product code	MPDL3280A
D.3.4	Pharmaceutical form	Concentrate for 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	ATEZOLIZUMAB
D.3.9.2	Current sponsor code	ATEZOLIZUMAB
D.3.9.4	EV Substance Code	SUB178312
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	60
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

High-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of the bladder (TURBT) and pathological assessment.

E.1.1.1

Medical condition in easily understood language

Local bladder cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone in patients with high-risk NMIBC as measured by recurrence-free survival.

E.2.2

Secondary objectives of the trial

•To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone as measured by progression free survival,
•To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone as measured by disease-specific survival,
•To evaluate the efficacy of atezolizumab in association with BCG versus BCG alone as measured by overall survival,
•To evaluate disease worsening in each arm,
•To evaluate complete response rate in each arm,
•To evaluate complete response rate among patient with CIS.
Safety and patient self-reported treatment tolerance objectives
•To evaluate the safety and tolerability of atezolizumab in association with BCG versus BCG alone,
•To assess quality of life in patient treated by atezolizumab in association with BCG versus BCG alone as measured by the EORTC QLQ-C30.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

•To identify predictive and prognostic biomarkers of recurrence and bladder cancer detection in tumor tissue, blood and urine.

E.3

Principal inclusion criteria

1. Signed informed consent form after the last endoscopic surgery (TURBT)
2. Adult man and women ( age ≥ 18 years)
3. Any high risk non muscle invasive urothelial carcinoma histologically confirmed (mixed histology tumors allowed if urothelial carcinoma histology is predominant) defined on the TURBT as any of the following
T1 tumor and/or
High grade (WHO 2004) and/or
Grade 3 (WHO 1973) and/or
Carcinoma in situ (CIS)
4. Tumor tissue available from the surgery for central confirmation of the diagnosis and analysis the expression of PD-L1
5. At least one additional (second) resection of the primary tumor has been performed in any of the following cases [without upstaging toward MIBC (EAU guidelines, 2017)] :
- T1 tumors at physician’s discretion,
- incomplete initial TURBT,
- no muscle in the specimen (can be omitted if TaLG/G1 tumors or primary CIS only was found).
6. Absence of metastasis in the pelvis, abdomen, or chest, as confirmed by a negative baseline computed tomography (CT) or magnetic resonance imaging (MRI) scan no more than 90 days prior to the first study treatment
7. ECOG performance status of ≤ 2
8. Life expectancy ≥ 12 weeks
9. Systolic blood pressure (BP) <160 mmHg and diastolic BP <95 mmHg, as documented within 7 days prior to the first study treatment (hypertension allowed provided it is controlled)
10. Adequate hematologic and end-organ function, as defined by the following laboratory results obtained within 7 days prior to the first study treatment:
ANC ≥ 1500 cells/μL
WBC counts > 2500/μL
Lymphocyte count ≥ 300/μL
Platelet count ≥ 100,000/μL
Hemoglobin ≥ 9.0 g/dL
ASAT, ALAT, and alkaline phosphatase ≤ 2.5 × the upper limit of normal (ULN)
Serum bilirubin ≤ 1.0 ×ULN
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
Partial thromboplastin time (PTT)/Prothrombin Time (PT) ≤ 1.5 × ULN or INR < 1.7 × ULN
Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)
11. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab
12. Patients affiliated to the social security system
13. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up

E.4

Principal exclusion criteria

1. Patient having received previous BCG therapy for bladder cancer
2. Any approved anti-cancer therapy, including systemic chemotherapy, or hormonal therapy within 3 weeks prior to initiation of study treatment. Hormone-replacement therapy or oral contraceptives are allowed
3. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to day 1 of study treatment
4. Malignancies other than UC within 5 years prior to Day 1 of cycle 1 of treatment
5. Pregnancy or breastfeeding
6. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
7. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
8. History of autoimmune disease or history of immunosuppression, or conditions associated with congenital or acquired immune deficiency , including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
9. Serum albumin < 2.5 g/dL
10. Known HIV infection
11. Patients with active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test prior to randomization) or hepatitis C.
12. Known active tuberculosis
13. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
14. Signs or symptoms of urinary infection and/or other signs and symptoms > grade 1 (NCI CTCAE v5.0) within 2 weeks prior to Cycle 1, Day 1.
Patients receiving therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1 are not eligible. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
15. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months before Cycle 1, Day 1, unstable arrhythmias, or unstable angina.
16. Major surgical procedure other than for diagnosis within 4 weeks prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study
17. Prior allogeneic stem cell or solid organ transplant
18. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation if such a live, attenuated vaccine will be required during the study
19. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
20. Prior treatment with CD137 agonists or immune checkpoint−blockade therapies, including anti-CD40, anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies
21. Treatment with systemic immunostimulatory agents (including but not limited to interferons, IL-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
22. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
23. Person deprived of their liberty or under protective custody or guardianship

E.5 End points

E.5.1

Primary end point(s)

Recurrence-free survival defined as the time from randomization to the time of first RFS event (recurrence or death). Recurrence is defined as reappearance of disease (local recurrence or occurrence of any metastasis) after the start of therapy.

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

Efficacy:
• Progression-free survival is defined as the time from randomization to the date of recurrence and progression defined as increase of stage from Ta to T1 or from CIS to T1; progression to MIBC (T≥ 2) or to lymph node N+ or to distant disease M+
• Disease-specific survival defined as the time from randomization to the date of death from bladder cancer;
• Overall Survival, defined as the time from randomization to the date of death from any cause;
• Disease worsening, defined as cystectomy or indicative change in therapy, including systemic chemotherapy or radiation therapy. The date of diagnosis (cystoscopy or CT) leading to cystectomy or chemotherapy/radiotherapy will be considered as the time of disease worsening.
•Complete response will measured one the whole population: 3 months after induction (ie about 6 weeks after inclusion) and 1 year after the end of treatment (ie 2 years after inclusion). It will be defined by normal cystoscopy and normal cytology.
•Complete response will be measured among patients with In situ carcinoma with the same timeline

Safety and patient self-reported treatment tolerance:
• Frequency, nature, and severity of adverse events graded according to NCI CTCAE v5.0 and immune-related event (irAE)

• Quality of life will be measured using EORTC QLQ-C30 assessed at baseline and then every 12 weeks for year 1-2 then every 24 weeks for year 3-5

Exploratory endpoints:
• Status of tumor immune-related biomarkers in archival and /or freshly obtained tissues;
• Status of exploratory biomarkers in urine, plasma, whole blood collected before and during treatment with atezolizumab or at recurrence and association with outcome.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Biomarkers study

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

standard arm with BCG

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

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:

258

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

258

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

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

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

516

F.4.2.2

In the whole clinical trial

516

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-05-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-10

P. End of Trial
P.	End of Trial Status	Ongoing

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