Clinical Trials Register

Summary
EudraCT Number:	2019-003375-19
Sponsor's Protocol Code Number:	B8011006
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-04-10
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

France - ANSM

A.2

EudraCT number

2019-003375-19

A.3

Full title of the trial

A Phase 3, Multinational, Randomized, Open-Label, Three Parallel-Arm Study of PF-06801591, an anti-PD-1 antibody, in Combination with Bacillus Calmette-Guerin (BCG Induction With or Without BCG Maintenance) Versus BCG (Induction and Maintenance) in Participants with High-Risk, BCG-Naïve Non-Muscle Invasive Bladder Cancer

Étude internationale de phase III, randomisée, en ouvert, à trois bras parallèles, visant à évaluer le PF-06801591, un anticorps anti-PD-1, en association avec le vaccin bilié de Calmette et Guérin (BCG d'induction, avec ou sans BCG d'entretien) par rapport au BCG (d'induction et d'entretien) chez des participants naïfs de BCG et atteints d'un cancer de la vessie à risque élevé non invasif sur le plan musculaire

A.3.1

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

Phase 3 Study of PF-06801591 in Combination with Bacillus Calmette-Guerin (BCG) in Participants with High-Risk Non-Muscle Invasive Bladder Cancer

Étude de phase III visant à évaluer le PF-06801591 en association avec le vaccin bilié de Calmette et Guérin (BCG) chez des participants atteints d'un cancer de la vessie à risque élevé non invasif sur le plan musculaire

A.4.1

Sponsor's protocol code number

B8011006

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04165317

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	ClinicalTrials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1800 7181021
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	No
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	PF-06801591
D.3.2	Product code	PF-06801591
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PF-06801591, PD-1 mAb, PD-1 antagonist
D.3.9.2	Current sponsor code	PF-06801591
D.3.9.3	Other descriptive name	PF-06801591, PD-1 mAb, PD-1 antagonist
D.3.9.4	EV Substance Code	SUB182580
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	150
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	Yes
D.3.11.13.1	Other medicinal product type	Recombinant humanized monoclonal antibody (immunoglobulin gamma-4 with kappa light chains, IgG4 kappa)

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

E.1.1.1

Medical condition in easily understood language

Non-Muscle Invasive 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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10022877
E.1.2	Term	Invasive bladder cancer
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

- To demonstrate that PF-06801591 + BCG (induction and maintenance) is superior to BCG (induction and maintenance) in prolonging event-free survival (EFS) in participants with high-risk NMIBC.
- To demonstrate that PF-06801591 + BCG (induction) is superior to BCG (induction and maintenance) in prolonging EFS in participants with high-risk NMIBC.

E.2.2

Secondary objectives of the trial

- To demonstrate that PF-06801591 + BCG (induction and maintenance) is superior to BCG (induction and maintenance) in prolonging overall survival (OS) in participants with high-risk NMIBC.
- To demonstrate that PF-06801591 + BCG (induction) is superior to BCG (induction and maintenance) in prolonging OS in participants with high-risk NMIBC.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age
1. Participant must be ≥18 years of age, at the time of signing the informed consent (except in Japan, where participants must be ≥20 years).

Type of Participant and Disease Characteristics
2. Histological confirmed diagnosis of high-risk, non-muscle invasive transitional cell carcinoma (TCC) of the urothelium of the urinary bladder (tumors of mixed transitional/non-transitional cell histology are allowed, but TCC must be the predominant histology) defined as any of the following:
a. T1 tumor;
b. High-grade Ta tumor;
c. Carcinoma in situ (CIS);
3. Complete resection of all Ta/T1 papillary disease (including participants with concurrent CIS), with most recent TURBT occurring within 12 weeks prior to randomization. A second TURBT must have been performed if indicated according to the current locally applicable guidelines, ie, American Urological Association,
European Association of Urology.
4. Availability of the tumor tissue from the most recent TURBT for the assessment of the PD-L1 expression.
5. ECOG Performance Status (PS) ≤ 2.
6. Adequate Bone Marrow Function (without hematopoietic growth factor or transfusion support within 14 days prior to study randomization), including:
a. Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
b. Platelets ≥100,000/mm3 or 100 x 109/L;
c. Hemoglobin ≥9 g/dL (≥5.6 mmol/L).
7. Adequate renal function defined by an estimated creatinine clearance ≥30 mL/min according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine clearance, or according to local institutional standard method.
8. Adequate liver function, including:
a. Total serum bilirubin ≤1.5 × the upper limit of normal range (ULN).
Participants with Gilbert syndrome who should have total serum bilirubin <3 x ULN;
b. Aspartate and alanine aminotransferase (AST and ALT) ≤ 2.5 × ULN.
9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.

Sex
10. Male or Female
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
Male Participants: Male participants are eligible to participate if they agree to the following during the
intervention period and for at least 6 months after the last dose of study treatment:
 Refrain from donating sperm
PLUS either:
 Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
 Must agree to use contraception/barrier as detailed below
 Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant.

Female Participants:
A female participant is eligible to participate if she is not pregnant or breast-feeding, and at least one of the following conditions applies:
 Is not a woman of childbearing potential; (WOCBP) refer to Appendix 10.4 for definition.
OR
 Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in Appendix 10.4 during the intervention period and for at least 6 months after the last dose of study treatment. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.
 A WOCBP must have a negative highly sensitive (at least 25 IU/Ml) pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study treatment.
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
 Additional requirements for pregnancy testing during and after study treatment are located in Appendix 10.2.
 The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

Informed Consent
11. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol

E.4

Principal exclusion criteria

Medical Conditions
1. Evidence of muscle-invasive, locally advanced or metastatic urothelial cancer or concurrent extravesical, non-muscle invasive TCC of the urothelium.
2. Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
3. Severe active infections including pulmonary tuberculosis requiring systemic therapeutic oral or IV antibiotics within 2 weeks prior to randomization. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection) are eligible.
4. 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 other concurrent malignancy investigator feels has a very low likelihood to become metastatic.
5. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis.
6. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C -eg, presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result at screening or within 3 months prior to randomization) is acceptable if the participant otherwise meets entry criteria.

Prior/Concomitant Therapy
7. Intravesical BCG therapy within 2 years prior to randomization. Prior intravesical chemotherapy for NMIBC is allowed.
8. Prior immunotherapy with anti PD-1, anti PD-L1, anti PD-L2, or anti cytotoxic Tlymphocyte-
associated antigen-4 (CTLA-4) antibody.
9. Prior treatment with immunostimulatory agents including interleukin (IL)-2, IL-15, interferon (INF)-gamma.
10. Prior radiation therapy to the bladder.
11. Treatment with systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
12. Vaccination within 4 weeks from randomization and while on study treatment is prohibited except for administration of inactivated vaccines.
13. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

Prior/Concurrent Clinical Study Experience
14. Participation in other studies involving investigational drug(s) within 4 weeks prior to randomization.

Diagnostic assessments
15. Known or documented absolute and/or relative contraindication of adjuvant intravesical BCG treatment:
a. Prior BCG sepsis or systemic infection (including current urinary tract infection)
b. Total bladder incontinence defined as use more than 6 pads in 24 hours
c. Adverse experience to previous BCG instillation that resulted in treatment discontinuation or precludes re-treatment.
16. Clinically significant (ie, active) cardiovascular disease including the following: cerebral vascular accident/stroke (<6 months prior to randomization); myocardial infarction (<6 months prior to randomization); unstable angina; congestive heart failure (≥New York Heart Association Classification Class II); or serious cardiac arrhythmia (uncontrolled, clinically significant) requiring medication.
17. Q-T interval corrected for heart rate (QTc) >450 msec for male participants or QTc >470 msec for female participants or QTc >480 msec in participants with right bundle branch block

E.5 End points

E.5.1

Primary end point(s)

EFS as assessed by the investigator

E.5.1.1

Timepoint(s) of evaluation of this end point

Cystoscopy and cytology every 12 weeks for 2 years.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

5 years after the last participant randomized

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

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

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

Arm C: no IMP + standard of care (BCG) [induction and maintenance period]

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

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

Australia

Belgium

Canada

China

France

Germany

Italy

Japan

Korea, Republic of

Poland

Portugal

Russian Federation

Spain

United Kingdom

United States

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

The end of the study is defined as 5 years after randomization of the last participant.

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:

299

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

700

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

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

309

F.4.2.2

In the whole clinical trial

999

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)

Patients will move to standard of care treatment.

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

2020-04-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-20

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

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