Clinical Trials Register

Summary
EudraCT Number:	2018-003809-26
Sponsor's Protocol Code Number:	MK-3475-905
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-03-28
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.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-003809-26

A.3

Full title of the trial

A Phase 3 Randomized Study of Cystectomy plus Perioperative Pembrolizumab versus Cystectomy Alone in Cisplatin-ineligible Participants with Muscleinvasive Bladder Cancer (KEYNOTE-905)

A.3.1

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

A Phase 3 trial of perioperative pembrolizumab for cisplatin-ineligible patients with MIBC

A.3.2

Name or abbreviated title of the trial where available

Perioperative MK-3475 for cisplatin-ineligible patients with MIBC

A.4.1

Sponsor's protocol code number

MK-3475-905

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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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	Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., 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	Merck Sharp & Dohme (UK) Ltd.
B.5.2	Functional name of contact point	Global Clinical Trial Operations
B.5.3	Address:
B.5.3.1	Street Address	Hertford Road
B.5.3.2	Town/ city	Hoddesdon, Hetfordshire
B.5.3.3	Post code	EN11 9BU
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0115 9892226
B.5.6	E-mail	karen.mcferran@msd.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	PEMBROLIZUMAB
D.3.2	Product code	MK-3475
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	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	AS1
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	25
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)	Yes
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.IMP: 2
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	KEYTRUDA (pembrolizumab, MK-3475)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme 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	KEYTRUDA (pembrolizumab, MK-3475)
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	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	AS2
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	25
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)	Yes
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

Muscle-invasive Bladder Cancer (MIBC)

E.1.1.1

Medical condition in easily understood language

Participants with muscle-invasive urothelial carcinoma who are ineligible for cisplatin-based chemotherapy

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

1. To compare pathologic complete response (pCR) rates obtained in Arm A (preoperative pembrolizumab [MK-3475] and radical cystectomy [RC] + pelvic lymph node dissection [PLND]) and Arm B (RC+PLND), based on central pathologic review, evaluated in participants whose tumors express programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥10 and all participants, irrespective of CPS score.
2. To compare event-free survival (EFS) between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in participants whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS score.

E.2.2

Secondary objectives of the trial

1. To compare overall survival (OS) between Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in individuals whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS score.
2. To assess disease-free survival (DFS) in participants from Arm A (perioperative pembrolizumab and RC+PLND) and Arm B (RC+PLND) who are disease free after surgery based on participants whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS score.
3. To compare the rates of pathologic downstaging (pDS) between Arm A (preoperative pembrolizumab and RC+PLND) and Arm B (RC+PLND), evaluated in participants whose tumors express PD-L1 CPS ≥10 and all participants, irrespective of CPS score.
4. To evaluate the safety and tolerability of perioperative pembrolizumab with RC+PLND.

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

Merck will conduct Future Biomedical Research on DNA (Blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time

E.3

Principal inclusion criteria

-Have a histologically confirmed diagnosis of muscle invasive bladder cancer (T2-T4aN0M0) with predominant (≥50%) urothelial histology (histology and presence of muscle invasion to be confirmed by BICR)
*Participants with mixed histology are eligible provided the urothelial component is ≥50%
*Urothelial carcinomas not originating from the bladder (eg, upper tract [ureters, renal pelvis], urethra) are not eligible
*Participants whose tumors contain any neuroendocrine component are not eligible
-Have clinically non-metastatic bladder cancer (N0M0) determined by imaging (CT chest and CT or MRI of the abdomen/pelvis), confirmed by BICR
-Be deemed eligible for RC + PLND by his/her urologist and/or oncologist and agree to undergo curative intent standard RC + PLND (including prostatectomy if applicable) as per AUA/ASTRO/ASCO/SUO guidelines
-Be ineligible for treatment with cisplatin, as defined by meeting at least one of the following criteria:
*Impaired renal function with measured or calculated CrCl 30 to 59 mL/min (calculated by Cockcroft-Gault method or measured by 24-hour urine collection)
*ECOG Performance Status 2
*CTCAE v.4 Grade ≥2 audiometric hearing loss (25 dB in two consecutive wave ranges))
*CTCAE v.4 Grade ≥2 peripheral neuropathy
*NYHA Class III heart failure
-Have a transurethral resection (TUR) of a bladder tumor (obtained within 60 days prior to study enrollment [ICF signed]) which is submitted and adequate for evaluation of histology, muscle invasion and PD-L1 status. In the event the sample is not evaluable for PD-L1, the participant will be assigned to the CPS <10 group for stratification.
Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides
-Must have an ECOG performance status of 0, 1, or 2
-Demonstrate adequate organ function (all screening labs should be performed within 14 days prior to randomization)
-Participant is male or female at least 18 years of age, at the time of signing the informed consent
-A male participant must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
-A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
*Not a woman of childbearing potential (WOCBP) or
*A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after study interventions
-The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study. The participant may also provide consent/assent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research

E.4

Principal exclusion criteria

-Has a known additional non-urothelial malignancy that is progressing or has required active treatment ≤3 years of study randomization
-Has received any prior systemic anti-neoplastic treatment for MIBC
-Has an abdomino-pelvic lymph node ≥15 mm in the short axis
-Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
-Has received prior systemic anti-cancer therapy including investigational agents within 3 years prior to randomization
-Has received any prior radiotherapy to the bladder
-Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
-Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
-Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug
-Has hypersensitivity to monoclonal antibodies (including pembrolizumab) and/or any of their excipients
-Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
-Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
-Has an active infection requiring systemic therapy. Participant may be rescreened once after resolution of the infection
-Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
-Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as detectable HCV RNA via qualitative nucleic acid testing) infection
-Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
-Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
-Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention
-Has had an allogenic tissue/solid organ transplant

E.5 End points

E.5.1

Primary end point(s)

1. Pathological Complete Response (pCR) Rate in All Participants
2. pCR Rate in Participants Whose Tumors Express Programmed Cell Death Ligand 1 (PD-L1) at a Combined Positive Score (CPS) ≥10
3. Event-Free Survival (EFS) in All Participants
4. EFS in Participants Whose Tumors Express PD-L1 at a CPS ≥10

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Up to approximately 3 months (Time of surgery)
2. Up to approximately 3 months (Time of surgery)
3. Up to approximately 5.5 years
4. Up to approximately 5.5 years

E.5.2

Secondary end point(s)

1. Overall Survival (OS) in All Participants
2. OS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
3. Disease-Free Survival (DFS) in All Participants
4. DFS in Participants Whose Tumors Express PD-L1 at a CPS ≥10
5. Pathologic Downstaging (pDS) Rate in All Participants
6. pDS Rate in Participants Whose Tumors Express PD-L1 at a CPS ≥10
7. Percentage of Participants Experiencing an Adverse Event (AE)
8. Percentage of Participants Discontinuing Study Treatment due to an AE
9. Percentage of Participants Experiencing Perioperative Complications

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Up to approximately 6.5 years
2. Up to approximately 6.5 years
3. Up to approximately 5.5 years
4. Up to approximately 5.5 years
5. Up to approximately 3 months (Time of surgery)
6. Up to approximately 3 months (Time of surgery)
7. Up to approximately 6.5 years
8. Up to approximately 1 year
9. Up to approximately 1 year

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

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

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

Cystectomy

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

105

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

Denmark

France

Germany

Hungary

Ireland

Israel

Italy

Korea, Republic of

Mexico

Poland

Russian Federation

Spain

Sweden

Thailand

Turkey

Ukraine

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

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

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