Clinical Trials Register

Summary
EudraCT Number:	2016-002267-33
Sponsor's Protocol Code Number:	OCTO-089
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-24
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

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2016-002267-33

A.3

Full title of the trial

A parallel group phase I/II marker lesion study to assess the safety, tolerability and efficacy of intravenous or intravesical pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer

A.3.1

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

A clinical trial to test the safety, tolerability and side effects of a drug called pembrolizumab in patients with recurrent bladder cancer. Participants will be randomly assigned to receive the drug in one of two different ways; into the vein or into the bladder.

A.3.2

Name or abbreviated title of the trial where available

PemBla

A.4.1

Sponsor's protocol code number

OCTO-089

A.5.4

Other Identifiers

Name:

ClinicalTrials.gov

Number:

NCT03167151

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	University of Oxford
B.1.3.4	Country	United Kingdom
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	Merck Sharp & Dohme Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Oxford
B.5.2	Functional name of contact point	Oncology Clinical Trials Office
B.5.3	Address:
B.5.3.1	Street Address	Department of Oncology, ORCRB, Roosevelt Drive
B.5.3.2	Town/ city	Headington, Oxford
B.5.3.3	Post code	OX37DQ
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01865617013
B.5.6	E-mail	octo-pembla@oncology.ox.ac.uk

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.2.1.1.1	Trade name	KEYTRUDA
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharpe & Dohme Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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
D.3.2	Product code	MK-3475
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 Intravesical 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.3.9.3	Other descriptive name	Anti-PD-1 monoclonal antibody
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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Intermediate risk recurrent non-muscle invasive bladder cancer

E.1.1.1

Medical condition in easily understood language

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	PT
E.1.2	Classification code	10005056
E.1.2	Term	Bladder neoplasm
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 test the safety, tolerability and side effects of a drug called pembrolizumab in patients with recurrent bladder cancer.

E.2.2

Secondary objectives of the trial

To test the anti-tumour activity of pembrolizumab given directly into the bladder (intravesical) or into the blood steam via the veins (intravenous.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial and comply with the protocol scheduled follow-up visits and examinations for the duration of the study
2. Be equal to or over 18 years of age on day of signing informed consent
3. Have recurrent NMIBC for which adjuvant treatment post TURBT would be a reasonable treatment option
4. Main study only:
a. Have recurrent, multiple (minimum 2) tumours consistent with NMIBC
b. Have at least one lesion of between 5-10mm in size clinically that can be left un-resected at TURBT as the marker lesion
c. Have histologically confirmed low grade transitional cell NMIBC at original and any subsequent diagnosis

5. Have a normal upper urinary tract (as evidenced by ultrasound or CT urography within 2 years prior to randomisation) and no evidence of tumour in prostatic urethra at flexible cystoscopy
6. Have a performance status of 0 or 1 on the ECOG Performance Scale
7. Have adequate organ function as defined in the table below:

Lab Test Value required
Haemoglobin (Hb) ≥ 9 g/dL without transfusion or EPO dependency
Absolute neutrophil count ≥ 1.5 x 109/L
Platelet count ≥ 100 x 109/L
Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN
Serum alanine aminotransferase (ALT) and/or serum aspartate aminotransferase (AST) ≤ 2.5 x ULN
Serum creatinine OR
Measured or calculated creatinine clearancea ≤ 1.5 x ULN OR
≥ 60ml/min for subject with creatinine levels > 1.5 x institutional ULN
Albumin ≥ 25g/L
International Normalized Ratio (INR) or Prothrombin Time (PT) and
Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or APTT is within therapeutic range of intended use of anticoagulants

8. Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
9. Both male and female subjects of childbearing potential (Section 5.1) must be willing to use an adequate method of contraception as outlined in section 5.1 for the course of the study and until 120 days after the last dose of the study medication

E.4

Principal exclusion criteria

he subject must be excluded from participating in the trial if the subject:
1. Has received prior radiotherapy to the pelvis
2. Has significant urinary incontinence or known bladder instability
3. Main study only:
a. Has more than 2 out of 3 of the following present at the current time:
i. ≥8 tumours
ii. Tumour ≥3cm in size
iii. Frequent recurrence (>1/year)

b. Has a previous history of any of the following: T1 tumour, high grade/G3 tumour, carcinoma in situ, multiple recurrent large (>3cm) Ta, G1 or G2 tumours.
c. Had a primary tumour of unknown pathological stage or grade
d. Has disease for which resection of all visible tumours is not possible

4. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 28 days of the first dose of trial treatment
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Subjects requiring use of inhaled or intranasal corticosteroids or local steroid injections would not be excluded
6. Has a known history of active TB
7. Has received intravesical BCG treatment within 30 days prior to the first dose of trial treatment
8. Has hypersensitivity to pembrolizumab or any of its excipients
9. Has had treatment with any other anti-cancer monoclonal antibody within 28 days prior to enrolment or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
10. Has had treatment with prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of administration of study drug or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.)
11. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
12. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurological symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for a t least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
13. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
14. Has a known history of, or any evidence of active, non-infectious pneumonitis
15. Has an active or intractable infection requiring systemic therapy
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator
17. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through to 120 days after the last dose of trial treatment
19. Has received prior therapy with an anti-PD-1, anti PD-L1, or anti-PD-L2 agent
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
21. Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA [qualitative] is detected)
22. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

E.5 End points

E.5.1

Primary end point(s)

Incidence and severity of adverse events (NCI CTCAE v4.03)

E.5.1.1

Timepoint(s) of evaluation of this end point

Incidence and severity of adverse events will be evaluated on an ongoing basis throughout the study.

E.5.2

Secondary end point(s)

• Complete response rate of marker-lesion as assessed clinically at TURBT and confirmed on biopsy of tumour bed
• Recurrence and progression free interval

Tertiary/Exploratory Endpoints
• Tumour/stromal cell PD-L1 expression and presence of PD-1+ infiltrating lymphocytes in pre, on and post treatment tumour samples measured by immunohistochemistry and FACS analysis
• Perform gene expression profiling and DNA sequencing on pre-treatment blood and tumour samples
• Analysis of TCR repertoire and clonality of infiltrating T cells in resected tumour specimens, urine and normal bladder tissue
• Analysis of TCR repertoire and clonality of PBMC before, during and after treatment
• Analysis of cytokines in blood and urine
• Determine blood levels of Pembrolizumab during treatment

E.5.2.1

Timepoint(s) of evaluation of this end point

All secondary and exploratory endpoint will be evaluated on an ongoing basis through the study.

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

Yes

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1 Dose escalation with Phase II randomised main study.

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

Different method of administration

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

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 plus 24 months follow-up of medical records

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