Clinical Trials Register

Summary
EudraCT Number:	2017-001476-33
Sponsor's Protocol Code Number:	CO17/94837
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:	2018-05-10
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

UK - MHRA

A.2

EudraCT number

2017-001476-33

A.3

Full title of the trial

A randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

A.3.1

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

A randomised phase II trial comparing two different ways of combining nivolumab and ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma.

A.3.2

Name or abbreviated title of the trial where available

PRISM

A.4.1

Sponsor's protocol code number

CO17/94837

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 Leeds
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	Bristol Myers Squibb
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	Clinical Trials Research Unit
B.5.2	Functional name of contact point	Geraldine Murden
B.5.3	Address:
B.5.3.1	Street Address	University of Leeds
B.5.3.2	Town/ city	Leeds
B.5.3.3	Post code	LS2 9JT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01133439369
B.5.5	Fax number	01133434345
B.5.6	E-mail	medctprs@leeds.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	Yes
D.2.1.1.1	Trade name	Yervoy
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
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	Yervoy
D.3.2	Product code	BMS-734016
D.3.4	Pharmaceutical form	Sterile concentrate
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	Ipilimumab
D.3.9.2	Current sponsor code	BMS-734016
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	5
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)	No
	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	No
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	OPDIVO
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb Pharma EEIG
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	OPDIVO
D.3.2	Product code	BMS-936558
D.3.4	Pharmaceutical form	Sterile concentrate
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	Nivolumab
D.3.9.1	CAS number	946414-94-4
D.3.9.2	Current sponsor code	BMS-936558
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	10
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)	No
	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	No
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

Previously untreated metastatic clear cell renal cell carcinoma.

E.1.1.1

Medical condition in easily understood language

Previously untreated metastatic clear cell renal cell carcinoma.

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	10050513
E.1.2	Term	Metastatic renal cell carcinoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10067946
E.1.2	Term	Renal cell carcinoma
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

The overall aim of the study is to determine whether alternative scheduling of ipilimumab (12 weekly versus standard 3 weekly), when given in combination with nivolumab, results in fewer side effects but retains sufficient activity to warrant further investigation. This will be defined by the number of participants experiencing grade 3/4 side effects within 12 months of starting treatment and the number of participants who are progression-free at 12 months.

E.2.2

Secondary objectives of the trial

Secondary objectives include discontinuation rates, overall response rates, overall survival rates, how many patients experience side effects and their severity, how well the treatment is tolerated, the duration of response and health related quality of life. For patients who continue to receive treatment after disease progression their response rate post-progression will also be assessed. Exploratory objectives include exploration of circulating and tissue-based predictive biomarkers of response.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Aged 18 years or over
• Diagnosed with advanced (not amenable to curative surgery) or metastatic RCC
• Histopathologically confirmed clear cell renal cell cancer (or with a component of clear cell)
• Evidence of measurable disease as per RECIST v1.1 (ie, ≥1 malignant tumour mass that can be accurately measured in at least 1 dimension ≥ 20 mm with conventional computerized tomography scan or Magnetic Resonance Imaging [MRI], or ≥10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable
• Life expectancy of ≥ 6 months
• Karnofsky Performance Status (KPS) of at least 70%

• Required laboratory values within 14 days prior to registration:

o WBC ≥ 2000/μL
o Neutrophils ≥ 1500/μL
o Platelets ≥ 100 x103/μL
o Haemoglobin > 9.0 g/dL
o Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 40 mL/min (Cockcroft and Gault or Wright formula may be used according to local practice)
o AST and ALT ≤ 3 x ULN
o Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
• Able to give written informed consent and willing to follow trial protocol
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug (See Appendix A for details).
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product (see Appendix A for details).
• Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception

E.4

Principal exclusion criteria

Participants meeting any of the following exclusion criteria are not eligible to enrol in this trial.
• Breast feeding
• Prior systemic therapy for RCC (previous participation in adjuvant studies allowed, providing the patient was on the observation/placebo arm – this may require unblinding of the patient)

• Participants who have undergone any prior systemic anti-cancer treatment, including with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways (previous participation in adjuvant studies allowed, providing the patient was on the observation/placebo arm – this may require unblinding of the patient)
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• Participants who test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• Participants who test positive for human immunodeficiency virus (HIV) or have known acquired immunodeficiency syndrome (AIDS)
• Untreated brain metastases. (Patients are not eligible if brain metastases treated only with whole brain radiotherapy. Patients are eligible if previous brain metastases treated with complete surgical resection, Stereotactic Brain Radiation Therapy (SBRT), or gamma knife with no subsequent evidence of progression and asymptomatic. Patients are not eligible if brain metastases treated only with whole brain radiotherapy).

• Active, known or suspected autoimmune disease. (Subjects are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger).
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) 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).
• Uncontrolled adrenal insufficiency
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
• Palliative radiotherapy less than 14 days prior to first dose of study drug
• Any history of hypersensitivity to any of the trial medications or excipients
• Poorly controlled or serious medical or psychiatric illness that, in the Investigator’s opinion, is likely to interfere with participation and/or compliance in this clinical trial

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint for the study is the proportion of patients experiencing a grade 3 or 4 adverse reaction within the initial 12 months of treatment as graded by CTCAE v4.03.

The trial also has a key secondary endpoint of progression-free survival at 12 months which is detailed further in A58.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint: Twelve months from first dose for each participant. This is appropriately measured from first dose rather than baseline due to the endpoint being treatment related adverse events.

Key secondary: At 12 months post randomisation.

E.5.2

Secondary end point(s)

Safety and toxicity: reported based on occurrence of ARs, SAEs, SARs and SUSARs as graded by CTCAE V4.03.
Treatment tolerability: including but not limited to the proportion of participants experiencing a treatment delay/ interruption, the average number of treatment delays/ interruption per participant and duration of delay/interruption.
Treatment discontinuation rates due to treatment related toxicity.
Treatment discontinuation rates due to 'other' reasons.
Overall response.
Duration of response.
Overall survival.
Response rate amongst participants treated beyond RECIST-defined progression.
Health related quality of life: assessed using the functional assessment of cancer therapy kidney symptoms index-19, the EORTC QLQ-C30; and the EQ-5D-5L and scored using the correspondence scoring manuals.

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety and toxicity: assessed via ongoing monitoring from randomisation until 100 days post end of trial treatment
Tolerability: assessed during the treatment period for each participant
Treatment discontinuation: at time of treatment discontinuation for each participant
Overall response: 12-weekly until first progression
Duration of response: From first observation of at least partial response until disease progression or death
Overall survival: Up to 12 months post last patient randomised
Response rate amongst patients treated beyond progression: 12-weekly from time of first-progression to time of treatment cessation
Quality of life: Baseline, 7 and 13 weeks and then 12-weekly until week 61 or disease progression (whichever is earlier)

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

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)

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

Same medicinal products with different treatment schedule

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

The collection of the last participant last data item.

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