Clinical Trials Register

Summary
EudraCT Number:	2014-004065-25
Sponsor's Protocol Code Number:	CCR4251
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:	2015-07-20
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

2014-004065-25

A.3

Full title of the trial

Randomised Phase II Trial of Pembrolizumab and Radiotherapy in Melanoma

A.3.1

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

A Randomised Phase II Trial of Pembrolizumab and Radiotherapy in the treatment of advanced Melanoma.

A.3.2

Name or abbreviated title of the trial where available

PERM

A.4.1

Sponsor's protocol code number

CCR4251

A.5.4

Other Identifiers

Name:

Clinical Trails.gov

Number:

NCT02562625

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	Royal Marsden
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	Cancer Research UK
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Merck, Sharp & Dohme Corp.
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	Royal Marsden NHS Foundation Trust
B.5.2	Functional name of contact point	James Larkin
B.5.3	Address:
B.5.3.1	Street Address	Downs Rd
B.5.3.2	Town/ city	Sutton
B.5.3.3	Post code	SM2 5PT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02089156666
B.5.5	Fax number	02089156762
B.5.6	E-mail	perm.trial@rmh.nhs.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.2.5	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	Powder 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	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK 3475 (Anti PD-1)
D.3.9.3	Other descriptive name	SCH 900475 (Anti PD-1)
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	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

Advanced or unresectable melanoma.

E.1.1.1

Medical condition in easily understood language

Skin cancer that has spread to other organs and/or cannot be removed surgically.

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 effectiveness of pembrolizumab alone and in combination with high dose radiotherapy in patients with metastatic melanoma over 12 weeks of treatment.

E.2.2

Secondary objectives of the trial

-To evaluate the response to pembrolizumab alone and with radiotherapy 6 months post treatment.

-To evaluate the response of individual lesions that have and have not been treated by radiotherapy to see if any effect from the radiotherapy can be seen in distant tumours.

-To assess patient safety when combining pembrolizumab with radiotherapy.

-To assess progression free survival at 1, 2 and 3 years after the treatment has finished.

-To assess overall survival of patients in both study treatment groups.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Be willing and able to provide written informed consent for the trial.

2. Diagnosis of Stage III (unresectable) or stage IV cutaneous melanoma or melanoma of unknown primary, as per AJCC staging system.

3. Confirmed metastatic disease by diagnostic biopsy.

4. Be more than or equal to 18 years of age on day of signing informed consent.

5. Have at least one lesion and a maximum of 3 which are appropriate targets for high dose radiotherapy. This lesion must be 1cm-5cm in size and measurable by RECIST v1.1. The lesions should also be asymptomatic or, in the opinion of the investigator, threaten to become symptomatic.

6. Have in addition at least one other lesion which will not be irradiated but must be measurable by RECIST v1.1 to assess the abscopal effect of the treatment.

7. Have a performance status of 0 or 1 on the ECOG Performance Scale.

8. Demonstrate adequate organ function as defined in Table 1 of the protocol. All screening labs should be performed within 7 days of randomisation.

9. Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to randomisation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

10. Female patients of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

11. Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

E.4

Principal exclusion criteria

1. Has lesions that if irradiated would result in unacceptable radiation induced toxicity to normal tissue, in particular to the CNS and bowel

2. Requires palliative radiotherapy for symptom control

3. Is currently participating in or has participated in a study of an investigational agent or device within 4 weeks of the first dose of trial treatment.

4. 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.

5. Has had a monoclonal antibody within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

6. Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
- Note: Patients with an AE ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
- Note: If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

7. Has history of severe colitis related to previous immunotherapy treatment.

8. Has a past or current history of SjÖgrens Syndrome.

9. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.

10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants 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 neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.

11. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Participants with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Participants that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Participants with hypothyroidism stable on hormone replacement will not be excluded from the study.

12. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

13. Has an active infection requiring systemic therapy.

14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

16. 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 120 days after the last dose of trial treatment.

17. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137.

18. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

19. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).

20. 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)

The difference in response rate(RR)between the treatment arms will be calculated at 12 weeks post treatment start in the intention to treat (ITT) population. This will be presented using the percentage of patients, including 95% confidence intervals, who achieve CR or PR according to the RECIST v1.1 criteria in each treatment group. Analysis of the primary endpoint will be carried out when all patients have completed treatment and 12 week follow-up assessments.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will be assessed 12 weeks after the start of pembrolizumab. The analysis of this endpoint will be performed when the last patient completes their 12 weeks of treatment or comes off study for any other reason.

E.5.2

Secondary end point(s)

- To determine response rates by RECIST v1.1 at 6 months post treatment
- Individual lesion response assessment to assess abscopal effect.
- To assess the toxicity of the combination of pembrolizumab and high dose radiotherapy.
- To assess Progression-free survival at 1, 2 and 3 years post treatment.
- To assess Overall survival in the arms of the study.

E.5.2.1

Timepoint(s) of evaluation of this end point

• RR will be determined at 6 months post treatment start.
• Individual lesion response assessment every 12 weeks taking account of within patient data.
• Toxicity will be assessed after 12 weeks of treatment.
• PFS will be calculated at 1, 2 and 3 years from treatment start until PD or death from any cause.
• OS will be calculated from treatment start until date of death from any cause.

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

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

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 study definition is defined as last patient last visit.

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