Clinical Trials Register

Summary
EudraCT Number:	2015-003928-31
Sponsor's Protocol Code Number:	GN15ON133
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:	2019-11-07
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

2015-003928-31

A.3

Full title of the trial

A Phase I/IIA Study to Assess Safety, Tolerability and Preliminary Activity of the Combination of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Patients with Advanced Solid Malignancies

A.3.1

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

FAK-PD1 - A Phase I/IIa Study to Assess Safety, Tolerability and Preliminary Activity of the Combination of FAK (Defactinib) and PD-1 (Pembrolizumab) Inhibition in Patients with Advanced Solid Malignancies.

A.3.2

Name or abbreviated title of the trial where available

FAK-PD1

A.4.1

Sponsor's protocol code number

GN15ON133

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02758587

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	NHS Greater Glasgow and Clyde
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CRUK Clinical Trials Unit Glasgow
B.5.2	Functional name of contact point	Lorna Sweeting
B.5.3	Address:
B.5.3.1	Street Address	1053 Great Western Road
B.5.3.2	Town/ city	Glasgow
B.5.3.3	Post code	G12 0YN
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01413017194
B.5.6	E-mail	lorna.sweeting@glasgow.ac.uk
B.Sponsor: 2
B.1.1	Name of Sponsor	University Of Glasgow
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	CRUK New Agents Committee
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	MSD
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Verastem 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
B.5.2	Functional name of contact point

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	Defactinib (VS-6063)
D.3.2	Product code	VS-6063
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Defactinib
D.3.9.1	CAS number	1073154-85-4
D.3.9.3	Other descriptive name	VS-6063
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	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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	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	No
D.2.1.1.1	Trade name	KEYTRUDA
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Limited
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	Pembrolizumab (MK-3475)
D.3.2	Product code	MK-3475
D.3.4	Pharmaceutical form	Powder for concentrate 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.3.9.3	Other descriptive name	MK-3475
D.3.9.4	EV Substance Code	AS2
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	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

Advanced, incurable cancer with no remaining standard-of-care treatment options that are suitable. Or where pembrolizumab is a licensed treatment option at that line of therapy. In Phase I, this may be any solid cancer. In Phase II, this will be pancreatic cancer, non-small cell lung cancer (NSCLC) or mesothelioma.

E.1.1.1

Medical condition in easily understood language

Incurable cancer with no remaining standard treatment options that they should have first. All cancer types in the first part, then just pancreatic, non-small cell lung and mesothelioma in the second.

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	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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	HLT
E.1.2	Classification code	10033633
E.1.2	Term	Pancreatic neoplasms malignant (excl islet cell and carcinoid)
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	HLT
E.1.2	Classification code	10029664
E.1.2	Term	Non-small cell neoplasms malignant of the respiratory tract cell type specified
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	HLT
E.1.2	Classification code	10027414
E.1.2	Term	Mesotheliomas malignant and unspecified
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

- Assess the safety and tolerability of combination treatment with defactinib (VS-6063) and pembrolizumab

E.2.2

Secondary objectives of the trial

- Determine the recommended doses of the two agents to be used in combination
- Preliminary assessment of clinical anti-tumour activity as assessed by imaging
- Preliminary assessment of defactinib (VS-6063) monotherapy and defactinib (VS-6063) + pembrolizumab combination therapy on the cell types making up the tumour, by evaluation of tissue samples for changes in immune cell infiltrate on treatment
- Preliminary assessment of defactinib (VS-6063) monotherapy and defactinib (VS-6063) + pembrolizumab combination therapy on FAK signalling (defactinib is a FAK inhibitor), by evaluation of phosphorylated FAK

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All parts of study
1. Informed, written consent
2. Male or female, aged 18 years or older at the time consent is given
3. ECOG performance status 0 or 1, with no deterioration over the previous 2 weeks
4. Life expectancy of at least 3 months
5. Measurable disease according to irRECIST criteria, with at least one measurable lesion that has objectively progressed since (or on) any previous therapy
6. Adequate bone marrow, liver and renal function on blood investigations within 7 days prior to treatment initiation:
a. Creatinine ≤ 1.5 x ULN OR GFR ≥ 60 mls/min for patients with creatinine levels > 1.5 x ULN. (using the standard methodology at the investigating centre - i.e Cockcroft-Gault, Wright, MDRD or CKD-EPI formulae, EDTA clearance or 24 urine collection)
b. Total bilirubin ≤ 1.5 x ULN
c. Alanine transaminase (ALT) and/or aspartate transaminase (AST) ≤ 2.5 x ULN (if both measured, both must meet criteria)
d. White blood cell count ≥ 3.0 x 109/L
e. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
f. Platelets ≥ 100 x 109/L
g. Haemoglobin ≥ 90 g/L
h. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN, UNLESS patient is receiving anticoagulation therapy, in which case INR or PT must be within the intended therapeutic range.
7. Patients must have been offered all appropriate standard-of-care treatments (or all those indicated before anti-PD-1/PD-L1 therapy, if licensed)
8. Patients must agree to use adequate contraceptive measures for the course of the study through 120 days after the last dose of study medication
9. Women of child-bearing potential must have a negative pregnancy test within 72 hours prior to start of dosing
10. Consent to supply any available archival tissue

Dose escalation (Phase I)
11. Pathological diagnosis of any advanced solid tumour type, with confirmation that a tissue sample (core biopsy or resected specimen) is available

Pancreatic expansion (Phase IIa)
12. Pathological diagnosis of pancreatic ductal adenocarcinoma, with confirmation that a tissue sample (core biopsy or resected specimen) is available

NSCLC expansion (Phase IIa)
13. Pathological diagnosis of non-small cell lung cancer (NSCLC)
14. Lesion suitable for repeat biopsy
15. Baseline biopsy containing tumour material during eligibility
16. Consent for paired biopsies on study

Mesothelioma expansion (Phase IIa)
17. Pathological diagnosis of mesothelioma
18. Lesion suitable for repeat biopsy
19. Baseline biopsy containing tumour material during eligibility
20. Consent for paired biopsies on study

E.4

Principal exclusion criteria

All parts of study
1. An additional invasive cancer in the last 5 years (other than treated and controlled localised non-melanoma skin cancer or cervical carcinoma-in-situ, or indolent prostate cancer that has been stable for > 1 year)
2. Any central nervous system metastases unless treated and asymptomatic, as well as stable on imaging and not requiring steroids in the preceding 4 weeks
3. Any interventional studies, systemic cancer therapies or monoclonal antibodies in the preceding 4 weeks (6 weeks for mitomycin C and nitrosureas)
4. Any live vaccines in the preceding 4 weeks
5. Systemic immunosuppressive agents in the preceding 2 weeks. Immunosuppressive agents include steroids such as prednisolone (doses ≥ 15 mg daily) or dexamethasone (doses ≥ 2 mg daily)
Replacement therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc) is not considered a form of systemic treatment.
6. Diagnosis of immunodeficiency
7. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
8. Known interstitial lung disease or active, non-infectious pneumonitis
9. Known history of Tuberculosis (TB), Human Immunodeficiency Virus (HIV) or active Hepatitis B or C
10. Other severe or uncontrolled systemic diseases (e.g. uncontrolled hypertension, recent myocardial infarction, organ failure or active infection)
11. Baseline (non-laboratory) toxicities greater than grade 1 (CTCAE v4.03) despite optimal supportive therapy, including fatigue, anorexia, nausea or diarrhoea, but with the exception of alopecia
12. Pregnancy or lactation
13. Limited ability to swallow or absorb oral medications
14. Hypersensitivity to defactinib (VS-6063), pembrolizumab or excipients (including L-histidine, L-histidine hydrochloride monohydrate, sucrose or polysorbate 80)
15. 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

E.5 End points

E.5.1

Primary end point(s)

Adverse events (AEs) using CTCAE v4.03, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) assessment

The primary outcome measure of the dose escalation phase is the maximum tolerated dose of defactinib(VS-6063) and pembrolizumab in combination, based on clinical and laboratory toxicity which will be classified and graded according to CTCAE v 4.03. The primary outcome measure of the dose expansion phase is the toxicity/tolerability of the combination at the recommended dose level in three specific disease types (mesothelioma, pancreas, NSCLC). The causality of each adverse event to the combination will be classified and graded according to CTCAE v4.03.

E.5.1.1

Timepoint(s) of evaluation of this end point

Adverse events will be monitored throughout chemotherapy/while on study drug at each clinic visit and details recorded in the study CRF. All adverse events will be followed up until resolution. In terms of dose escalation decisions, the adverse events recorded during cycle 1 are key.

E.5.2

Secondary end point(s)

1. Objective response rate (ORR) using best objective response rate by irRECIST
2. Duration of response
3. Progressions free survival using irRECIST
4. Overall survival
5. Change in FAK Y397 phoporylation
6. Change in immune call infiltrate

E.5.2.1

Timepoint(s) of evaluation of this end point

For ORR, duration of response, progression free survival:
Disease evaluation (CT with contrast (chest/abdomen/pelvis) or alternative MRI) should be performed every 6 weeks for the first 24 weeks, thereafter every 12 weeks. Disease evaluation days will be timed from cycle 1 day 1, irrespective of any dose delays and may be carried out within a 7 day window either side of the scheduled day.

For overall survival:
Contact with treating site 6 monthly.

For change in phosphorylation and immune cell infiltrate:
Paired biopsies prior to treatment and after 14 days approximately (only in NSCLC and mesothelioma patients)

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

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

First administration of the combination in humans, however each agent has monotherapy data.

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

E.8.1.1

Randomised

E.8.1.2

Open

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

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

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