Clinical Trials Register

Summary
EudraCT Number:	2011-000642-37
Sponsor's Protocol Code Number:	AZD4547-2011
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-09-09
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

2011-000642-37

A.3

Full title of the trial

A Phase I/IIa trial of AZD4547 in combination with Cisplatin and Capecitabine (CX)

A.3.1

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

A Phase I/IIa Study of AZD4547 in combination with cisplatin and capecitabine

A.3.2

Name or abbreviated title of the trial where available

A Phase I/IIa Trial of AZD4547 in combination with CX

A.4.1

Sponsor's protocol code number

AZD4547-2011

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN66171897

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	Greater Glasgow Health Board
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
B.5.2	Functional name of contact point
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
B.4.2	Country
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	AZD4547
D.3.2	Product code	AZD4547
D.3.4	Pharmaceutical form	Film-coated 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	AZD4547
D.3.9.1	CAS number	Not availabl
D.3.9.2	Current sponsor code	AZD4547
D.3.9.3	Other descriptive name	AZD4547
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	range
D.3.10.3	Concentration number	20 to 80
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	Yes
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	Cisplatin
D.3.2	Product code	Not applicable
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	Cisplatin
D.3.9.1	CAS number	15663-27-1
D.3.9.2	Current sponsor code	Not applicable
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	1
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: 3
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.2.5	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	Capecitabine
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	Film-coated 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	Capecitabine
D.3.9.1	CAS number	154361-50-9
D.3.9.2	Current sponsor code	Not applicable
D.3.9.4	EV Substance Code	AS3
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	500
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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Stage 1 - Patients with advanced solid tumours.

Stage 2 - Histologically proven adenocarcinoma or undifferentiated carcinoma of the oesophagus, gastro-oesophageal junction, or stomach.

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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor
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	16.0
E.1.2	Level	LLT
E.1.2	Classification code	10030139
E.1.2	Term	Oesophageal adenocarcinoma NOS
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	16.0
E.1.2	Level	PT
E.1.2	Classification code	10060139
E.1.2	Term	Antineutrophil cytoplasmic antibody decreased
E.1.2	System Organ Class	10022891 - Investigations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	PT
E.1.2	Classification code	10001150
E.1.2	Term	Adenocarcinoma gastric
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

(Stage 1) To identify a recommended dose of AZD4547 when administered in combination with Cisplatin and Capecitabine (CX).

(Stage 2) To determine the effect of AZD4547 in combination with Cisplatin and Capecitabine (AZD4547-CX) compared with Cisplatin and Capecitabine (CX) and placebo on progression-free survival (PFS) when administered to patients with locally advanced or metastatic gastro-oesophageal adenocarcinoma and with FGFR2 polysomy or amplification (FISH > 4)

E.2.2

Secondary objectives of the trial

Stage 1:

•To identify the DLT (Dose-Limiting Toxicity) of AZD4547 when administered in combination with Cisplatin and Capecitabine
•To explore the safety and tolerability of AZD4547 when administered in combination with Cisplatin and Capecitabine
•To determine the pharmacokinetic profile of AZD4547 when administered in combination with Cisplatin and Capecitabine

Stage 2:

•To compare the mean change in tumour size assessments from baseline after 9 weeks of treatment between the study arms
•To compare objective overall (complete and partial) response rates in these patients treated with either AZD4547-CX or CX-placebo
•To compare overall survival in these patients treated with either AZD4547-CX or CX-placebo
•To compare PFS in the FISH 6 and FISH 4/5 sub-groups
•To compare the effect of AZD4547 between the FISH 6 and the FISH 4/5 sub-groups
•To further describe the safety and toxicity profiles of AZD4547-CX and CX-placebo in this patient population

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria (Stage 1 and Stage 2)

1. Male/Female and over 25 years of age.
2. ECOG performance status 0, or 1 (Appendix 1).
3. Written Informed Consent.
4. No chemotherapy, hormonal therapy, immunotherapy, targeted systemic cancer therapy, or investigational therapy within 4 weeks of study entry (6 weeks for mitomycin C and nitrosureas)
5. No radiotherapy within 4 weeks of study entry.
6. Adequate haematological function, as follows:
- Haemoglobin > 10g/dl
- Neutrophils > 1.5 x 109/l
- Platelets > 100 x 109/l
7. Adequate biochemical function, as follows:
- Bilirubin < 1.5 x ULN (Upper Limit of Normal)
- ALT or AST < 2.5 x ULN
- Alkaline Phosphatase < 2.5 x ULN
- Serum Phosphate < ULN
- Serum Calcium < ULN
- Serum Magnesium < ULN
8. Adequate renal function with creatinine clearance / glomerular filtration rate > 60 mls/min. If the creatinine clearance / glomerular filtration rate is less than 60 mls/min as calculated by the Cockroft-Gault formula, then the creatinine clearance / glomerular filtration rate should be measured by either a radio-isotope technique or by 24-hour urine collection.
9. Life expectancy >12 weeks
10. Able to reliably tolerate and comply with oral medication

Additional Dose-finding Inclusion Criteria:

1. Histologically or cytologically proven advanced solid tumour that is refractory to standard therapies, or for whom no standard therapies exist, or for whom cisplatin and capecitabine is an acceptable treatment option.
2. No concomitant use of another anti-cancer therapy with the exception of patients with prostate cancer who are on a LHRH analogue who can continue this during the study.
3. Disease which is either measurable (RECIST 1.1) or evaluable.

Additional randomised component Inclusion Criteria:

1. Histologically or cytologically proven adenocarcinoma or undifferentiated carcinoma of the oesophagus, gastro-oesophageal junction, or stomach.
2. Locally advanced (inoperable) disease (that is not suitable for a combined chemo-radiation approach for tumours confined to the lower oesophagus) or metastatic disease.
3. Tumours with FGFR2 polysomy or amplification (FISH 4/5 or FISH 6)
4. No prior neo-adjuvant or adjuvant chemotherapy, and no prior chemotherapy for advanced disease.
5. No concomitant use of another anti-cancer therapy during the study.
6. At least one bi-dimensional measurable lesion as defined by RECIST 1.1

E.4

Principal exclusion criteria

Exclusion Criteria (Stage 1 and Stage 2)

1. History of physical or psychiatric disorder that would prevent informed consent and compliance
2. Pregnant or lactating women.
3. Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least six months afterwards. Fertile men who are not willing to use a barrier method of contraception (condoms with spermicidal jelly). Fertile men should also refrain from donating sperm from the start of dosing until 16 weeks after discontinuing study treatment. Male patients wishing to subsequently father children should attend for freezing of sperm samples prior to dosing. It is not known whether AZD4547 can induce hepatic enzymes. If oral contraception is used, it is recommended that this is used in combination with a barrier method as well.
4. Evidence of uncontrolled infection (defined as infection that cannot be resolved readily with antibiotics prior to patient entry into the trial)
5. Major surgery within 28 days prior to study entry or anticipated to occur while on study
6. Prolonged QTc (corrected) interval of > 470ms on ECG or a family history of long QT syndrome
7. History of active or treated brain metastases (with the exception of patients with resected brain metastases and no evidence of recurrence on CT or MRI of the brain)
8. CNS disease (uncontrolled seizures or cerebrovascular accident/transient ischaemic attack /subarachnoid haemorrhage within 6 months)
9. Any unresolved toxicity > CTC Grade 1 from previous systemic anti-cancer therapy except alopecia
10. Pre-existing sensory or motor neuropathy > grade 1
11. Known hypersensitivity to cisplatin
12. Known DPD deficiency or hypersensitivity to capecitabine
13. Known hypersensitivity to AZD4547
14. History of significant cardiac disease including myocardial infarction within the previous 6 months, uncontrolled ischaemic heart disease, second or third degree heart block, any other persistent or intermittent cardiac arrhythmia requiring medication, congestive cardiac failure > NYHA Grade 2, or left ventricular ejection fraction of < 50%
15. Patients with a lack of physical integrity of the GI tract leading to a malabsorption syndrome or intestinal obstruction
16. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications
17. Patients with significant hearing loss such that Cisplatin is contra-indicated
18. Patients taking CYP3A4 and CYP2D6 inducers or inhibitors
19. Current evidence or previous history of retinal pigmented epithelial detachment (RPED)
20. Previous laser treatment or intra-ocular injection for treatment of macular degeneration
21. Current evidence or previous history of dry or wet age-related macular degeneration
22. Current evidence or previous history of retinal vein occlusion (RVO)
23.Current evidence or previous history of retinal degenerative diseases (e.g. hereditary)
24.Current evidence or previous history of any other clinically relevant chorioretinal defect

THERE IS NO ADDITIONAL STAGE 1 EXCLUSION CRITERIA

Additional Stage 2 Exclusion Criteria:

History of prior malignancy within the last 5 years other than patients with basal cell carcinoma of the skin or in situ neoplasia of the cervix uteri who have undergone potentially curative treatment

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the dose-finding component of the study will be the optimal dose of AZD4547 to be used in combination with Cisplatin and Capecitabine (CX) based on clinical and laboratory toxicity (NCI-CTC version 4.02), and the primary endpoint of the randomised component of the study will be the progression-free survival of patients with advanced gastro-oesophageal adenocarcinoma treated with AZD4547-CX or with placebo-CX.

E.5.2

Secondary end point(s)

Secondary Objectives - Stage 1:

•To identify the DLT (Dose-Limiting Toxicity) of AZD4547 when administered in combination with Cisplatin and Capecitabine
•To explore the safety and tolerability of AZD4547 when administered in combination with Cisplatin and Capecitabine
•To determine the pharmacokinetic profile of AZD4547 when administered in combination with Cisplatin and Capecitabine

Secondary Objectives - Stage 2:

•To compare the mean change in tumour size assessments from baseline after 9 weeks of treatment between the study arms
•To compare objective overall (complete and partial) response rates in these patients treated with either AZD4547-CX or CX-placebo
•To compare overall survival in these patients treated with either AZD4547-CX or CX-placebo
•To compare PFS in the FISH 6 and FISH 4/5 sub-groups
•To compare the effect of AZD4547 between the FISH 6 and the FISH 4/5 sub-groups
•To further describe the safety and toxicity profiles of AZD4547-CX and CX-placebo in this patient population

E.5.2.1

Timepoint(s) of evaluation of this end point

•Ongoing evaluation throughout each treatment cycle
•Formal assessment every 9 weeks
•During follow up

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

Yes

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 in combination therapy

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

Yes

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

Yes

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

For the purposes of the Clinical Trial Authorisation, the trial is deemed to have ended 30 days after the last patient remaining on treatment received the last dose of AZD4547 or placebo.

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