Clinical Trials Register

Summary
EudraCT Number:	2010-021951-26
Sponsor's Protocol Code Number:	UoL000621/R&D3963
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:	2011-02-22
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

2010-021951-26

A.3

Full title of the trial

VIP: A prospective, phase II, double blinded, multicentre, randomised clinical trial comparing combination gemcitabine and vandetanib therapy with gemcitabine therapy alone in locally advanced or metastatic pancreatic carcinoma.

A.3.1

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

Clinical trial comparing combination chemotherapy(gemcitabine and vandetanib) therapy with gemcitabine therapy alone in advanced pancreas cancer

A.3.2

Name or abbreviated title of the trial where available

VIP Version: 4

A.4.1

Sponsor's protocol code number

UoL000621/R&D3963

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN74555382

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 Liverpool
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	AstraZeneca
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
B.5.2	Functional name of contact point
B.Sponsor: 2
B.1.1	Name of Sponsor	Royal Liverpool and Broadgreen University Hospitals Trust
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	AstraZeneca
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
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	Vandetanib
D.3.2	Product code	ZD6474
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	vandetanib
D.3.9.1	CAS number	443913-73-3
D.3.9.2	Current sponsor code	ZD6474
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	100
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

Locally advanced or metastatic pancreatic cancer

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10033600
E.1.2	Term	Pancreatic adenocarcinoma non-resectable
E.1.2	System Organ Class	100000004864

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 assess whether overall survival time using gemcitabine plus vandetanib is longer than that using gemcitabine alone as the first treatment for advanced or metastatic pancreatic cancer.

E.2.2

Secondary objectives of the trial

To compare between the two treatment groups
- Progression free survival (PFS)
- Objective response rate (ORR)
- Disease control rate
- Toxicity and safety
- Patient pain assessment

Exploratory objectives
To discover possible biomarkers to predict additional benefit of vandetanib over gemcitabine alone for subsequent validation in larger scale studies.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years.
2. Histologically or cytologically proven pancreatic ductal adenocarcinoma or undifferentiated carcinoma of the pancreas.*
3. Locally advanced or metastatic disease precluding curative surgical resection or definitive locally directed therapies such as chemo radiation. Patients who have relapsed following previously resected Pancreatic Cancer can be included.
4. Contrast enhanced computerised tomography (CT) scan of the thorax, abdomen and pelvis within 28 days prior to commencing treatment.
5. Unidimensionally measurable disease as shown by CT scan, in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) guidelines (version 1.1).
6. ECOG performance status 0, 1 or 2 where the investigator feels that treatment with combination chemotherapy, for example FOLFIRINOX, is not appropriate.
7. Platelets ≥100 x 109/l; WBC ≥ 3 x 109/l; neutrophils ≥ 1.5 x 109/l at entry.
8. Documented Life expectancy > 3 months.
9. Informed written consent

*Patients will be approached for consenting to provide either an additional core of tissue material for biomarker discovery at the same time as diagnostic biopsy or in those patients that have already had a diagnostic biopsy to undergo a second biopsy after randomisation into the trial. Neither of these biopsies are compulsory. Patient who don't wish to have extra tissue taken for Biomarker discovery will be approached for consent to released surplus tissue from the original diagnostic specimen if this exists.

E.4

Principal exclusion criteria

1. Laboratory results:
• Serum bilirubin ≥ 1.5x the upper limit of reference range (ULRR).
• Haemoglobin < 10G/dl
• Creatinine clearance < 30 mL/minute (calculated by Cockcroft-Gault formula) **. Patients with a creatinine clearance of ≥30mL/minute and <50mL/minute should begin vandetanib on a reduced dose of 200mg.
• Potassium, ≤4.0 mmol/L despite supplementation; or > 5.5 mmol/L
• Magnesium below the normal range despite supplementation, or > 1.23 mmol/L
• Serum calcium is > 2.9 mmol/L. In cases where serum calcium is below the normal range this can be substituted with the value for calcium adjusted for albumin, if this is below the normal range despite supplementation patients should be excluded.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or alkaline phosphatase (ALP) >2.5 x ULRR or > 5x ULRR if judged by the investigator to be related to liver metastases.
2. Medical or psychiatric conditions compromising informed consent.
3. Intracerebral metastases or meningeal carcinomatosis.
4. Major surgery within 4 weeks or incompletely healed surgical incision before starting study therapy.
5. Evidence of severe or uncontrolled systemic disease or any concurrent condition which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.
6. Clinically significant cardiovascular event (e.g. myocardial infarction, superior vena cava syndrome (SVC), New York Heart Association (NYHA) classification of heart disease ≥2 within 3 months before entry; or presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia.
7. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation), which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is not excluded.
8. QTc prolongation with other medications that required discontinuation of that medication.
9. Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age.
10. Presence of left bundle branch block (LBBB).
11. QTc with Bazett’s correction that is un-measurable or ≥ 480 msec on screening ECG. (Note: If a subject has a QTc interval ≥ 480 msec on screening ECG, the screening ECG may be repeated up to two times and the ECGs must be at least 24 hours apart. The average QTc of the ECGs (either two or three) must be <480msec in order for the patient to be eligible. Patients who are receiving a drug that has a risk of inducing Torsades-de-Pointes (see appendix C) are excluded if QTc is ≥ 460 msec.
12. Any concurrent medication with a known risk of inducing Torsades-de-Pointes that cannot be stopped 2 weeks prior to first dose(please see Appendix C). Any concurrent medication with a possible or conditional risk of inducing Torsades de Pointes, that in the investigator’s opinion cannot be discontinued, are allowed; however, these patients must be monitored closely (please see Appendix C).
13. Concomitant medications that are potent inducers (e.g rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital and St. John’s Wort) of CYP3A4 function.
14. Hypertension not controlled by medical therapy (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg).
15. Currently active diarrhoea that may affect the ability of the patient to absorb the vandetanib or tolerate diarrhoea secondary to vandetanib should that occur as a side effect.
16. Malabsorption syndrome which may impair the absorption of vandetanib (e.g. partial gastrectomy, small bowel resection), This may include previous partial gastrectomy and small bowel resection or active Crohn’s disease, ulcerative colitis.
17. Pregnancy or breast feeding.
18. Previous chemotherapy for locally advanced and metastatic disease. Adjuvant chemotherapy for resected pancreatic cancer will be permitted provided that chemotherapy was completed > 12 months previously.
19. Radiotherapy within the last 4 weeks prior to start of study treatment.
20. Concurrent malignancies or invasive cancers diagnosed within past 5 years except for adequately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine cervix or resected pancreatic cancer.
21. Chemotherapy directed at tumour apart from that described in this protocol.
22. All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be a condom.
** An EDTA blood

E.5 End points

E.5.1

Primary end point(s)

Overall survival (OS) time in patients receiving gemcitabine and vandetanib therapy versus gemcitabine alone

E.5.2

Secondary end point(s)

• Comparison between the two treatment groups for:
o Progression-free survival time
o objective response rate
o disease control rate
o toxicity and safety
o Patient Pain assessment
• To discover possible biomarkers to predict additional benefit of vandetanib for subsequent validation in larger scale studies.

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

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

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.8.2.4

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 end of the trial is defined as the last follow−up visit of the last patient randomised on to the trial.

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