Clinical Trials Register

Summary
EudraCT Number:	2014-005576-28
Sponsor's Protocol Code Number:	VB-C-01
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-02-24
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

Germany - PEI

A.2

EudraCT number

2014-005576-28

A.3

Full title of the trial

An Exploratory Safety and Immunogenicity Study of Human Papillomavirus (HPV16+) Immunotherapy VB10.16 in Women with High Grade Cervical Intraepithelial Neoplasia (HSIL; CIN 2/3)

Exploratorische Sicherheits- und Immunogenitätsstudie mit VB10.16 zur Immuntherapie von Frauen mit humanen Papillomvirus (HPV16) positiven hochgradigen Cervikalen Intraepithelialen Neoplasien (CIN 2/3)

A.3.1

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

A study of pVB10.16 immunotherapy in women with high grade premalignant cervical lesions

Studie mit VB10.16 Immuntherapie von Frauen mit hochgradigen cervicalen Krebsvorstufen

A.4.1

Sponsor's protocol code number

VB-C-01

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	VACCIBODY A.S.
B.1.3.4	Country	Norway
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Vaccibody A.S
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Theradex (Europe) Ltd
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	2nd Floor, The Pinnacle, Station Way
B.5.3.2	Town/ city	Crawley
B.5.3.3	Post code	RH10 1JH
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441293510319
B.5.5	Fax number	+441293510322
B.5.6	E-mail	mmoores@theradex.co.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	VB10.16
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VB10.16
D.3.9.2	Current sponsor code	VB10.16
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	3
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Doc Ref: EMA/CAT/240515/2014
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

High grade cervical intraepithelial neoplasia (HSIL, CIN 2/3)

E.1.1.1

Medical condition in easily understood language

High grade premalignant lesions of the cervix (HSIL, CIN 2/3)

E.1.1.2

Therapeutic area

Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13]

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 assess the safety/tolerability of 3 mg/ml VB10.16 immunotherapy in patients with HPV16+ Cervical Intraepithelial Neoplasia Grade 2/3 (HSIL; CIN 2/3).

E.2.2

Secondary objectives of the trial

• To assess immunogenicity of 3 mg/ml VB10.16 immunotherapy in patients with HPV16+ Cervical Intraepithelial Neoplasia Grade 2/3 (HSIL; CIN 2/3).
• To make a preliminary assessment of efficacy of VB10.16 immunotherapy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Women ≥18 years who, after counselling by their clinicians consider the risk to future pregnancies from treating cervical abnormalities to outweigh the risk of developing cancer during observation of those abnormalities. In this context no specific upper age threshold is intended at the time of clinical trial entry.
2. Women with ectocervical HPV16+ associated High Grade Cervical Intraepithelial Neoplasia as verified by local pathology (biopsy) obtained within four weeks prior to start of treatment.
2.1. Dosing Phase: Women with histologically confirmed HPV16+ associated CIN 2 high grade Cervical Intraepithelial Neoplasia (HSIL; CIN 2).
2.2. Expansion Phase: Women with histologically confirmed HPV16+ associated CIN 2/3 high grade Cervical Intraepithelial Neoplasia (HSIL; CIN 2/3).
3. Satisfactory colposcopic examination documented with colpo-photography (digital Photography) defined as:
3.1. Visibility of the entire transformation zone including the squamocolumnar junction.
3.2. Visibility of the entire lesion margin.
4. ECOG performance status ≤ 1.
5. Written informed consent.
6. Has agreed to the mandatory biological sampling schedule in the study.

E.4

Principal exclusion criteria

Concomitant conditions
1. More than 2 cervical quadrants of CIN 3 as visualised by colposcopy.
2. Atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) on cytology, malignant cells on cytology or histology or other suspicion of either micro-invasive or invasive disease.
3. Current severe pelvic inflammatory disease, severe cervicitis, or other severe gynaecological infection as per colposcopy and clinical examination.
4. Positive serological test for hepatitis C virus or hepatitis B virus surface antigen (HBsAg) or human immunodeficiency virus (HIV).
5. Administration of any blood product within 3 months of enrolment.
6. Concomitant or prior malignant disease, with exception of adequately treated basal cell carcinoma or other non-melanomatous skin cancer, low grade bladder cancer or other malignancies treated with curative intent 2 or more years pre study entry and in remission at study entry.
7. Clinically significant autoimmune disease.
8. Known allergy to Kanamycin or other aminoglycosides
9. Known immunodeficiency and or immunosuppression.
10. History of toxic shock syndrome.
11. Evidence or history of clinically significant cardiac disease including congestive heart failure, unstable angina, acute myocardial infarction or cerebrovascular accident within the last six months, and symptomatic arrhythmia requiring therapy (with the exception of extra systoles or minor conduction abnormalities and controlled and well treated chronic atrial fibrillation).
12. Active infection requiring parenteral antibiotics.
13. Tattoos, scars, or active lesions/rashes within 2 cm of the site of vaccination or any implantable leads.
Current and prior treatment
14. Immunosuppression including the continued use of systemic or topical steroids at or near the injection site [deltoid, upper arm] (excluding inhaled and eye drop-containing corticosteroids) or the use of immunosuppressive agents for any concurrent condition. All other corticosteroids must be discontinued > 4 weeks prior to first study vaccine administration.
15. Major surgery within 3 months of trial entry.
16. Current or recent (within 30 days of the first study treatment) participation in a clinical trial or treatment with another investigation medicinal product.
17. Previous vaccination (either therapeutic and/or prophylactic) against HPV.
18. Administration of any live vaccine within 90 days of trial entry.
19. Concomitant anticancer therapies.
Haematology, coagulation and biochemistry:
20. Inadequate bone marrow function:
20.1. Absolute Lymphocyte count: < 0.8 x 10^9/L.
20.2. Platelet count <100 x 10^9/L or haemoglobin <6 mmol/L (transfusion allowed up to 12 weeks prior to screening).
21. Inadequate liver function:
21.1. Serum total bilirubin >1.5 x the Upper Limit of Normal (ULN) for the institution.
21.2. Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) >3.0 x ULN.
21.3. Alkaline phosphatase levels >5.0 x ULN.
22. Clinically significant uncorrected electrolyte abnormalities (Sodium, Potassium, Magnesium, Phosphate) that are greater than CTCAE grade 3 for both low and high values).
Other
23. Women of child bearing age (defined as < 2 years after last menstruation and not surgically sterile) not willing to use an effective form of contraception such as hormonal birth control, intrauterine device or double barrier method during study participation and for at least 6 months thereafter unless she has a partner who is sterile (e.g. after vasectomy).
24. Pregnancy or intention to become pregnant during the study period. Urine or serum pregnancy test to be performed within 7 days prior to study treatment start.
25. Nursing women.
26. Evidence of any other medical conditions (such as psychiatric illness, infectious diseases, physical examination or laboratory findings) that may interfere with the study participation, affect patient compliance or place the patient at high risk from treatment-related complications.

E.5 End points

E.5.1

Primary end point(s)

The percentage of patients with adverse events (AEs), including any dose-limiting toxicities (DLT), laboratory assessments and physical findings.

E.5.1.1

Timepoint(s) of evaluation of this end point

AEs - from time of signing the informed consent form until 30 days after the final vaccination, unless a causal relationship to treatment is suspected.
DLT - All CTCAE Grade 3 and 4 toxicities which are clinically unexpected and causally related to VB10.16 and occur within 30 days of the last vaccination.
Haematology/biochemistry done at screening, week 1, week 16 and week 24.
Coagulation done at screening and week 1.
Physical exam and vital signs done at screening, week 1, week 8, week 16 and week 24.
ECG done at screening.

E.5.2

Secondary end point(s)

• The monitoring of immune response by means of:
− The percentage of patients with E6/E7 specific cellular immune response in the blood.
− The percentage of patients with cellular immune response in the target lesions.
− The percentage of patients with humoral response against the E6/E7 viral antigen.
• The percentage of patients with HPV16+ clearance.
• The percentage of patients with lesion regression (Lesion regression is defined as a regression from CIN 3 or CIN 2 [HSIL; high grade] at baseline to CIN1 or less [LSIL; low grade or normal] at any time during the study).

E.5.2.1

Timepoint(s) of evaluation of this end point

Immune response at week 1 and at pre-specified timepoints up to week 24.
HPV16+ COBAS testing done at screening, week 8, week 16 and week 24.
Colposcopy (+ digital photography) done at screening, (or at week 1), week 8, week 16 and week 24.
Liquid Based Cytology done at screening, week 8, week 16 and week 24.
Biopsies and IHC done at screening and week 24. Week 16 biopsies will be done if sufficient tissue can be taken from the lesion.

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)

Yes

E.7.1.1

First administration to humans

Yes

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

E.8.1.1

Randomised

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After study completion, patients will be treated at the discretion of the investigator.
Patients will be contacted at 9 months and 12 months after the last visit to document disease status (Histology, therapeutic resection: yes or no) and any potential late emerging safety events.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-07-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-01-17

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