Clinical Trials Register

Summary
EudraCT Number:	2018-002165-19
Sponsor's Protocol Code Number:	20177308
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-11-06
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

Austria - BASG

A.2

EudraCT number

2018-002165-19

A.3

Full title of the trial

Neo-BCC trial: Neoadjuvant treatment of difficult to resect, locally advanced basal cell carcinoma (BCC) with Talimogene laherparepvec (T-VEC)

A.3.1

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

Reduction of the size of a wide spread white skin cancer with an oncolytic virus before surgery

A.4.1

Sponsor's protocol code number

20177308

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	Medical University Vienna
B.1.3.4	Country	Austria
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	Amgen
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	Medical University Vienna
B.5.2	Functional name of contact point	Julia Ressler
B.5.3	Address:
B.5.3.1	Street Address	Spitalgasse 23
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1090
B.5.3.4	Country	Austria
B.5.4	Telephone number	0043014040077020
B.5.5	Fax number	00014040076990
B.5.6	E-mail	julia.ressler@meduniwien.ac.at

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	Yes
D.2.1.1.1	Trade name	Imlygic Talimogene Laherparepvec
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
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	Talimogene laherparepvec (Imlygic)
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	Intralesional use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Imlygic
D.3.9.2	Current sponsor code	AMG 678
D.3.9.3	Other descriptive name	TALIMOGENE LAHERPAREPVEC
D.3.9.4	EV Substance Code	SUB168372
D.3.10	Strength
D.3.10.1	Concentration unit	PFU/ml plaque forming unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000000
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	Classified as a Gene Therapy Medicinal Product EV Number SUB168372
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	Yes
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.2.1.1.1	Trade name	Imlygic Talimogene Laherparepvec
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
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	Talimogene laherparepvec (Imlygic)
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	Intralesional use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Imlygic
D.3.9.2	Current sponsor code	AMG 678
D.3.9.3	Other descriptive name	TALIMOGENE LAHERPAREPVEC
D.3.9.4	EV Substance Code	SUB168372
D.3.10	Strength
D.3.10.1	Concentration unit	PFU/ml plaque forming unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100000000
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	Classified as a Gene Therapy Medicinal Product EV Number SUB168372
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	Yes
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

Basal cell carcinoma (BCC) is the most common malignant neoplasm in fair skinned humans (Rubin et al., 2005). Over the last decades its incidence has increased (Chinem and Miot, 2011). Especially when it comes to BCCs of intermediate size, a surgical approach, while still feasible is often associated with complications and often requires major reconstructive surgery with a suboptimal cosmetic outcome. We hypothesize that neoadjuvant Talimogene laherparepvec minimizes the size of the BCC.

E.1.1.1

Medical condition in easily understood language

White skin cancer is a very common disease. Wide spread white skin cancer is difficult to treat. We hypothesize that the size of the tumor reduces through oncolytic virotherapy before surgery.

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 number of patients with a BCC that become resectable with primary wound closure without the need for plastic reconstructive surgery like skin flaps or skin grafts.
Hypothesis:
H0: < 25% of “difficult to resect” laBCC become resectable without the need for plastic reconstruction
H1: ≥ 25% of “difficult to resect” laBCC become resectable without the need for plastic reconstruction

E.2.2

Secondary objectives of the trial

- To assess the safety of T-VEC in patients with locally advanced BCC
- To assess relapse free survival, defined as the time from complete resection of any residual tumor until local recurrence, in patients with locally advanced BCC under neoadjuvant treatment with T-VEC
- To assess relapse free survival rate (RFS)
- To assess the rate of appearance of BCCs on other body sites during the follow up period
- To assess the biological read outs in respect to tumor related immunity before and after therapy in biopsy samples

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Subject has provided informed consent prior to initiation of any study-specific activities/procedures
2) Male or female age ≥ 18 years at the time of informed consent
3) BCC, excluding superficial and sclerodermiform BCC either newly developed or recurring/progressing after prior treatment; In clinically suspected BCCs, without a prior histopathological confirmation, the confirmation with the baseline biopsy is sufficient
4) Subjects have to be willing to undergo a tumor biopsy at baseline
5) The tumor has to be assessed by an expert panel (see section 8.1.1.) as being locally advanced but resectable if reconstructive plastic surgery (i.e. flap or skin graft) is used for wound closure
6) Tumors must be measurable by caliper
7) ECOG Performance Status 0
8) Adequate hematological, renal, hepatic and coagulation function within 14 days prior to enrollment
9) Any systemic therapy for advanced BCC must have been stopped at least 8 weeks before study treatment and patients must have recovered from any acute toxicity associated with prior therapy
10) Life expectancy of more than three months
11) Female Subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to enrollment

E.4

Principal exclusion criteria

1) Metastatic BCC
2) History of any other malignancy within the past 3 years with the following exceptions:
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Adequately treated breast ductal carcinoma in situ without evidence of disease
• Prostatic intraepithelial neoplasia without evidence of prostate cancer
• Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ
3) Active infection (herpetic skin lesions, or prior complications of herpetic infection, HIV, Hep A, B, C)
4) Previous treatment with T-VEC or any other oncolytic virus
5) Prior therapy with tumor vaccines, chemotherapy, radiotherapy, biological cancer therapy, targeted therapy < 28 days prior to enrollment
6) Any concurrent medical condition requiring the use of systemic steroids or antiviral drugs
7) History or evidence of active autoimmune disease that requires systemic treatment (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) Evidence of clinically significant immunosuppression
9) Any underlying medical condition which, in the Investigator's opinion, will make the administration of study drugs hazardous or obscure the interpretation of Adverse Events
10) Female Subjects who are pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of T-VEC
11) Sexually active Subjects and their partners unwilling to use male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with T-VEC
12) Female Subjects of childbearing potential who are unwilling to use acceptable method(s) of effective contraception during study treatment and through 3 months after the last dose of T-VEC
13) Live vaccines within 28 days prior to enrollment
14) Major surgery prior to enrollment 28 days prior to enrollment

E.5 End points

E.5.1

Primary end point(s)

- The number of patients with a BCC that become resectable with primary wound closure without the need for plastic reconstructive surgery like skin flaps or skin grafts

Null and alternative hypotheses:
H0: < 25% of “difficult to resect” laBCC become resectable without the need for plastic reconstruction
H1: ≥ 25% of “difficult to resect” laBCC become resectable without the need for plastic reconstruction

E.5.1.1

Timepoint(s) of evaluation of this end point

Stage I after one year, and Stage II after two years

E.5.2

Secondary end point(s)

- RFS, defined as the time from complete resection of any residual tumor until recurrence,
- Biological difference of immunological read outs at baseline and after therapy in tumor samples
- Incidence of local relapse
- Time of appearence of a new BCC in any other site of the body

E.5.2.1

Timepoint(s) of evaluation of this end point

after 3 years

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

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

Yes

E.8.1.7.1

Other trial design description

This is a two-stage, single-armed exploratory phase multicenter trial, structured in two stages

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

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 primary completion is anticipated to occur when all subjects have undergone surgery.
End of Trial, is the time when the last subject is assessed or receives an intervention for evaluation in the study. The end of study will occur when the last subject discontinues T-VEC and undergoes surgery and has had the opportunity to complete the safety follow-up visit or the last long term follow-up visit, whichever occurs later.

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

Yes

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

Yes

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)

Follow-up visits will be conducted every 3 months for 12 months following surgery
Clinical assessment
Photographs of the tumor area
AEs, SAEs
concomitant medication
Physical examination
Vital Signs
ECOG
Laboratory
Monthly serum ß-HCG in WOCBP until the first Follow-up visit
Swabs of herpetic lesions qPCR
Reporting of pregnancy
In case of a possible recurrent BCC this should be verified by histopathology, either by punch biopsy or surgical excision if clinically indicated

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

2019-04-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-03-13

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