Clinical Trials Register

Summary
EudraCT Number:	2016-002856-26
Sponsor's Protocol Code Number:	ADO-EP02(ML29328)
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-09-21
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

Germany - BfArM

A.2

EudraCT number

2016-002856-26

A.3

Full title of the trial

A PHASE II, SINGLE-ARMED, MULTICENTER TRIAL OF NEOADJUVANT VISMODEGIB IN PATIENTS WITH LARGE AND/OR RECURRENT RESECTABLE BASAL CELL CARCINOMA

A.3.1

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

A PHASE II, SINGLE-ARMED, MULTICENTER TRIAL OF NEOADJUVANT VISMODEGIB IN PATIENTS WITH LARGE AND/OR RECURRENT RESECTABLE BASAL CELL CARCINOMA

A.3.2

Name or abbreviated title of the trial where available

NICCI

A.4.1

Sponsor's protocol code number

ADO-EP02(ML29328)

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	SRH Wald-Klinikum Gera GmbH
B.1.3.4	Country	Germany
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	Roche Pharma AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SRH Wald-Klinikum Gera GmbH
B.5.2	Functional name of contact point	PD Dr. med. habil. Martin Kaatz
B.5.3	Address:
B.5.3.1	Street Address	Straße des Friedens 122
B.5.3.2	Town/ city	Gera
B.5.3.3	Post code	07548
B.5.3.4	Country	Germany
B.5.4	Telephone number	+493658287758
B.5.5	Fax number	+493658287754
B.5.6	E-mail	kaatz.studienzentrum@wkg.srh.de

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	Erivedge®
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration 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	Vismodegib
D.3.4	Pharmaceutical form	Capsule, hard
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	VISMODEGIB
D.3.9.1	CAS number	879085-55-9
D.3.9.3	Other descriptive name	VISMODEGIB
D.3.9.4	EV Substance Code	SUB32354
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	150
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with large and/or recurrent resectable basal cell carcinoma

E.1.1.1

Medical condition in easily understood language

Patients with large and/or recurrent resectable basal cell carcinoma

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	PT
E.1.2	Classification code	10004146
E.1.2	Term	Basal cell carcinoma
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

The primary objectives for this study are as follows:
• To evaluate the disease control rate (DCR) defined as
CR, PR, or SD after 12 weeks of treatment with
vismodegib in the neoadjuvant treatment setting
• To assess the objective and relative (%) reduction of
the involved skin surface after 12 weeks of treatment with vismodegib (involved skin surface intended for excision at baseline versus surface of the finally excised specimen)

E.2.2

Secondary objectives of the trial

• To evaluate the DCR (CR, PR, or SD) after 12 weeks
of treatment with vismodegib in the neoadjuvant treatment setting for different basal cell carcinoma histotypes (superficial, scleroderma, nodular, others)
• To assess the duration of overall response (DoR)
• To characterize the toxicity and tolerability profile in
patients receiving vismodegib in the neoadjuvant setting.
• To evaluate health-related quality of life in patients
receiving vismodegib for neoadjuvant treatment of basal cell carcinoma as measured by the Skindex-16
• To explore the diagnostic suitability of non-invasive
imaging techniques (in vivo confocal laserscan-microscopy (CLSM) and/or optical coherence tomography (OCT)) for the evaluation of response status of patients receiving vismodegib in the neoadjuvant setting

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Optional use of additional techniques i.e. confocal laser scanning microscopy and/ or optical coherence tomography:
In this sub-study the use of optical technologies for visualization of the scope of BCCs will be evaluated. The captured images are transmitted to a reference center: SRH Wald-Klinikum Gera GmbH, Zentrum für Klinische Studien, Straße des Friedens 122, 07548 Gera. The reference center will detect the scope of BCCs with special software.

E.3

Principal inclusion criteria

1. Male or female patient aged ≥ 18 years
2. Able to participate and willing to give written informed consent including consent for photographs prior to performance of study-related procedures and to comply with the study protocol.
3. Patients with at least 1 large (≥ 2 cm in diameter in head/neck region, ≥ 5 cm for trunk/extremities) basal cell carcinoma (BCC), still resectable, but with increased risk for cosmetic disfigurement or functional defects by assessment of the enrolling physician. Patients with large (as defined above) recurrent basal cell carcinoma are also eligible.
4. Patients must be naïve to treatment with vismodegib or other hedgehog pathway inhibitors
5. Local histopathologic confirmation of BCC (3 mm punch biopsy)
6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
7. Consent to undergo mapping biopsies upon reaching complete response
8. Adequate hematologic and organ function, defined by the following laboratory results, to be obtained within 7 days prior to registration and prior to first dose of study drug treatment:
• Absolute neutrophilic count > 1,0 x 109/L
• Platelet count ≥ 75 x 109/L
• Hemoglobin ≥ 8,5 g/dL
• Albumin ≥ 2.5 g/dL
• Bilirubin ≤ 1.5 x the upper limit of normal (ULN) or within 3 x ULN for patients with documented Gilbert syndrome
• AST, ALT, and AP ≤ 3 x ULN
• Serum creatinine ≤ 1.5 x ULN
9. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of this study. Females have to continue to always use 2 effective forms of contraception for at least 24 months after completion of study therapy, and males for at least 2 months after end of therapy. Breast feeding is likewise not allowed for at least 24 months after completion of study therapy.
• Females of childbearing potential are defined as sexually mature women without prior hysterectomy and who have had menses within the last 12 months.
• Females are considered NOT to be of childbearing potential if amenorrheic for >12 months and follicle-stimulating hormone (FSH) level ≥ 40 IU/L.
• Females who are amenorrheic ≥ 2 years, FSH requirement are waived.
• Effective forms of contraception includes surgical sterilization, a reliable barrier method with spermicidal, birth control pills, or contraceptive hormone implants
• Female patients of childbearing potential who desire to have children in the future should be informed about measures regarding conservation of fertility
10. Negative serum pregnancy test within 7 days prior to commencement of dosing in women of childbearing potential (including pre-menopausal women with tubal ligation).
11. Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and follow-up as defined by the treatment discontinuation schedule.
12. Agreement not to donate blood or blood products during the study and for at least 24 months after discontinuation of vismodegib. Because vismodegib has been detected in seminal fluid, in addition for men, agreement not donate sperm during the study or for at least 2 months after discontinuation of therapy.
13. Optional: Consent to undergo non-invasive imaging examinations by means of confocal laserscan-microscopy (CLSM) and/or optical coherence tomography (OCT), during and after end of study treatment.

E.4

Principal exclusion criteria

1. History of prior treatment with vismodegib or any other hedgehog pathway inhibitor.
2. Radiotherapy that involved the field of the target lesion(s) within 6 months prior to registration. Only one radiotherapy of the target lesion(s) performed > 6 months prior to registration is allowed. If a second radiotherapy in this field took place, patient will be excluded.
3. Any metastatic BCC
4. Metatypic BCC
5. Known or suspected Gorlin-Goltz syndrome
6. Uncontrolled medical illness, including advanced malignancies (no activities of the malignancies in the past 3 years), at the discretion of the Investigator
7. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or renders the patient at high risk for treatment complications
8. History or current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances
9. Any medical or psychological illness or condition preventing adequate consent or ability to comply with the protocol
10. Inability or unwillingness to swallow capsules
11. Inability or unwillingness to comply with study and follow-up procedures
12. Current severe, uncontrolled systemic disease
13. History of malabsorption or other conditions that would interfere with the absorption of the orally applicated study drug
14. Pregnant, lactating, or breast feeding women
15. Patients with one of the following rare hereditary conditions: galactose intolerance, primary hypolactasia, or glucose-galactose malabsorption
16. Participation in another clinical drug study within 28 days before registration
17. Known or suspected alcohol or drug abuse in the opinion of the investigator
18. Known hypersensitivity reaction to vismodegib or any of the other ingredients of this medicine
19. Treatment with St John’s wort (Hypericum perforatum)

E.5 End points

E.5.1

Primary end point(s)

• the evaluation of disease control rate (DCR) after 12 weeks of treatment with vismodegib in the neoadjuvant treatment setting.
• the assessment of the objective and relative (%) reduction of the involved skin surface after 12 weeks of treatment with vismodegib (involved skin surface intended for excision at baseline versus surface of the finally excised specimen)

E.5.1.1

Timepoint(s) of evaluation of this end point

after 12 weeks of treatment

E.5.2

Secondary end point(s)

• DCR (CR + PR + SD) after 12 weeks of treatment with vismodegib in the neoadjuvant treatment setting for different basal cell carcinoma histotypes (superficial, scleroderma, nodular, others)
• Duration of overall response
• Safety and tolerability
Safety variables to be analysed during the treatment period include:
 ECOG
 Incidence, type, and severity of AEs
 Incidence and nature of serious adverse events (SAEs)
 Incidence of AEs leading to vismodegib discontinuation or interruption
 Adherence to the treatment, measured by number of patients discontinuing the treatment (for any reason) and treatment interruptions
• Health-related quality of life assessed by using the Skindex-16 questionnaire
• Correlation of the efficacy by means of non-invasive imaging techniques (CLSM or OCT):
o Objective (in mm) and relative (%) reduction of the BCC-involved skin and resection area before and after vismodegib treatment
o Deviation (in %) between histopathology of punch biopsies and non-invasive imaging techniques

E.5.2.1

Timepoint(s) of evaluation of this end point

• DCR (CR + PR + SD): after 12 weeks of treatment
• All other endpoints: during the whole study

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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

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

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

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

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)

Following the end of treatment evaluation or the end of treatment for any other cause, eligible patients will undergo surgery. Further treatment for all patients will be performed according to the guidelines of the German Cancer Society.

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

2016-12-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-01-05

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IMP with orphan designation in the indication
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