Clinical Trials Register

Summary
EudraCT Number:	2008-004945-27
Sponsor's Protocol Code Number:	SHH4476g
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-03-04
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2008-004945-27

A.3

Full title of the trial

A PIVOTAL PHASE II, MULTICENTER, SINGLE ARM, TWO-COHORT TRIAL EVALUATING THE EFFICACY AND SAFETY OF GDC-0449 IN PATIENTS WITH ADVANCED BASAL CELL CARCINOMA

A.3.1

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

To test whether the experimental drug GDC-0449 is safe
and effective for advanced basal cell carcinoma.

A.4.1

Sponsor's protocol code number

SHH4476g

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Genentech, Inc.
B.1.3.4	Country	United States
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	Genentech, Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffman-La Roche Ltd
B.5.2	Functional name of contact point	Trial Information Support Line TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41616881111
B.5.5	Fax number	+41616919319
B.5.6	E-mail	global.rochegenentechtrials@roche.com

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	Vismodegib (GDC-0449)
D.3.2	Product code	GDC-0449
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.9.2	Current sponsor code	GDC-0449
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

• metastatic BCC with histologic confirmation of a distant BCC metastasis (e.g., lung, liver, lymph nodes, or bone)
• locally advanced BCC considered inoperable or with medical contraindication to surgery
• nevoid BCC syndrome (Gorlin syndrome), meeting the criteria for locally advanced or metastatic disease

E.1.1.1

Medical condition in easily understood language

Basal Cell Carcinoma (cancer)

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	14.1
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 objective of this study is
- to estimate the clinical benefit of Vismodegib given as therapy for patients with locally advanced or metastatic BCC, as measured by overall response rate (ORR).

E.2.2

Secondary objectives of the trial

The secondary objectives of this study are the following:
• To estimate the duration of response, progression-free survival (PFS),
and overall survival (OS)
• To assess the safety and tolerability of vismodegib in this patient population
• To assess the pharmacokinetics of vismodegib in this population (at participating sites only)
• To assess patient-reported outcomes
• To assess the histopathologic effect of vismodegib in tumor biopsies obtained at baseline and following vismodegib treatment in patients with locally advanced BCC
• To evaluate the status of the Hh signaling pathway using quantitative reverse
transcriptase polymerase chain reaction (qRT-PCR) in archival tissue

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

Study Title, 28 July 2008, amended 17 November 2008:
DNA REPOSITORY SUBSTUDY IN ASSOCIATION WITH PROTOCOL SHH4476g (17 November 2008)

The exploratory objectives of this study are the following:
• To evaluate the effect of GDC-0449 treatment on the Hh signaling pathway
using qRT-PCR and/or other approaches in tissue obtained at baseline
and/or following GDC-0449 treatment
• To evaluate the relationship between the effects of GDC-0449 treatment on
the Hh signaling pathway and efficacy

E.3

Principal inclusion criteria

• Signed informed consents
• Men and women age ≥ 18 years
• ECOG performance status 0, 1, or 2
• For patients with mBCC, histologic confirmation of distant BCC metastasis (e.g., lung, liver, lymph nodes, or bone), with metastatic disease that is RECIST measurable using CT or MRI
• For patients with locally advanced BCC, at least one histologically confirmed lesion ≥ 10 mm in the longest diameter that is considered to be inoperable or to have a medical contraindication to surgery (see below), in the opinion of a Mohs dermatologic surgeon, head and neck surgeon, or plastic surgeon
• For patients with locally advanced BCC, radiotherapy must have been
previously administered for their locally advanced BCC, unless radiotherapy is contraindicated or inappropriate (e.g., hypersensitivity to radiation due to genetic syndrome such as Gorlin syndrome, limitations because of location of tumor, or cumulative prior radiotherapy dose). For patients whose locally advanced BCC has been irradiated, disease must have progressed after radiation.
• Patients with nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must meet the criteria for locally advanced or metastatic disease listed above.
• For patients with locally advanced BCC, willingness to consent to biopsy of tumor(s) at baseline and during the study, as mandated by the protocol
• For all patients, representative tumor specimens in paraffin blocks (preferred)or at least 15 unstained slides, with an associated pathology report, obtained at any time prior to entry of study
• Adequate hematopoietic capacity, as defined by the following:
Hemoglobin > 8.5 g/dL and not transfusion dependent
Granulocyte count ≥ 1000/μL
Platelet count ≥ 75,000/μL
• Adequate hepatic function, as defined by the following:
AST and ALT ≤ 3 × the upper limit of normal (ULN)
Total bilirubin ≤ 1.5 × the ULN or within 3 × the ULN for patients with
Gilbert disease
• For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 7 months after discontinuation of vismodegib
• For men with female partners of childbearing potential, agreement to use a condom, and to advise their female partner to use an additional method of contraception during the study and for 7 months after discontinuation of vismodegib)
• Agreement not to donate blood or blood products during the study and for 7 months after discontinuation of GDC-0449; for male patients, agreement not to donate sperm during the study and for 2 months after discontinuation of vismodegib

E.4

Principal exclusion criteria

•Inability or unwillingness to swallow capsules
•Prior treatment with Vismodegib or other antagonists of the Hh pathway
•Pregnancy or lactation See Inclusion Criteria for women of childbearing potential and men withfemale partners of childbearing potential. Patients who are unable or are unwilling to adhere to the required contraceptive methods are excluded from the study.
•Life expectancy of < 12 weeks
•Patients with superficial multifocal BCC who may be considered unresectable due to breadth of involvement
•Concurrent non–protocol-specified anti-tumor therapy (e.g., chemotherapy, other targeted therapy, topical therapy such as 5-fluorouracil or imiquimod, radiation therapy, or photodynamic therapy). For patients with multiple cutaneous BCCs at baseline that are not designated by the investigator as target lesions, treatment of these non-target BCCs with surgery may be permitted but must be discussed with the Medical Monitor prior to any surgical procedure. For patients with locally advanced BCC whose target lesion(s) is/are inoperable at baseline but is/are later deemed potentially operable because of tumor response to vismodegib, surgery with curative intent may be permitted but must be discussed with the Medical Monitor prior to any surgical procedure.
•Recent (within 4 weeks of Day 1), current, or planned participation in an experimental drug study
•History of other malignancies within 3 years of Day 1, except for tumors with a negligible risk for metastasis or death, such as adequately treated squamous-cell carcinoma of the skin, ductal carcinoma in situ of the breast, or carcinoma in situ of the cervix
•Uncontrolled medical illnesses such as infection requiring treatment with intravenous antibiotics
•History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or renders the patient at high risk from treatment complications

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint for this study is ORR. ORR will be assessed
separately for patients with mBCC and locally advanced BCC:
• For patients with metastatic BCC, RECIST will be used.
• For patients with locally advanced BCC, a composite response endpoint will
be used that incorporates externally visible tumor dimension and tumor
ulceration, as well as RECIST for lesions with a RECIST-measurable
component. In patients achieving a clinical response,
tumor biopsies will be used in the final determination of complete versus
partial response.

E.5.1.1

Timepoint(s) of evaluation of this end point

Objective response is defined as a complete or partial response determined on two consecutive assessments ≥ 4 weeks apart and such patients will be referred to as ‘responders’.
ORR will be defined as the proportion of responders. Patients without a
post-baseline tumor assessment will be considered non-responders.

E.5.2

Secondary end point(s)

• Duration of response, PFS, and OS
PFS and OS will be defined from the time of first treatment with vismodegib.
• The number and attribution of all adverse events (including vital signs, physical findings, and clinical laboratory results) in patients who receive any amount of study drug.
• Steady-state plasma concentrations of vismodegib at Week 8 for patients enrolled at selected sites.
• Change from Day 1 in patient-reported outcomes, as measured on the Short Form 36 (SF-36) Health Survey, Version 2 (see Appendix E)
• Absence of residual BCC in patients with locally advanced BCC achieving a clinical response to vismodegib, as measured by independent pathological review
• The relative expression of GLI1 and PTCH2 in archival tissue as measured by qRT PCR

E.5.2.1

Timepoint(s) of evaluation of this end point

Duration of PFS will be defined as the time from the initial dose of vismodegib until the earlier of documented disease progression or death within 30 days of last exposure to study treatment. Duration of OS will be defined as the time from the initial dose of vismodegib until death from any cause.

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

Yes

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

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.8.2.3.1

Comparator description

None

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Belgium

France

Germany

United Kingdom

United States

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

All patients will receive vismodegib until documented evidence of disease progression, intolerable toxicities most probably attributable to vismodegib, or withdrawal from the study.

Patients who discontinue study treatment will be followed for survival approximately every 3 months until death, loss to follow-up, or study termination by Genentech.

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