Conditions: Carcinoma, Basal Cell
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
Basal cell carcinoma (BCCA) is the most common human cancer, and frequently affects facial structures. While rarely fatal, facial BCCA can be disfiguring and expensive to treat.

Vismodegib is a small molecule inhibitor of SMO developed for the treatment of tumors in which the Hh signaling pathway appears to contribute to the development and maintenance of tumorigenesis. Vismodegib was recently approved by the Food and Drug Administration (FDA) for treatment of metastatic and locally advanced BCCA. Recent reports have suggested that vismodegib treatment for orbital BCCA may facilitate eye preservation even if surgery is eventually required

In order to assess the potential of vismodegib to improve the ophthalmic outcomes following treatment for orbital and/or periocular BCCA, this study will follow patients with globe-threatening orbital and lacrimal-threatening periocular BCCA who are being treated with vismodegib as standard of care.

Patients with tumors that do not respond to treatment with Vismodegib, and those who have a good response but poor tolerance of Vismodegib, will be offered surgical excision of the tumor. Patients with a good response and good tolerance of Vismodegib may continue the treatment as long as clinically indicated.

Detailed description:

Arms:
arm 1: 150mg taken orally once daily

Interventions: intervention 1: Vismodegib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENTIAL 
This is a University of Michigan document that contains confidential information.  It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from the University of Michigan. 
Protocol:  VISORB 
11Jun2020 
PROTOCOL 
STUDY TITLE: 
VISmodegib for ORbital and periocular Basal cell carcinoma 
(VISORB). 
STUDY DRUG: 
ERIVEDGE® (vismodegib)
NCT02436408   


CONFIDENTIAL 
This is a University of Michigan document that contains confidential information.  It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from the University of Michigan. 
 
Protocol:  VISORB 
 
11Jun2020 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
University of Michigan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
This is a University of Michigan document that contains confidential information.  It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from the University of Michigan. 
 
Protocol:  VISORB 
 
11Jun2020 
INVESTIGATOR: 
Cagri Besirli, MD, PhD 
University of Michigan 
  
 
Tel: 
 
Fax: 
 
 
Email: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
This is a University of Michigan document that contains confidential information.  It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from the University of Michigan. 
 
Protocol:  VISORB 
 
11Jun2020 
SUB-INVESTIGATORS: 
 
Francis Worden, MD 
University of Michigan Rogel Cancer Center 
 
May Chan, MD 
University of Michigan Department of Pathology 
 
Scott Tomlins, MD 
University of Michigan Department of Pathology 
 
Victor Elner, MD 
University of Michigan Department of Ophthalmology 
 
Hakan Demirci, MD 
University of Michigan Department of Ophthalmology 
 
Christine Nelson, MD 
University of Michigan Department of Ophthalmology 
 
Christopher Bichakjian, MD  
University of Michigan Department of Dermatology 
 
Denise Kim, MD 
University of Michigan Department of Ophthalmology 
 
Shannon Joseph, MD  
University of Michigan Department of Ophthalmology 
 
Paul Swiecicki, MD  
University of Michigan Rogel Cancer Center  
 
Scott Bresler, MD 
University of Michigan Department of Pathology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
This is a University of Michigan document that contains confidential information.  It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from the University of Michigan. 
 
Protocol:  VISORB 
 
11Jun2020 
RESEARCH 
COORDINATOR: 
 
BIOSTATISTICIAN: 
 
 
Munira Hussain, MS, COA, CCRP / Laura Rozek, COA 
Kellogg Eye Center 
 
 
Chris Andrews, PhD 
Kellogg Eye Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY NUMBER: 
ML29160 
 
 
 
 
 
 
 
 
 
 
PROTOCOL 
VERSION/DATE: 
v.19– 11Jun2020 
 
 
 
 
 
 
 
 


Protocol:  VISORB page 1 
 
04Feb2019 
TABLE OF CONTENTS 
1. 
INTRODUCTION ...................................................................................................................... 2 
1.1 
DISEASE BACKGROUND ........................................................................................................ 2 
1.2 
THE HEDGEHOG SIGNALING PATHWAY AND BASAL CELL CARCINOMA PATHOGENESIS ............ 3 
1.3 
CLINICAL EXPERIENCE, VISMODEGIB SAFETY AND EFFICACY .................................................. 4 
1.4 
BACKGROUND FOR OTHER STUDY DRUGS .......................................................................... 16 
2. 
STUDY OBJECTIVES ............................................................................................................ 16 
2.1 
PRIMARY OBJECTIVES ........................................................................................................ 16 
2.2 
SECONDARY OBJECTIVES ................................................................................................... 16 
3. 
STUDY PROTOCOL .............................................................................................................. 17 
3.1 
DESCRIPTION OF THE STUDY .............................................................................................. 17 
3.2 
RATIONALE FOR STUDY DESIGN ......................................................................................... 21 
3.3 
OUTCOME MEASURES ........................................................................................................ 21 
3.4 
SAFETY PLAN .................................................................................................................... 23 
3.5 
COMPLIANCE WITH LAWS AND REGULATIONS ....................................................................... 23 
4. 
MATERIALS AND METHODS ............................................................................................... 23 
4.1 
SUBJECT SELECTION ......................................................................................................... 23 
4.2 
METHOD OF TREATMENT ASSIGNMENT ............................................................................... 24 
4.3 
STUDY TREATMENT ............................................................................................................ 25 
4.4 
CONCOMITANT AND EXCLUDED THERAPY ............................................................................ 26 
4.5 
STUDY ASSESSMENTS ........................................................................................................ 27 
4.6 
DISCONTINUATION OF PROTOCOL-SPECIFIED THERAPY ....................................................... 27 
4.7 
SUBJECT DISCONTINUATION ............................................................................................... 28 
4.8 
STUDY DISCONTINUATION .................................................................................................. 28 
4.9 
STATISTICAL METHODS ...................................................................................................... 28 
4.10 DATA QUALITY ASSURANCE ................................................................................................ 30 
5. 
REPORTING OF ADVERSE EVENTS ................................................................................... 30 
5.1 
ASSESSMENT OF SAFETY ................................................................................................... 30 
5.2 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES ..................... 32 
5.3 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS ................... 33 
5.4 
SAFETY REPORTING REQUIREMENTS FOR IND EXEMPT STUDIES ......................................... 36 
5.5 
STUDY CLOSE-OUT ............................................................................................................ 36 
6. 
RETENTION OF RECORDS .................................................................................................. 36 
REFERENCES ............................................................................................................................... 37 
APPENDICES ................................................................................................................................ 40 
Appendix 1: Study Flowchart 
Appendix 2: Definition of Women of Childbearing Potential 
Appendix 3: Material Safety Data Sheet (MSDS) 
Appendix 4: Schedule of Events (Table 16) 
Appendix 5: Safety Reporting Fax Cover Sheet 


Protocol:  VISORB page 2 
 
04Feb2019 
1. 
INTRODUCTION  
 
 
Basal cell carcinoma (BCCA) is the most common human cancer, 
and frequently affects facial structures. While rarely fatal, facial BCCA can 
be disfiguring and expensive to treat. Treatment of facial BCCA typically 
includes Mohs micrographic surgery followed by plastic reconstructive 
surgery. Success rates of treatment for non-metastatic BCCA that is 
limited to skin can approach 99%. However, deeply invasive BCCA can 
involve vital organs, such as the eye or lacrimal drainage system, 
requiring aggressive surgical interventions that often compromise organ 
function. Hence, there is a critical need for improved treatments of 
invasive BCCA in the face. 
 
Vismodegib is a small, orally administrable molecule that functions 
as an antagonist of the smoothened receptor (SMO), which is part of the 
hedgehog signaling pathway. Vismodegib (Erivedge, Genentech), was 
recently approved by the Food and Drug Administration (FDA) for 
treatment of recurrent, locally advanced or metastatic BCCA. Its primary 
indication in these cases is organ preservation. Initial results from clinical 
usage have been very promising. However, it remains to be determined 
whether use of vismodegib in treating locally advanced periocular or 
orbital BCCA would increase the chance of preserving visual function. 
Furthermore, chronic use of vismodegib is associated with side effects, 
such as muscle spasms, weight loss, hair loss, fatigue, and loss of 
appetite. Some side effects, such as muscle spasms, can be functionally 
debilitating. Recent reports have suggested that vismodegib treatment for 
orbital BCCA may facilitate globe preservation even if surgery is 
eventually required (Kahana, Worden and Elner, JAMA Ophthalmol, 
2013). The goal of this study is to test whether treatment with 
vismodegib for periocular and orbital BCCA is associated with 
preservation of a functioning globe and lacrimal apparatus. 
Recruitment will be limited to patients who meet the standard criteria for 
vismodegib treatment of locally advanced periocular/orbital BCCA, for 
whom vismodegib has the potential to be organ-preserving. 
 
1.1 
Disease Background 
 
Background on Basal Cell Carcinoma  
Basal cell carcinoma (BCC) is the most common human cancer, affecting 
approximately 750,000 Americans per year (Epstein 2008). Based on 
rapidly rising tumor incidence rates, it is estimated that almost 1 in 3 
Caucasians born in the United States after 1994 will develop a BCC 
during their lifetime (Miller and Weinstock 1994). Like other skin cancers, 
BCC risk is correlated inversely with the degree of skin pigmentation and 
positively with exposure to ultraviolet or ionizing radiation. In states near 


Protocol:  VISORB page 3 
 
04Feb2019 
the equator, such as Hawaii, BCC incidence is approaching 3-fold that of 
states in the Midwest, such as Minnesota. 
BCC incidence also varies globally. The highest rates of skin cancer occur 
in South Africa and Australia, areas that receive high amounts of UV 
radiation (Marks et al. 1989). Australia has a trend toward increasing BCC 
incidence, whereas Finland has a low reported incidence that is 
approximately one quarter that in Minnesota; nonetheless, BCC incidence 
in Finland appears to be increasing, especially among young women. A 
study from the Netherlands found that high socioeconomic status was 
associated with increased incidence of BCC among men, suggesting that 
BCC is changing from a disease of the poor to a disease of the rich, at 
least in northern Europe (van Hattem et al. 2009).  
BCCs are generally treated by local excision, which in many cases is 
associated with scarring and potential disfigurement. Until recently, there 
has been no reliable medical (non-surgical) therapy for BCC, particularly 
for advanced forms of the disease. 
 
1.2 
The Hedgehog Signaling Pathway and Basal Cell 
Carcinoma Pathogenesis 
The vast majority of cases of BCC occur sporadically. However, a rare 
autosomal dominant inherited condition has been identified – Gorlin 
syndrome (also known as basal cell nevus syndrome [BCNS] or nevoid 
basal cell carcinoma syndrome) – in which individuals develop many 
BCCs (tens to thousands) from a relatively early age (Gorlin 1987; 
Online Mendelian Inheritance in Man 2012).  The mutant gene in Gorlin 
syndrome has been mapped using genetic linkage studies to human 
chromosome 9q22 and, subsequently, to the Patched 1 (PTCH1) gene 
(Gailani et al. 1992; Hahn et al. 1996). PTCH1 is a member of the 
Hedgehog (Hh) signaling pathway, a critical regulator of both cellular 
growth and differentiation during embryonic development (Caro and Low 
2010).   
The Hh pathway operates in both time- and position-dependent 
mechanisms to allow developing tissues to attain their correct size, 
location, and cellular content (Caro and Low 2010).  The pathway was 
originally identified in the fruit fly Drosophila melanogaster, where 
mutations in the Hh gene gave rise to embryos covered in spiky 
processes, suggesting the “hedgehog” name.  In fruit flies, as well as 
humans, signaling in the pathway is initiated by the hydrophobic secreted 
Hh protein, which binds to PTCH1, a 12-transmembrane domain protein 
located on the cell membrane. This binding releases inhibition of the 
Smoothened (SMO) protein, a 7-transmembrane G-protein-coupled-like 
receptor located on the membrane of intracellular endosomes.  Activated 
SMO, in turn, transmits a signal via interacting proteins, leading to 


Protocol:  VISORB page 4 
 
04Feb2019 
activation of the Gli family of zinc finger transcription factors.  In patients 
with Gorlin syndrome, loss of function of PTCH1 constitutively turns on the 
Hh pathway by allowing SMO to constitutively activate its downstream 
targets, thereby leading to the high incidence of BCCs.   
Subsequent studies have shown that approximately 90% of sporadic 
BCCs also have de novo mutations in PTCH1, whereas the remaining 
10% have activating mutations in SMO that prevent inhibition by normal 
PTCH1 protein (Epstein 2008; Scales and de Sauvage 2009).  Thus, a 
common genetic basis exists for the sporadic and syndrome-associated 
forms of BCC, suggesting both may be amenable to treatment with 
inhibitors of the Hh pathway.  
The feasibility of blocking Hh signaling in vivo was first demonstrated in 
studies of teratogenic phenomena that were observed in lambs born of 
ewes that had ingested the forage plant, Veratrum californicum (Binns et 
al. 1963).  The active agent in the plant was shown to be cyclopamine, a 
steroidal alkaloid that induces midline deformities, including cyclopia, 
which blocks SMO signaling in the developing lamb fetus (Chen et al. 
2002).  
Cyclopamine has proven to be a valuable tool to confirm the importance of 
Hh signaling in a subset of malignancies.  One study, for instance, showed 
that chronic oral administration of cyclopamine reduced the development 
of UVB-induced BCCs in the skin of Ptch1 (+/-) mice, an animal model for 
Gorlin syndrome, by approximately 67% (Athar et al. 2004).  Another 
study found that 25% of small-cell lung cancers expressed elevated levels 
of Hh ligand and GLI1 and that cyclopamine inhibited the growth of SCLC 
cell lines in culture (Watkins et al. 2003). Similarly, systemic cyclopamine 
treatment slowed the growth of pancreatic cancer xenografts and blocked 
the metastatic potential of prostate cancer cells in mice (Thayer et al. 
2003; Karhadkar et al. 2004). Finally, activation of Hh signaling in some 
types of extracutaneous tumors has been shown to be due to tumor cell 
expression and secretion of Hh ligand and subsequent activation of the 
pathway in stromal cells, which leads to secondary growth stimulation of 
the tumor cells by stromally-expressed cytokines (Yauch et al. 2008). 
 
1.3 
Clinical Experience, Vismodegib Safety and Efficacy 
 
Background on Vismodegib 
Vismodegib is a small molecule inhibitor of SMO developed by 
Genentech, Inc. for the treatment of tumors in which the Hh signaling 
pathway appears to contribute to the development and maintenance of 
tumorigenesis.  Vismodegib, a systemic Hh pathway antagonist, has been 
shown to have oral bioavailability and potent anti-tumor activity in a variety 
of primary human tumor xenografts and tumor cell line xenograft models 


Protocol:  VISORB page 5 
 
04Feb2019 
(see the Vismodegib Investigator Brochure and the US package insert for 
further details).  
 
 
1.3.1 Malignancies with Mutation Driven Hh Pathway Signaling 
 
1.3.1.1 Basal Cell Carcinoma 
 
Phase I Study SHH3925g - Safety and Pharmacokinetics Assessment 
A Phase I, company-sponsored clinical trial (SHH3925g) assessed the 
safety and pharmacokinetics (PK) of vismodegib and responses of 
metastatic or locally advanced BCC to the drug (Von Hoff et al. 2009). 
Thirty-three patients with metastatic or locally advanced BCC received 
oral vismodegib at one of three doses: 17 patients received 150 mg per 
day, 15 patients received 270 mg per day, and 1 patient received 540 mg 
per day (median duration of treatment was 9.8 months). Of the 33 
patients, 18 had an objective response to vismodegib, according to 
assessment on imaging (7 patients), physical examination (10 patients), or 
both (1 patient). Of the patients who had a response (see Table 1), 2 had 
complete responses (CRs) and 16 had partial responses (PRs). The other 
15 patients had either stable disease (11 patients) or progressive disease 
(4 patients). Eight Grade 3 adverse events (AEs) that were deemed to be 
possibly related to the study drug were reported in 6 patients (see Table 
2), including fatigue (4 AEs), hyponatremia (2 AEs), muscle spasm (1 AE), 
and atrial fibrillation (1 AE). One patient withdrew from the study because 
of AEs. 
 
Table 1: SHH3925g Phase I Efficacy Results 
  
aBCC 
(n=33) 
Objective response, n (%) 
18 (54.5%) 
Complete response, n (%) 
  2 ( 6.1%) 
Partial response, n (%) 
16 (48.5%) 
Stable disease, n (%) 
11 (33.3%) 
Progressive disease, n (%) 
 4 (12.1%) 
 
 
 
 
 
 


Protocol:  VISORB page 6 
 
04Feb2019 
Table 2: SHH3925g Phase I Adverse Events in Patients With aBCC (n=33) 
Clinical Event 
Grade 2 
Grade 3 
Grade 4 
Number of Patients With Event 
Fatigue 
0 
4 
0 
Hyponatremia 
0 
2 
1 
Muscle spasm 
3 
1 
0 
Atrial fibrillation 
0 
1 
0 
Dysgeusia 
2 
n/a 
n/a 
Anorexia 
2 
0 
0 
Weight loss 
2 
2 
0 
Dyspepsia 
1 
0 
0 
Dyspnea 
0 
2 
0 
Aspiration 
0 
1 
0 
Back pain 
0 
1 
0 
Corneal abrasion 
0 
1 
0 
Dehydration 
0 
1 
0 
Keratitis 
0 
1 
0 
Lymphopenia 
0 
1 
0 
Pneumonia 
0 
1 
0 
Urinary tract infection 
0 
1 
0 
Electrocardiographic event 
(prolonged QT interval) 
0 
1 
0 
 
Phase II Study ERIVANCE (SHH4476g) in Metastatic and Locally 
Advanced Basal Cell Carcinoma 
A multicenter, international, two-cohort, nonrandomized, pivotal, Phase II, 
company-sponsored study (SHH4476g) enrolled patients with metastatic 
BCC and those with locally advanced BCC who had inoperable disease or 
for whom surgery was inappropriate (because of multiple recurrences and 
a low likelihood of surgical cure, or substantial anticipated disfigurement) 
(Sekulic et al. 2012). In 33 patients with metastatic BCC (see Table 3), the 
independently assessed response rate was 30% (95% confidence interval 
[CI], 16 to 48; p=0.001). In 63 patients with locally advanced BCC (see 
Table 4), the independently assessed response rate was 43% (95% CI, 31 
to 56; p<0.001), with complete responses in 13 patients (21%). The 
median duration of response was 7.6 months in both cohorts at the time of 
data cutoff.  Muscle spasms, alopecia, dysgeusia, weight loss, and fatigue 
occurred in more than 30% of patients, whereas serious adverse events 


Protocol:  VISORB page 7 
 
04Feb2019 
(SAEs) were reported in 25% of patients. Seven deaths due to AEs were 
reported and none of the deaths were related to vismodegib. 
Based on the results of this pivotal trial, vismodegib was approved on 
January 30, 2012 by the United States Food and Drug Administration (US 
FDA) for the treatment of adults with metastatic basal cell carcinoma, or 
with locally advanced basal cell carcinoma that has recurred following 
surgery or who are not candidates for surgery, and who are not 
candidates for radiation. (Erivedge [package insert] 2013). 
 
Table 3: Efficacy Results from Primary Analysis 
Metastatic BCC  
(n=33) 
Locally Advanced BCC 
(n=63) 
IRF (1°) 
INV (2°) 
IRF (1°) 
INV (2°) 
Response ORR 
10 (30%) 
15 (45%) 
27 (43%) 
38 (60%) 
95% CI 
(16%, 48%) 
(28%, 62%) 
(30%, 56%) 
(47%, 72%) 
P value 
0.001 
<0.001 
SD 
21 (64%) 
15 (45%) 
24 (38%) 
15 (24%) 
PD 
1 (3%) 
2 (6%) 
8 (13%) 
6 (10%) 
Unevaluable/ missing 
1 (3%) 
1 (3%) 
4 (6%) 
4 (6%) 
Median DoR, mos 
7.6 
12.9 
7.6 
7.6 
 
Table 4: ERIVANCE Investigator Assessed Efficacy at the18-Month Update 
Investigator Assessed (INV) 
mBCC  
(n = 33) 
laBCC  
(n = 63) 
Total 
(n = 96) 
ORR, n (%)  
[95% CI] 
16 (48.5) 
[30.8-66.2] 
38 (60.3) 
[47.2-71.7] 
54 (56.3) 
[45.7-66.4] 
 Complete   response 
0 
20 
20 
  Partial response 
16 
18 
34 
  Stable disease 
14 
15 
29 
  Progressive disease 
2 
6 
8 
Median duration of response, 
months,  
(95% CI) 
(n = 16) 
14.7  
(5.6-17.0) 
(n = 38) 
20.3  
(9.0-NE) 
(n = 54) 
16.8  
(9.5-NE) 
Median PFS, months,  
(95% CI) 
9.3 
(7.4-16.6) 
12.9  
(10.2-31.4) 
12.8 
(9.5-18.0) 
Median OS, months,  
(95% CI) 
30.9 
(18.1-NE) 
NE 
(NE-NE) 
NE 
(NE-NE) 
1-Year survival rate, %  
(95% CI) 
78.7 
(64.7-92.7) 
93.1 
(86.6-99.6) 
NA 


Protocol:  VISORB page 8 
 
04Feb2019 
Table 5: ERIVANCE Safety Results at the 18-Month Update 
 
Metastatic 
BCC 
(n = 33) 
Locally 
Advanced BCC 
(n = 71) 
All AE 
33 (100%) 
71 (100%) 
Grade 3-5 Adverse Event 
14 (42.4%) 
40 (56.4%) 
Grade 5 Adverse Event§ 
1 (3%) 
6 (8.5%) 
Serious Adverse Events 
8 (24.2%) 
28 (39.4%) 
Adv. Events Leading To Treatment Discontinuation 
5 (15.2%) 
16 (22.5%) 
§ No new deaths on study since the primary data analysis. Fatal events included: Death of unknown 
cause (n=3), acute myocardial infarction (n=1), ischemic stroke (n=1), meningeal disorder (n=1), 
and hypovolemic shock (n=1). In all cases, clinically significant risk factors or comorbid conditions 
were present at baseline. Relationship between study drug and event is unknown. 
 
Table 6: Most Frequent Treatment Emergent Adverse Events (>10% of 
patients) at the 18-Month Update 
Adverse Event, n (%) 
NCI CTCAE Grade, (N = 104) 
Total 
1 
2 
3 
4 
5 
Any adverse events 
104 (100.0) 
11 
(10.6) 
38 
(36.5) 
34 
(32.7) 
13 
(12.5) 
7 
(6.7) 
Muscle spasms 
74 (71.2) 
49 
(47.1) 
19 
(18.3) 
6 
(5.8) 
0 
0 
Alopecia 
68 (65.4) 
48 
(46.2) 
20 
(19.2) 
n/a 
n/a 
n/a 
Dysgeusia 
57 (54.8) 
31 
(29.8) 
26 
(25.0) 
n/a 
n/a 
n/a 
Weight decreased 
53 (51.0) 
29 
(27.9) 
17 
(16.3) 
7 
(6.7) 
n/a 
n/a 
Fatigue 
44 (42.3) 
32 
(30.8) 
7 
(6.7) 
4 
(3.8) 
1 
(1.0) 
0 
Nausea 
34 (32.7) 
25 
(24.0) 
9 
(8.7) 
0 
0 
0 
Decreased appetite 
28 (26.9) 
18 
(17.3) 
7 
(6.7) 
3 
(2.9) 
0 
0 
Diarrhea 
28 (26.9) 
20 
(19.2) 
5 
(4.8) 
3 
(2.9) 
0 
0 
Constipation 
20 (19.2) 
14 
(13.5) 
6 
(5.8) 
0 
0 
0 
Cough 
20 (19.2) 
16 
(15.4) 
4 
(3.8) 
0 
0 
0 
Vomiting 
18 (17.3) 
15 
(14.4) 
3 
(2.9) 
0 
0 
0 


Protocol:  VISORB page 9 
 
04Feb2019 
Adverse Event, n (%) 
NCI CTCAE Grade, (N = 104) 
Total 
1 
2 
3 
4 
5 
Arthralgia 
17 (16.3) 
12 
(11.5) 
4 
(3.8) 
1 
(1.0) 
0 
0 
Headache 
15 (14.4) 
12 
(11.5) 
3 
(2.9) 
0 
0 
0 
Nasopharyngitis 
13 (12.5) 
11 
(10.6) 
2 
(1.9) 
0 
0 
0 
Squamous cell 
carcinoma 
12 (11.5) 
3 (2.9) 
5 
(4.8) 
3 
(2.9) 
0 
0 
Ageusia 
12 (11.5) 
8 (7.7) 
4 
(3.8) 
n/a 
n/a 
n/a 
Hypogeusia 
11 (10.6) 
10 
(9.6) 
1 
(1.0) 
n/a 
n/a 
n/a 
 
Expanded Access Study (SHH4811g) in Advanced BCC 
An open-label, single-arm, multicenter, expanded access study (SHH4811g) of 
an oral repeating dose of vismodegib was conducted in patients with locally 
advanced or metastatic BCC, who are otherwise without satisfactory treatment 
options. Safety of vismodegib and objective response in patients with 
measurable disease (RECIST v1.0) were assessed (Weiss G, et al. Poster, 
ESMO 2012). The study has been completed following FDA approval and 
commercial availability of vismodegib. 
Among 95 efficacy evaluable patients (56 patients with laBCC and 39 patients 
with mBCC) at the time of final analysis data cutoff date of 23 April 2012 the 
observed objective response rates (see Table 7) were 46.4% (95% CI, 33.0%, 
60.3%) for patients with laBCC (n = 56) and 30.8% (95% CI, 17.0%, 47.6%) for 
patients with mBCC (n = 39). Complete response, partial response and stable 
disease were observed in 10.7%, 35.7%, and 48.2%, respectively, of patients 
with laBCC; no patients in this cohort exhibited PD as best response. For 
patients with mBCC, complete response, partial response and stable disease 
rates observed were 5.1%, 25.6%, and 51.3%, respectively. 7.7% of patients in 
this cohort exhibited PD as best response. Among patients with laBCC who 
responded the median and mean times to response were 2.6 months and 3.5 
months, respectively; and among patients with mBCC who responded the 
median and mean times to response were 2.6 months and 3.8 months, 
respectively. 
As of the final analysis data cutoff date of 23 April 2012, 116 of 119 safety 
evaluable patients (97.5%) experienced at least one adverse event (22 SAEs 
total, see Table 8). Adverse events that had the highest reported occurrences ( 
20%) in 119 safety evaluable patients were: muscle spasms (84 patients; 
70.6%), dysgeusia (84 patients; 70.6%), alopecia (69 patients; 58.0%), and 
diarrhea (30 patients; 25.2%). Only one of 22 SAEs (4.5%) was assessed as 
being related to treatment with vismodegib:  a Grade 3 muscle spasm, reported 


Protocol:  VISORB page 10 
 
04Feb2019 
in 1 patient. There have been three deaths among 119 safety-evaluable patients 
(2.5%); 2 assessed as unrelated to study drug, and 1 patient with PD. 
 
Table 7: EAP SHH4811g Overall Response (RECIST) at Study Termination 
  
laBCC 
(n=56) 
mBCC 
(n=39) 
Objective response, n (%) 
26 (46.4) 
12 (30.8) 
(95% CI) 
(32.4-59.3) 
(17.0-47.6) 
Complete response, n (%) 
6 (10.7) 
2 (5.1) 
Partial response, n (%) 
20 (35.7) 
10 (25.6) 
Stable disease, n (%) 
27 (48.2) 
20 (51.3) 
Progressive disease, n (%) 
0 
3 (7.7) 
Unevaluable/missing, n (%) 
3 (5.4) 
4 (10.3) 
Median time to response (range), monthsa 
2.6 (1.0-11.0) 
2.6 (1.4-12.6) 
 
Table 8: SHH4811g Vismodegib Expanded Access Study Common 
Treatment-Emergent Adverse Events 
TEAEs (n=120) 
Median Time 
to AE Onset, 
Days 
 (95% CI)* 
All 
AEs, 
n (%) 
Gr 1, 
n (%) 
Gr 2, 
n (%) 
Gr 3, 
n (%) 
Gr 4, 
n (%) 
Gr 5, 
n (%) 
Muscle spasms 
37 (28-44) 
84 
(70.0) 
63 
(52.5) 
19 
(15.8) 
2 (1.7) 
– 
– 
Dysgeusia 
41 (30-51) 
84 
(70.0) 
68 
(56.7) 
16 
(13.3) 
n/a 
n/a 
n/a 
Alopecia 
87 (74-104) 
69 
(57.5) 
57 
(47.5) 
12 
(10.0) 
n/a 
n/a 
n/a 
Diarrhea 
38 (22-116) 
30 
(25.0) 
23 
(19.2) 
5 (4.2) 
1 (0.8) 
1 (0.8) 
– 
Nausea 
30 (11-130) 
23 
(19.2) 
19 
(15.8) 
4 (3.3) 
– 
– 
– 
Fatigue 
42 (16-120) 
23 
(19.2) 
14 
(11.7) 
8 (6.7) 
1 (0.8) 
– 
– 
Weight 
decreased 
175 (114-293) 
19 
(15.8) 
12 
(10.0) 
7 (5.8) 
– 
– 
– 
*For those patients experiencing the TEAE 
 
 
 


Protocol:  VISORB page 11 
 
04Feb2019 
Phase II BCNS Study (SHH4685s)  
The anti–BCC efficacy of vismodegib was tested in a randomized, double-
blinded, placebo-controlled, Investigator-sponsored trial in Gorlin 
syndrome (BCNS) patients with surgically eligible BCCs (Tang et al. 
2012).  Forty-one patients were randomized 2:1 to receive oral vismodegib 
(n=26) or placebo (n=15). After a mean follow up of 8 months (range, 1 to 
15 months), the per-patient rate of new surgically eligible BCCs (SEBs) 
was lower with vismodegib than with placebo (2 vs. 29 cases per group 
per year, p<0.001), as was the size (percent change from baseline in the 
sum of the longest diameter) of existing clinically significant BCCs (–65% 
vs. –11%, p=0.003). In some patients, all BCCs clinically regressed.  No 
tumors progressed during treatment with vismodegib.  Patients receiving 
vismodegib routinely had Grade 1 or 2 AEs of loss of taste, muscle 
cramps, hair loss, and weight loss.  Overall, 54% of patients (14 of 26) 
receiving vismodegib discontinued drug treatment due to AEs.  At 1 
month, vismodegib use had reduced the Hh pathway's target-gene 
expression in BCC cells by 90% (p<0.001) and diminished tumor-cell 
proliferation, but apoptosis was not affected.  No residual BCC was 
detectable in 83% of biopsy samples taken from sites of clinically 
regressed BCCs.  At the second pre-specified interim analysis, a data 
safety and monitoring board concluded that the pre-determined threshold 
for a significant difference between the two groups had been reached 
(p<0.0113), and the treatment with placebo in this arm was terminated. 
See the Vismodegib Investigator Brochure and the US package insert for 
additional details on nonclinical and clinical studies on vismodegib. 
 
Table 9: Phase II BCNS Study (SHH4685s) Adverse Events Reported in 
≥10% of Patients 
Grade 1 or 2 AEs,  n (%) 
Vismodegib 
(n=26) 
Placebo 
(n=15) 
P Value 
Taste disturbance, n 
22 (85) 
1 (7) 
<0.001 
Muscle cramps 
21 (81) 
0 (0) 
<0.001 
Hair loss 
16 (62) 
1 (7) 
0.004 
>5% weight decrease 
11 (42) 
0 (0) 
0.003 
GI upset 
5 (19) 
1 (7) 
0.14 
Acne 
3 (12) 
1 (7) 
0.60 
 
 
 
 


Protocol:  VISORB page 12 
 
04Feb2019 
Phase II STEVIE (MO25616) Safety Study 
Study MO25616 is an ongoing Phase II open-label, single-arm, 
multicenter (ex-U.S.) study of vismodegib in patients with locally aBCC or 
mBCC who are otherwise without satisfactory treatment options.  The 
primary objective is to assess the safety of vismodegib in patients with 
locally aBCCor mBCC.  Secondary objectives are to assess the overall 
response (according to RECIST Version 1.1) in those patients with 
measurable disease as permitted by local regulatory requirement and to 
assess other efficacy parameters such as time to response, duration of 
response, PFS, and overall survival (OS). 
All patients receive 150 mg vismodegib orally (PO) daily (QD)until 
investigator-assessed progression of disease (PD), unmanageable 
toxicities, or withdrawal from study (investigator/patient request). 
As of  6 November 2013, a total of 1228 patients have been enrolled into 
the study.  Results of an interim analysis, when a total of 501 patients 
could be followed for 1 year, are presented below.  
As of the cutoff date of 6 November 2013, safety data were available for 
500 patients (469 with locally aBCC and 31 with mBCC) with followup 
information for at least 3 months after treatment.  Overall, 492 of 500 
safety-evaluable patients (98.4%) experienced at least one AE.  The most 
frequently reported AEs, regardless of relationship to study drug, in 
descending order of frequency, were:  muscle spasms (63.2%), alopecia 
(61.0%), dysgeusia (53.8%), weight decreased (32.4%), asthenia (28.2%), 
decreased appetite (25.4%), and ageusia (22.4%). 
As of 6 November 2013, 210 of 500 safety-evaluable patients (42.0%) 
experienced Grade 3−5 treatment-emergent adverse events (TEAEs).  Of 
500 patients, 165 patients (33.0%) experienced a Grade 3 AE, 24 patients 
(4.8%) experienced a Grade 4 AE, and 21 patients (4.2%) experienced a 
Grade 5 AE.  All of the Grade 5 AEs were considered by investigator to be 
unrelated to treatment with vismodegib except for cardio-respiratory arrest 
and myocardial infarction. 
Of the 500 patients, 107 (21.4%) experienced SAEs.  The most common 
events were in the following system organ classes:  infections and 
infestations, 30 patients (6.0%); neoplasms (benign, malignant, and 
unspecified, including cysts and polyps), 16 patients (3.2%); general 
disorders and administration site conditions, 12 patients (2.4%); nervous 
system disorders, 12 patients (2.4%); cardiac disorders, 11 patients 
(2.2%); injury,  poisoning and procedural complications, 10 patients 
(2.0%); and metabolism and nutrition disorders, 10 patients (2.0%). 
As of 6 November 2013, there have been 29 deaths among 500 safety-
evaluable patients.  The causes of death were PD in 4 patients, AE in 20 
patients, and 5 patients with “other” as cause of death.  Most patient 
deaths were considered unrelated to treatment with vismodegib.  Two 


Protocol:  VISORB page 13 
 
04Feb2019 
deaths (cardiopulmonary arrest and cardiac infarction) were assessed by 
the investigator as related to vismodegib; however, both patients had 
significant risk factors and comorbidities.  Both events were considered by 
the investigator to be related because of the temporal relationship 
between the onset of the event and administration of vismodegib; 
therefore, an association could not be excluded. 
As of 6 November 2013, 400 of 500 patients (80%) treated during Study 
MO25616 had discontinued study drug.  Reasons for discontinuation of 
study drug included: AE (178 patients, 35.6%); progression of disease (70 
patients, 14.0%); patient request (62 patients, 12.4%); death (10 patients, 
2.8%); investigator request (14 patients, 2.8%); lost to follow-up (4 
patients, 0.8%); and other (62 patients, 12.4%). 
The majority of patients (98.2%) in Study MO25616 (STEVIE) experienced 
TEAEs.  The most common ( 20%) TEAEs included muscle spasm 
(63.2 %), alopecia (61.0%), dysgeusia (53.8%), weight decreased 
(32.4%), asthenia (28.2%), decreased appetite (25.4%), and ageusia 
(22.4%).  Twenty-four (4.8%) Grade 4 events and 21 (4.2%) Grade 5 
events were reported.  Two of the deaths were considered related to 
vismodegib treatment (cardio-respiratory arrest and myocardial infarction).  
There were 107 (21.4%) patients who reported SAEs.  Common SAEs 
that were reported in  1% of patients were pneumonia (1.8%, n  9), 
general physical health deterioration (1.4%, n  7), and dehydration (1.0%, 
n  5). 
Interim results of the STEVIE study demonstrate that vismodegib is 
generally well tolerated in a patient population that is representative of 
patients treated in routine clinical practice, with a safety profile consistent 
with that previously observed in other vismodegib studies.  Investigator-
assessed response rates are consistent with those reported in the 
ERIVANCE study and confirm high rates of tumor control. 
As the trial is ongoing, efficacy analyses will be presented at final analysis. 
Phase II Operable Basal Cell Carcinoma (SHH4812g) Study 
The ability of vismodegib to induce complete histological clearance (CHC) 
of BCC tumors, an important step in assessing the role of the drug in the 
setting of smaller resectable lesions, was examined in a single-arm, 3-
cohort, Phase II study (Sofen et al. 2015). Patients in the trial were 
required to have one clinically operable, nodular BCC lesion on the scalp 
(0.5 - 2.0 cm maximum diameter) or in the "cape" area (chest, shoulders, 
or upper back; 1.0 - 3.0 cm maximum diameter). The nodular BCC 
required a positive biopsy that was limited to ≤ 25% of the target lesion. 
After 12 weeks of oral vismodegib (150 mg QD), patients were assessed 
clinically and then underwent excision of the target tumor site for 
pathologic assessment of residual carcinoma, followed by re-excision of 
the tumor site for margin assessment using standard Mohs techniques.  
 


Protocol:  VISORB page 14 
 
04Feb2019 
Efficacy objectives for CHC were not met in this study.  The CHC rates 
were 42% (10/24) in Cohort 1, 16% (4/25) in Cohort 2, and 44% (11/25) in 
Cohort 3; these clearance rates were not statistically significant (p-values 
of 0.8463, 0.9668, and 0.7878, respectively).  The low response rate in 
Cohort 2 (4 [16%] of 25 patients) indicates a lack of durable response.  
Investigator-assessed clinical response (CR and PR) did not correlate with 
CHC.  Time to complete clinical clearance in patients in Cohorts 1 (10 
patients), 2 (9 patients), and 3 (18 patients) with investigator-assessed 
CR, the time to first CR was 59.5 days 
days), respectively.  
 
No new safety signals were noted for patients in this study after dosing 
with vismodegib 150 mg QD PO.  No deaths occurred during this study.  
The safety profile of vismodegib 150 mg QD was similar among the 3 
cohorts.  The data generally showed reversibility of muscle spasms, 
dysgeusia, and ageusia 6 to 12 weeks after drug discontinuation, and 
reversibility of delayed-onset alopecia in most patients during the 24-week 
follow-up period in Cohort 2. 
 
Efficacy objectives for CHC were not met in this study. 
 
1.3.1.2 Medulloblastoma 
Data from a phase II clinical trial evaluated vismodegib treatment at 150 
mg QD in adult patients with medulloblastoma that was recurrent after or 
progressive while receiving standard care (n=40) [Gajjar et al 2013, 
Asklund et al 2013]. Patients were stratified by histologic subtypes based 
on immunohistochemical (IHC) analysis into three strata: non-SHH group, 
SHH group, and indeterminate group. The primary endpoint was objective 
response rate as assessed by RECIST using independent review. 
Responses must be sustained at least 8 weeks. The study met its primary 
endpoint of sustained objective response, with 3/20 patients in SHH group 
exhibiting sustained responses. Secondary efficacy endpoints were 
consistent with the primary endpoint. Grade 3-4 TEAEs reported were 
lymphocytopenia, thromboembolic event, syncope, back pain, myalgia, 
seizure, and hypophosphatemia. 
 
1.3.2 Malignancies with Ligand Driven Hh Signaling  
1.3.2.1 Colorectal Cancer 
A randomized phase II clinical trial evaluated addition of vismodegib or 
placebo to standard chemotherapy (mFOLFOX-6 or FOLFIRI) plus 
bevacizumab in patients with untreated metastatic colorectal cancer 
(n=199;Berlin et al 2013). Choice of chemotherapy regimen was based on 
investigator decision. The primary endpoint was improvement in 
progression-free survival (PFS). The study failed to meet its primary 


Protocol:  VISORB page 15 
 
04Feb2019 
endpoint of improved PFS vs. chemotherapy + placebo (hazard ratio 1.25 
[90%, CI 0.89 -1.76], p =0.28) Secondary efficacy endpoints were 
consistent with the primary endpoint. The TEAEs (all grades) that differed 
in frequency by 10% or more vs. placebo were vomiting, asthenia, weight 
loss, decreased appetite, dehydration, muscle spasms, and dysgeusia. 
Grade 3-5 TEAEs that differed in frequency by 5% or more vs. placebo 
were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, 
weight loss, decreased appetite, and dehydration. 
 
1.3.2.2 Ovarian Cancer 
A randomized phase II clinical trial evaluated the use vismodegib or 
placebo as maintenance treatment for patients with ovarian cancer in 
second or third complete remission (n=104;Kaye et al 2012). The primary 
endpoint was improvement of PFS. The study failed to meet its primary 
endpoint of improved PFS vs. placebo (hazard ratio0.79 95%CI 0.46-1.35, 
p=0.39). TEAEs occurring in greater than 10% of vismodegib treated 
patients were dysgeusia/ageusia, muscle spasms, alopecia, nausea, 
fatigue, constipation, abdominal pain, decrease appetite, upper abdominal 
pain, arthralgia, vomiting and hypomagnesemia. 
 
1.3.2.3 Pancreatic Cancer 
A randomized phase II clinical trial evaluated addition of vismodegib or 
placebo to standard chemotherapy (gemcitabine) in patients with 
untreated metastatic pancreatic cancer (n=106;Catenacci et al 2013). The 
primary endpoint was improvement in progression-free survival. The study 
failed to meet its primary endpoint of improved PFS vs. chemotherapy + 
placebo (HR = 0.81 95%CI 0.54 - 1.21, p=0.3) Secondary efficacy 
endpoints were consistent with the primary endpoint. The frequency of 
Grade ¾ TEAEs reported vs. placebo (V/P) were neutropenia (32%/28%), 
hyponatremia (4%/15%), fatigue (13%/8%), hyperglycemia (23%/19%), 
elevated alanine aminotransferase (ALT; 13%/9%). TEAEs that differed in 
frequency by 10% or more vs. placebo were vomiting, asthenia, weight 
loss, decreased appetite and dehydration. 
 
1.3.2.4 Glioblastoma Multiforme 
A phase II clinical trial evaluated vismodegib treatment at 150 mg QD in 
patients with glioblastoma multiforme that was recurrent after or 
progressive while receiving standard treatment (n=40;Sloan et al 2012). 
The primary endpoint was improvement in PFS at 6 months. The study 
failed to meet its primary endpoint of improved PFS at 6 months (median 
PFS 1.8 months 95%CI 1.40 - 1.9 months) Secondary efficacy endpoints 
were consistent with the primary endpoint. TEAE reported were abdominal 
infection, abdominal pain, atrial flutter, fatigue, hypophosphatemia, 
lymphocytopenia, and thrombocytopenia (1 patient each). 
1.3.2.5 Gastric Cancer 


Protocol:  VISORB page 16 
 
04Feb2019 
A randomized phase II clinical trial evaluated addition of vismodegib or 
placebo to chemotherapy (mFOLFOX-6) in patients with untreated 
metastatic gastric cancer (n=124;Cohen et al 2013). The primary endpoint 
was improvement in PFS. The study ailed to meet its primary endpoint of 
improved PFS vs. chemotherapy + placebo (hazard ratio 1.03 95%CI 0.69 
- 1.55, p=0.64) Secondary efficacy endpoints were consistent with the 
primary endpoint. No significant differences in the rates of common grade 
¾ TEAEs (> 5% incidence) were observed between the vismodegib and 
placebo arms. The rates of grade ½ TEAEs were comparable with no 
significant differences except for a higher incidence of dysgeusia in the 
vismodegib arm (42%/16%, p=0.003).  
 
1.3.2.6 Small Cell Lung Cancer 
A randomized phase II clinical trial evaluated addition of vismodegib or 
cixutumumab (IMC-A12) to standard chemotherapy (Cisplatin/Etoposide) 
in patients with untreated extensive stage SCLC (n=155;Belani et al 
2013). The primary endpoint was improvement in PFS. The study failed to 
meet its primary endpoint of improved PFS vs. cisplatin/etoposide 
chemotherapy (hazard ratio 1.32, p=0.21) Secondary efficacy endpoints 
were consistent with the primary endpoint. Grade ¾ TEAEs reported 
(chemotherapy alone vs. chemotherapy+vismodegib) included anemia 
(25%/ 9%), febrile neutropenia (15%/13%), neutropenia (48%/47%), 
thrombocytopenia (22%/6%), leukopenia (46%/41%), nausea (11%/11%), 
vomiting (9%/6%), hyperglycemia (2%/2%), muscle weakness (4%/0%),  
and renal dysfunction (6%/0%) 
 
1.4 
Background for Other Study Drugs 
There are no other study drugs. 
 
2. 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
The primary goal of this project is to determine whether treatment with 
vismodegib of patients with locally advanced or recurrent orbital and/or 
periocular BCCA will be associated with good ophthalmic outcomes, as 
measured using a novel Visual Assessment Weighted Score (Table 15). 
The primary objective emphasizes globe preservation and maintenance of 
visual acuity, and a score of 21 or greater (out of 50) will be considered a 
good outcome. 
 
2.2 
Secondary Objectives 
The secondary goals of this project are (1) to assess individual parts of the 
composite Visual Assessment Weighted Score to independently assess 
vision and lacrimal function after treatment, (2) to correlate visual function 


Protocol:  VISORB page 17 
 
04Feb2019 
to location and size of tumor over the course of treatment, (3) to identify 
histologic characteristics of periocular BCCA that correlate with tumor 
response, and (4) to characterize molecular markers that may identify 
opportunities for developing adjunct treatment approaches for recalcitrant 
tumors. An additional objective (5) is to characterize and validate the 
Visual Assessment Score for use in future investigations of orbital 
disorders. 
 
3. 
STUDY PROTOCOL 
 
3.1 
Description of the Study 
 
In order to assess the potential of vismodegib to improve the vision- and lacrimal-
related morbidities associated with orbital and periocular BCCA, this study will 
follow patients with globe-threatening orbital and lacrimal-threatening periocular 
BCCA treated with vismodegib as standard of care. The study will be 
prospective, open label, non-randomized, and will determine visual and lacrimal 
function of treated patients. 
 
Basic Protocol (see flow chart at the end of the section): 
 
ELIGIBILITY AND ENROLLMENT 
 
1) Patients will be enrolled based on Eligibility Criteria, Section 4.1, at which 
time a pre-treatment visual assessment score will be obtained as a 
baseline (Table 14). 
2) Enrollment will include Informed Consent and Baseline blood tests. 
3) Enrollment will be performed by the PI, Co-I, or qualified designee. 
 
Table 14: Pre-treatment Visual Assessment Score: 
(This score provides a non-weighted baseline that will be used for testing 
the consistency and internal validity of the Post-treatment Visual 
Assessment Score (Secondary Objective #5).) 
 
VA in affected eye of at least 20/200 
0/1 
Ocular Motility intact 
0/1 
No diplopia 
0/1 
Binocularity (Fusion) +/- prism 
0/1 
Normal tear lake, No complaint of persistent 
tearing 
0/1 
Intact lacrimal system by probing/irrigation 
(both canaliculi to NLD) 
0/1 
Patient assessment of visual function on the 
affected side (Poor, Fair, Good) 
0/1/2 
Score Maximum 
8 
 
 


Protocol:  VISORB page 18 
 
04Feb2019 
ONGOING TREATMENT (See Appendix 4, Schedule of Assessments) 
 
4) Vismodegib treatment initiated by Co-I (FW) per standards of care, within 
3 months of medical oncology screening visit. 
a. Formal enrollment will occur at the time of initiation of vismodegib 
treatment. 
b. Side effects and any adverse events will be assessed and 
documented at the time of each medical exam. 
c. Medical exams (by Medical Oncologist or qualified designee) will 
occur at the following time points following initiation of treatment: 
one, three, six, nine and twelve months. Subjects who complete the 
study prior to the 1-year term (see section 4.7) will no longer be 
required to undergo medical oncology exams as part of the study. 
(See Appendix 4, Table 16, Schedule of Assessments).  
d. Blood draws for biomarker analysis will be performed at screening 
and 6-month intervals (+/- 1 month) for 1 year or at time of early 
discontinuation of vismodegib. 
 
RESPONSE ASSESSMENT 
 
5) Assess response by ophthalmic exam at 3 month intervals or at time of 
early discontinuation of vismodegib (by treating physician or qualified 
designee), + MRI or CT with contrast at 5 and once in the timeframe from 
9-12 months (+/- 1 month) and clinical photography.  
6) Treatment response will be determined per Response Evaluation Criteria 
in Solid Tumors (RECIST) protocol, using clinical measurements and/or 
tumor imaging measurements (determined by treating physician): 
i. Complete response (CR) = complete disappearance of 
tumor 
ii. Partial response (PR) = at least 30% decrease in largest 
diameter 
iii. Progressive disease (PD) = at least 20% increase in largest 
diameter 
iv. Stable disease (SD) = neither PR nor PD 
7) Determination of whether the tumor is progressing (PD) vs. responding 
(SD, PR or CR) will be done at regular intervals (3 months), until 1 year 
after initiation of vismodegib treatment. Following the 1 year mark, patients 
will continue to be followed per SOC. 
 
OUTCOME ASSESSMENT 
 
8) The PRIMARY OUTCOME will be determined by analyzing visual function 
per Table 15 at 1 year following initiation of vismodegib treatment or at 2 
months +/- 1 month following surgery, whichever is longer (i.e. final 
assessment may be extended up to 15 months following initiation of 
vismodegib). A weighted score of at least 21 out of possible 50 would 
constitute a successful treatment outcome. 
 


Protocol:  VISORB page 19 
 
04Feb2019 
 
 
9) SECONDARY OUTCOMES will be assessed via subgroup analysis: 
a. If the tumor progresses (PD) while on vismodegib treatment, then 
treating physician may discontinue vismodegib and offer surgical 
resection or debulking per SOC  OUTCOME #1 (Progressive 
Disease). 
b. If patient refuses surgical option, then continue monitoring patient. 
c. Patients with stable or shrinking tumors (CR, PR or SD) will be 
considered “Responders.” 
d. If the tumor responds within the first year of treatment and patient 
tolerates side effects (per patient), CONTINUE vismodegib therapy 
and monitoring until the end of the study  OUTCOME #2 (SD, PR 
or CR and good tolerance) 
e. If patient reports subjectively intolerable side effects (per patient), 
then discontinue vismodegib, and treating physician can offer 
surgical resection or debulking  OUTCOME #3 (SD, PR or CR 
and poor tolerance). 
f. If patient refuses surgical options, continue monitoring. 
g.  A treatment break, or “drug holiday” will not be offered as an option 
as part of this study. 
h. If treatment with vismodegib is stopped but the patient later decides 
to restart vismodegib, then the patient’s exam findings at 
termination of treatment will be used for assessing the primary 
outcome. The patient can continue to be followed as part of the 
study, and additional exam findings can be used for secondary 
outcome assessment. 
 
 
EVALUATION 
 
10) VA, diplopia, motility, and tearing are assessed at each office visit (Visual 
Assessment Weighted Score see Table 15). 
11) Patients undergoing surgery will have their specimen assessed 
histologically for the presence of tumor, and used for comparison to 
baseline biopsy. 
a. The presence of tumor at the surgical margin will be determined by 
the pathologist. Absence of tumor at the surgical margin will lead to 
a presumptive cure. 
12) The primary outcome will be the Visual Assessment Weighted Score 
(Table 15) at 1 year following initiation of vismodegib or 2 (+/- 1) months 
after tumor excision/debulking surgery, whichever is longer. 
 
 
 
 
 
 


Protocol:  VISORB page 20 
 
04Feb2019 
 
 
Table 15: Follow-up Visual Assessment Weighted Score: 
 
Score (0=No; 1=Yes) Max Weighted score 
Intact globe (no 
enucleation or 
evisceration) 
0/1 
20 
VA within 4 Snellen lines 
of baseline VA or better 
 
0/1 
5 
VA at 20/200 or better 
0/1 
5 
No binocular diplopia in 
primary gaze 
0/1 
2 
Fusion (Fly) +/- prism 
0/1 
2 
No symptomatic tearing 
0/1 
3 
Intact lacrimal system by 
probing/irrigation (either 
canaliculus to NLD) 
0/1 
3 
Patient pleased with 
visual function (Poor, 
Fair, Good) 
0/1/2 
5 
Total possible: 
9 
50 
 
Because there are no validated measures for assessing the success of treating 
orbital disease, a new, non-validated measure must be used. The Visual 
Assessment Weighted Score (VAWS) was developed for the purpose of this 
study. It is made up of standard ophthalmic exam points, as well as a subjective 
assessment of tearing and overall patient satisfaction. Because it is a composite 
score, weighting is used to emphasize visual acuity and an intact globe.  
 
BASIC RESEARCH ARM 
 
13) Concomitant with the clinical arm of the study, a basic research arm will 
be performed to analyze the tumor specimens using histologic, 
immunohistochemical and molecular techniques. 
a. All patients will have a pre-treatment biopsy specimen. Adequacy of 
the biopsy specimen for laboratory investigation will not be a 
criterion for inclusion or exclusion from the study.  
b. For those patients who have an adequate biopsy specimen, the 
characteristics of the specimen will be analyzed and matched with 
treatment outcome. 
c. For patients who undergo surgery following initiation of vismodegib 
treatment - failure (outcome #1) or intolerance of side effect 
(outcome #3) - the pre- and post-treatment characteristics of the 
tumor within the surgical specimens will be analyzed and 
compared.  


Protocol:  VISORB page 21 
 
04Feb2019 
d. All patients will have blood drawn at initiation of therapy and at 6 
month intervals for 1 year or at time of early discontinuation of 
vismodegib. One 5 ml red top tube and two 10 ml purple top 
(EDTA) tubes will be drawn, in this order, for each interval.  Blood 
will be drawn at the Kellogg Eye Center and processed in Dr. 
Kahana’s laboratory.  Serum and blood will be barcoded and stored 
in a -80 freezer for marker and genetic analysis and correlation with 
histo-pathologic findings.   
 
See Table 16 (Appendix 4) for a Schedule of Assessments. 
 
3.2 
Rationale for Study Design 
 
Hypothesis: Treatment of orbital and periocular BCCA with oral vismodegib 
facilitates globe-sparing treatment of orbital BCCA, and lacrimal apparatus-
sparing treatment of medial canthal BCCA. 
  
This is a prospective study that will follow the interventional standard of care use 
of vismodegib in patients with locally advanced BCCA that threatens the globe or 
lacrimal drainage system (see flow chart), and utilize a laboratory approach to 
identify predictors of disease severity, progression and response to treatment. 
 
3.3 
Outcome Measures 
Primary Outcome Measure: 
OrbitalorMedialcanthalBCCA
Biopsy,+/-MRI/CT
PIEvalua onforstudy
enrollment
Vismodegib
Noresponse(+GROWTH)
SurgicalExcisionand
Reconstruc on
GoodResponseClinically&MRI/CT
(NOGROWTH)
Welltolerated
MaintainVismodegib
PoorlyTolerated
StopVismodegib
Pa entRefusesSurgery-follow
SurgicalExcisionand
Reconstruc on


Protocol:  VISORB page 22 
 
04Feb2019 
Determined by analyzing visual function per Table 15 at completion of the study. 
A weighted score of at least 21 out of possible 50 would constitute a 
successful treatment outcome. 
Secondary Outcome Measures: 
Visual function measures collected numerically at 3-month intervals will be 
correlated with size of tumor and timing of surgery (if any). 
 
In addition, a laboratory basic research protocol will utilize histologic and 
molecular analyses of the tumors, as outlined below. The aim of the basic 
research protocol is to characterize the tumor response to vismodegib 
treatment in order to determine the biology of tumor shrinkage/fibrosis, 
determine whether compensatory pro-oncogenic pathways are induced by 
treatment, and to identify potential markers that correlate with good 
treatment response. The specific aims are: 
 
1) Aim 1: Histologically assess the cellular characteristics and extent of residual 
tumor and its relationship to: 
a. Vascular supply 
b. Lymphatic vessels 
c. Nerves 
d. Leukocytes 
 
Hypothesis: the response to vismodegib is unevenly distributed, and is 
anatomically driven by the vascular bed, watershed zones, and the 
presence of tumor-clearing leukocytes. 
 
Using histologic and immunohistochemical techniques, the tumor will be 
assessed from pre-treatment biopsy specimens as well as post-treatment 
specimens. Micro-anatomical techniques, including high-resolution tile 
scanning of multiple sections, and immunofluorescence techniques, will be 
used to develop a reproducible system that will measure capillary and 
tumor cell densities, to develop possible predictors of vismodegib 
resistance based on tumor anatomy. When possible (per tissue 
availability), transmission electron microscopy will be used to characterize 
the cellular and stromal response to vismodegib treatment. 
 
2) Aim 2: Develop a profile of biomarkers within the tumors before and after 
treatment. 
 
Hypothesis: inhibition of hedgehog signaling with vismodegib alters the 
biology of other signaling pathways, which can lead to opportunities for 
multi-modal treatment synergies for resistant tumors, as well as identify 
risk factors for resistant tumors. 
 
Utilizing immunofluorescence and confocal microscopy techniques, each 
tumor will be profiled for expression of a comprehensive set of ligands and 
receptors of the above-mentioned pathways. Using laser microdissection 


Protocol:  VISORB page 23 
 
04Feb2019 
(LMD) and quantitative PCR technology (qPCR), specific regions within 
tumors will be profiled and compared within and between tumors for 
expression of ligand-receptor pairs before and after vismodegib treatment, 
along with the presence of mutations within genes that are known to 
bypass or confer resistance to hedgehog pathway inhibition. Expression of 
cancer stem cell markers will also be assessed via qPCR, in both tumor 
and in blood samples from patients before and after vismodegib treatment, 
to identify possible serum markers for tumor sensitivity and response. 
Collaborators include Prof. Andrzej Dlugosz, University of Michigan, and 
Frederic de Sauvage, Genentech, Inc. 
 
 
3.4 
Safety Plan 
Patients will be evaluated at regular clinic visits for the duration of the 
study participation 
Specific potential safety issues for this trial are outlined below.  
Please refer to the Vismodegib Investigator Brochure for a detailed 
description of the safety profile of vismodegib. 
See Section 5.1 (Assessment of Safety) for complete details of the safety 
evaluation for this study. 
3.5 
Compliance with Laws and Regulations 
This study will be conducted in accordance with current U.S. Food and 
Drug Administration (FDA) Good Clinical Practices (GCPs), and local 
ethical and legal requirements. 
 
4. 
MATERIALS AND METHODS 
4.1 
Subject Selection 
 
INCLUSION CRITERIA AND ENROLLMENT PROCESS 
 
1) Adult patients over 18 years of age with locally advanced or recurrent 
orbital or periorbital BCCA, or a medial canthal BCCA that threatens 
the lacrimal drainage system, as noted by clinical exam, Clinical 
photography, CT or MRI imaging and positive biopsy, and who do not 
have a contraindication to either surgical or vismodegib treatment. 
a. Treating physician to assess whether the patient is a candidate for 
vismodegib treatment.  
2) Clinical assessment score per Table 14 will be obtained, at baseline. 
3) Medical Oncology screening evaluation performed to assess medical 
indication/contra-indication to vismodegib treatment. 


Protocol:  VISORB page 24 
 
04Feb2019 
4) PI (AK) to review the exam findings, photos and imaging study and 
determine whether the patient meets inclusion criteria in the study, based 
on BCCA size, location of tumor, and clinical assessment score. 
a. Orbital invasion or impending invasion by BCCA 
b. Medial canthal BCCA within 7 mm of lacrimal apparatus 
5) Adequate liver function, renal function and hematocrit. 
6) Male patients must agree to use condoms for sexual intercourse with 
female partners of reproductive potential at all times, even after a 
vasectomy, during treatment with vismodegib and for 3 months after the 
last dose to avoid exposing a pregnant partner and unborn fetus to 
vismodegib (see Appendix 2). 
7) Male patients must agree not to donate sperm during the study and for 3 
months after discontinuation of vismodegib 
8) Agreement not to donate blood or blood products during the study and for 
7 months after discontinuation of vismodegib.  
9) Patient will be approached for enrolling in the study by the PI, treating 
physician or a designee. Informed consent will be obtained by the PI, Co-I 
or a qualified designee. 
10) If the patient consents to enroll, then blood will be drawn and stored for 
biomarker analysis. 
EXCLUSION CRITERIA 
Patients will be excluded from the study based on the following 
criteria: 
 Inability or unwillingness to swallow capsules 
 Inability or unwillingness to comply with study procedures and protocol 
 Pregnant, lactating or breast feeding women 
 Women of childbearing potential. 
 Uncontrolled medical illnesses  
 Age under 18 years 
 Dementia or significantly altered mental status that would prohibit the 
understanding or rendering of informed consent and compliance with the 
requirements of this protocol. 
 


Protocol:  VISORB page 25 
 
04Feb2019 
4.2 
Method of Treatment Assignment  
Treatment will be determined by the treating physicians in accordance 
with SOC. The PI will determine eligibility for the study and be the final 
arbiter for inclusion of patients.  There will be no randomization. 
 
4.3 
Study Treatment  
The study treatment will follow SOC protocol for BCCA that threatens the 
eye or lacrimal apparatus. The study aims to enroll 50 patients over 3 
years and follow each patient for 1 year. 
Vismodegib Dosage  
Vismodegib is 150 mg taken QD PO until disease progression or until 
unacceptable toxicity. Vismodegib may be taken with or without food. 
- 
Swallow capsules whole 
- 
Do not open or crush capsules 
- 
If a dose of vismodegib is missed, do not make up that dose; 
resume dosing with the next scheduled dose. 
 
Vismodegib Dose and Schedule Modifications 
Vismodegib dose modifications and schedule modifications during the 
study are not recommended due to the pharmacokinetic characteristics of 
the drug (see Vismodegib Investigator Brochure v9, Section 5.9.3). Briefly, 
vismodegib’s pharmacokinetic profile is a result of high affinity, reversible 
binding to Alpha-1 acid Glycoprotein (AAG) and binding to albumin, in 
addition to solubility limited absorption and slow metabolic elimination 
properties (Graham 2011). Initiation of less frequent administration 
schedules than the approved dose and schedule of vismodegib of 150 mg 
orally once daily, (i.e. 150 mg three times weekly [TIW] or 150 mg once 
weekly [QW] dosing), was associated with marked decrease in the 
pharmacologically active unbound fraction. 
Unbound steady-state vismodegib concentrations were 60% and 85% 
lower for the TIW and QW dose groups, respectively, relative to the QD 
dose group (LoRusso et al. 2011b).  Such decreases may be associated 
with loss of vismodegib activity based on findings from nonclinical models. 
Integrated PK/pharmacodynamic modeling of vismodegib in xenograft 
models has revealed a steep relationship between pathway modulation 
(GLI1 inhibition) and anti-tumor effect, suggesting that even small 
reductions in exposure could lead to dramatic loss in vismodegib activity 
(see Vismodegib Investigator’s Brochure v9, Section 4.1.2.8) 
Dose reduction of vismodegib is not permitted as there is only a 150-mg 
capsule strength available. Capsules should not be opened or crushed. If 


Protocol:  VISORB page 26 
 
04Feb2019 
a treatment interruption occurs, and it is determined that vismodegib will 
be re-started, the original dose will be maintained 
Vismodegib Overdosage 
There is no information on overdosage in humans. In clinical trials, 
ERIVEDGE capsule was administered at 540 mg QD; exposure did not 
increase between 150 mg and 540 mg daily.  
Vismodegib Clinical Formulation and Storage  
 
For the clinical studies, hard gelatin capsules containing 150 mg 
vismodegib are available. The 150-mg vismodegib drug product is a hard 
gelatin capsule formulation for oral administration. The capsule fill consists 
of vismodegib and the following excipients: microcrystalline cellulose 
PH101, lactose monohydrate, sodium lauryl sulfate, povidone K29/32, 
sodium starch glycolate, talc, magnesium stearate, and purified water. All 
of these excipients are compendial (USP/NF-EP) grade. The capsule shell 
consists of gelatin, red iron oxide, black iron oxide, and titanium dioxide. A 
compendial-grade black printing ink may be used. 
 
Vismodegib capsules should be stored in the recommended storage 
conditions at15°C−30°C. Information on the shelf life of the capsules is 
provided on the label.  
 
4.4 
Concomitant and Excluded Therapy  
 
Drugs that Inhibit or Induce Drug Metabolizing Enzymes  
Vismodegib elimination involves multiple pathways. Vismodegib is 
predominantly excreted as an unchanged drug. Several minor metabolites 
are produced by multiple CYP enzymes. Although vismodegib is a 
substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted 
to alter vismodegib systemic exposure since similar steady-state plasma 
vismodegib concentrations were observed in patients in clinical trials 
concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, 
modafinil, and phenobarbital) and those concomitantly treated with 
CYP3A4 inhibitors (i.e., erythromycin and, fluconazole).  
Drugs that Inhibit Drug Transport Systems  
In vitro studies indicate that vismodegib is a substrate of the efflux 
transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered 
with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, 
azithromycin), systemic exposure of vismodegib and incidence of AE of 
ERIVEDGE may be increased.  
Drugs that Affect Gastric pH  
Drugs that alter the pH of the upper gastrointestinal (GI) tract (e.g., proton 
pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility 


Protocol:  VISORB page 27 
 
04Feb2019 
of vismodegib and reduce its bioavailability. However, no formal clinical 
study has been conducted to evaluate the effect of gastric pH altering 
agents on the systemic exposure of vismodegib. Increasing the dose of 
ERIVEDGE when coadministered with such agents is not likely to 
compensate for the loss of exposure. When ERIVEDGE is coadministered 
with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic 
exposure of vismodegib may be decreased and the effect on efficacy of 
ERIVEDGE is unknown. 
Effects of Vismodegib on Other Drugs 
Results of a drug-drug interaction study conducted in cancer patients 
demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 
substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is 
not altered when either drug is co-administered with vismodegib. 
In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, 
CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not 
induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 
 
4.5 
Study Assessments 
Assessments during Treatment 
 Pregnancy test: All women of childbearing potential (including those 
who have had a tubal ligation) will be excluded from this study. This 
will have no bearing on their eligibility for treatment with vismodegib 
per SOC by their treating physician. 
Ophthalmologic Exam Follow-Up Assessments 
At month 3 and every 3 months a standard oculoplastic eye exam to 
assess visual function (see Table 15). The tumor size will be measured in 
two coordinates using a metric ruler at each clinic visit. This will be 
performed by the treating physician or a trained designee. 
MRI or CT with contrast and clinical photographs will be obtained prior to 
the onset of treatment (per SOC). Clinical photographs will be obtained at 
subsequent clinic visits (every 3 months), and a follow up MRI or CT will 
be obtained at 5 and 9-12 months (+/- 1 month) after initiation of 
vismodegib therapy to assess tumor response/progression, and 
additionally at the discretion of the treating physician (per SOC). 
Progression of disease, per ophthalmic/oculoplastic evaluation, will 
result in offering the patient a surgical approach. Patients will continue to 
be followed for the duration of the study period irrespective of vismodegib 
treatment status. If progression of disease is suspected by the Medical 
Oncology team, then an urgent ophthalmic evaluation will be obtained 
within 2 weeks or less. 
Patients will be followed for 1 year after initiation of vismodegib treatment, 
or 1 month (+/- 1 month) following surgery. 


Protocol:  VISORB page 28 
 
04Feb2019 
 
4.6 
Discontinuation of Protocol-Specified Therapy 
Protocol-specified therapy may be discontinued for any of the following 
reasons: 
 Patient election to discontinue study participation (for any reason) 
 Patient election to refuse treatment (for any reason) 
 Treating physician’s judgment 
 
4.7 
Subject Discontinuation 
 
All subjects who enroll in the study will be followed for 1 year, -1/+3 
months, at which point their study participation will be deemed completed. 
If patients undergo tumor resection surgery prior to completion of the 
study, they will be given their final study evaluation within 1 month after 
the surgery, at which time their enrollment will be deemed completed. 
Subjects who discontinue vismodegib prior to the end of the 1-year study 
period, do not restart vismodegib within 30 days, and refuse surgery, will 
be deemed to have completed the study and their evaluation within 1 
month of treatment discontinuation will be considered their exit time point 
and primary end point. Subjects who decide to resume vismodegib will be 
able to reenroll to complete the 1-year trial period. 
 
Subjects who discontinue vismodegib before completing the 1-year study 
will return for evaluation by Ophthalmology within the first month post-
operatively, at which point the final evaluation will be completed and their 
study enrollment will be deemed complete.  
 
Completion of a final Ophthalmology evaluation and Visual Assessment 
Score will constitute a subject’s completion of the study if so deemed by 
the PI.  
 
See Table 16. 
 
4.8 
Study Discontinuation 
The Principal Investigator has the right to terminate this study at any time.  
Reasons for terminating the study may include the following: 
 The incidence or severity of adverse events in this or other studies 
indicates a potential health hazard to subjects 
 Subject enrollment is unsatisfactory 
 


Protocol:  VISORB page 29 
 
04Feb2019 
4.9 
Statistical Methods 
Number of referrals to PI, number of eligible participants, and number of 
enrollees will be used to monitor accrual. AEs and SAEs will be 
documented for all enrollees.  All enrollees will be included in an intent-to-
treat analysis. Pre-post tumor comparisons will be made among enrollees 
with both samples. 
The study will use an exact binomial one-sided test to provide statistical 
measures to the outcomes.  
Analysis 
Treatment outcome (Visual Function Score; Table 15) will be measured 
overall (primary endpoint). The primary outcome will be the assessment 
of the visual system using a weighted assessment scale per Table 15. A 
weighted score of 21 or more (out of possible 50) constitutes a successful 
outcome. 
Exact binomial one-sided tests will be used to compare success rate of 
the primary outcome (Visual Function Score, Table 15) to 30% (a 
literature- and practice-based estimate of the loss of visual and lacrimal 
function after treatment of locally advanced periocular/orbital BCCA).  If 
the true success rate is 50%, the study will have 90% power to reject the 
null hypothsis (p=0.3) in favor of the alternative (p>0.3) at alpha=0.05. 
Secondary endpoints will utilize the three treatment modality groups: 
 #1: treatment stopped due to non-response (per RECIST);  
 #2: treatment continued for a full year with good response and good 
tolerance 
 #3: treatment stopped due to poor tolerance in spite of good 
response;  
Secondary outcomes will utilize the actual numerical values obtained 
during the assessment over time to correlate visual function with tumor 
size (measured at each visit and/or via MRI/CT imaging). The secondary 
outcome measures will assess each part of the composite visual 
assessment score to determine changes in vision and lacrimal function 
following vismodegib treatment. 
Histologic characteristics and molecular markers to be studied for the 
secondary objective include HMW keratin, proliferation markers such as 
Ki67, hedgehog and Wnt pathway markers.  These will be summarized 
overall, by treatment modalities, and by outcome groups (e.g., Good or 
Poor Visual or Lacrimal Function). No other subgroup analyses are 
planned. Please see page 20, BASIC RESEARCH ARM. 
Safety Analysis 
AEs and SAEs will be tabulated among all enrollees. 


Protocol:  VISORB page 30 
 
04Feb2019 
Missing Data 
Pre-treatment data will be reviewed prior to enrollment to ensure that all 
the required elements are documented. Incomplete post-treatment data 
will be completed via subsequent clinical exam and/or telephone interview. 
 
Determination of Sample Size 
 Endpoints used 
The endpoint used for determining sample size was a Visual 
Assessment Weighted Score of at least 21 (out of possible 50). 
 Methodology used 
The exact binomial one-sided test with n=50 has 90% power to 
reject the null hypothesis p=0.3 in favor of the alternative p=0.5 at 
alpha=0.05.   
 
A recruitment assessment will be performed at the 2 and 3 year time 
points (out of 4 years), in order to assess recruitment. The goal of the 
study is to enroll 50 patients over 3 years, or 16-17 patients per year. After 
year 1, if recruitment drops below a minimum 12 patients (or at least one 
per month on average) then the study will be adjusted by (1) extending the 
trial beyond 3 years of recruitment, and/or (2) extending patient 
recruitment to outside medical institutions. After year 2, if recruitment is 
greater than 20 but below 30 patients, then the trial will be extended by 1 
year. If recruitment is below 20 patients at the end of year 2 then the trial 
will be both extended by 1 year and patient recruitment extended to 
outside institutions. 
 
4.10 Data Quality Assurance 
Accurate, consistent, and reliable data will be ensured through the use of 
standard practices and procedures. 
 
5. 
REPORTING OF ADVERSE EVENTS 
 
5.1 
Assessment of Safety 
 
This study will be monitored in accordance with the NCI approved 
University of Michigan Rogel Cancer Center Data and Safety Monitoring 
Plan. 
 
The study team will meet quarterly or more frequently depending on the 
activity of the protocol. The discussion will include matters related to the 
safety of study participants (SAE/UaP reporting), validity and integrity of 
the data, enrollment rate relative to expectations, characteristics of 


Protocol:  VISORB page 31 
 
04Feb2019 
participants, retention of participants, adherence to the protocol (potential 
or real protocol deviations) and data completeness. At these regular 
meetings, the protocol specific Data and Safety Monitoring Report form 
will be completed and signed by the Principal Investigator or by one of the 
co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of 
Michigan Rogel Cancer Center Data and Safety Monitoring Committee 
(DSMC) on a quarterly basis for independent review. 
 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting AEs and 
SAEs per protocol.  This includes all events of death, and any study 
specific issue of concern. 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
 AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting including signs or symptoms 
associated with basal cell carcinoma that were not present prior to the 
AE reporting period. 
 Complications that occur as a result of protocol-mandated 
interventions (e.g., invasive procedures such as cardiac 
catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other 
protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
Serious Adverse Events 
An AE should be classified as an SAE if the following criteria are met: 
 It results in death (i.e., the AE actually causes or leads to death). 
 It is life threatening (i.e., the AE, in the view of the investigator, places 
the subject at immediate risk of death. It does not include an AE that, 
had it occurred in a more severe form, might have caused death.). 
 It requires or prolongs inpatient hospitalization. 


Protocol:  VISORB page 32 
 
04Feb2019 
 It results in persistent or significant disability/incapacity (i.e., the AE 
results in substantial disruption of the subject’s ability to conduct 
normal life functions). 
 It results in a congenital anomaly/birth defect in a neonate/infant born 
to a mother exposed to the IMP. 
 It is considered a significant medical event by the investigator based 
on medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed 
above). 
 
5.2 
Methods and Timing for Assessing AND Recording Safety 
Variables 
The investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study are collected and reported to the 
appropriate IRB(s), in accordance with CFR 312.32 (IND Safety Reports).  
Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins 
after informed consent is obtained and initiation of vismodegib treatment 
and ends 30 days following the last administration of vismodegib or study 
discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to prior study 
treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by 
study personnel during questioning, or detected through physical 
examination, laboratory test, or other means will be reported appropriately. 
Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the study drug (see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, 
investigators should apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE 
and administration of vismodegib, and the AE cannot be readily explained 
by the subject’s clinical state, intercurrent illness, or concomitant 
therapies; and/or the AE follows a known pattern of response to 
vismodegib; and/or the AE abates or resolves upon discontinuation of 
vismodegib or dose reduction and, if applicable, reappears upon re-
challenge 
No 


Protocol:  VISORB page 33 
 
04Feb2019 
Evidence exists that the AE has an etiology other than vismodegib (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal 
relationship to vismodegib administration (e.g., cancer diagnosed 2 days 
after first dose of vismodegib). 
 
Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert or current Investigator’s Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert or 
current Investigator’s Brochure ( or not identified. This includes adverse 
events for which the specificity or severity is not consistent with the 
description in the Package Insert or current Investigator’s Brochure. For 
example, under this definition, hepatic necrosis would be unexpected if the 
Package Insert or Investigator’s Brochure only referred to elevated hepatic 
enzymes or hepatitis. 
 
5.3 
Procedures for Eliciting, Recording, and Reporting 
Adverse Events  
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation 
timepoints will be adopted. Examples of non-directive questions include:  
 “How have you felt since your last clinical visit?” 
 “Have you had any new or changed health problems since you were 
last here?”  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when 
reporting AEs or SAEs. Avoid colloquialisms and abbreviations. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather 
than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases). 
However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it 
is acceptable to report the information that is currently available. If a 
diagnosis is subsequently established, it should be reported as follow-up 
information. 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period 
(see Section 5.2.1), regardless of attribution, will be reported to the 
appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the 


Protocol:  VISORB page 34 
 
04Feb2019 
single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, report “Unexplained Death”. 
c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the 
study. Such conditions should be reported as medical and surgical history. 
A preexisting medical condition should be re-assessed throughout the trial 
and reported as an AE or SAE only if the frequency, severity, or character 
of the condition worsens during the study. When reporting such events, it 
is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent 
headaches”). 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should 
be documented and reported as an SAE. If a subject is hospitalized to 
undergo a medical or surgical procedure as a result of an AE, the event 
responsible for the procedure, not the procedure itself, should be reported 
as the SAE. For example, if a subject is hospitalized to undergo coronary 
bypass surgery, record the heart condition that necessitated the bypass as 
the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
 Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for preexisting conditions 
 Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
 Hospitalization or prolonged hospitalization for scheduled therapy of 
the target disease of the study. 
e. Pregnancy 
Women of child bearing potential are not eligible to participate in the 
study.  If a male subject receiving study drug (or within 3 month after the 
last dose of study drug) impregnates a female partner, then the female 
partner will be requested to provide informed consented to permit a report 
of the pregnancy to be completed and expeditiously submitted to 
Genentech. 
Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always 
be classified as serious, and expeditiously reported as an SAE. Similarly, 
any congenital anomaly/birth defect in a child born to a female subject 
exposed to study drug should be reported as an SAE. 
Additional information on any vismodegib-exposed pregnancy and infant 
will be requested by Roche Drug Safety at specific timepoints (i.e., after 
having received the initial report, at the end of the second trimester, 2 


Protocol:  VISORB page 35 
 
04Feb2019 
weeks after the expected date of delivery, and at 3, 6, and 12 months of 
the infant’s life). 
 
f. Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a 
subject has completed or discontinued study participation if attributed to 
prior vismodegib exposure. If the investigator should become aware of the 
development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, this 
should be reported as an SAE.  
 
g. Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech 
and the Sponsor will agree to the reconciliation periodicity and format, but 
agree at minimum to exchange quarterly line listings of cases received by 
the other party. If discrepancies are identified, the Sponsor and 
Genentech will cooperate in resolving the discrepancies. The responsible 
individuals for each party shall handle the matter on a case-by-case basis 
until satisfactory resolution.  The sponsor shall receive reconciliation 
guidance documents within the “Activation Package.” 
 
MEDWATCH 3500a REPORTING GUIDELINES 
 
In addition to completing appropriate patient demographic and suspect 
medication information, the report should include the following information 
within the Event Description (section 5) of the MedWatch 3500A form: 
 Protocol description (and number, if assigned) 
 Description of event, severity, treatment, and outcome if known 
 Supportive laboratory results and diagnostics 
 Investigator’s assessment of the relationship of the adverse event to 
vismodegib, and suspect medication. 
Follow-up Information 
Additional information may be added to a previously submitted report 
by any of the following methods: 
 Adding to the original MedWatch 3500A report and submitting it as 
follow-up 
 Adding supplemental summary information and submitting it as follow-
up with the original MedWatch 3500A form 
 Summarizing new information and faxing it with a cover letter including 
patient identifiers (i.e. D.O.B. initial, patient number), protocol 
description and number, if assigned, brief adverse event description, 
and notation that additional or follow-up information is being submitted 


Protocol:  VISORB page 36 
 
04Feb2019 
(The patient identifiers are important so that the new information is 
added to the correct initial report).  
 Occasionally Genentech may contact the reporter for additional 
information, clarification, or current status of the patient for whom and 
adverse event was reported. For questions regarding SAE reporting, 
you may contact the Genentech Drug Safety representative noted 
above or the MSL assigned to the study. Relevant follow-up 
information should be submitted to Genentech Drug Safety as soon as 
it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
 
 
5.4 
Safety Reporting Requirements for IND Exempt Studies 
 
Postmarketing 15-Day “Alert Report”: 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the 
investigator to be possibly related to the use of vismodegib. An 
unexpected adverse event is one that is not already described in the 
Investigator Brochure. Such reports are to be submitted to the FDA (2 
copies) at the following address: Central Document Room, 12229 Wilkins 
Avenue, Rockville, MD 20852. 
 
All Postmarketing 15-Day “Alert Reports” submitted to the FDA by the 
Sponsor-Investigator must also be faxed to Genentech at: (650) 225-4682 
or (650) 225-4630. 
 
5.5 
Study Close-Out  
 
At the close of the study, all the patient data will be entered into a 
repository for 7 years, and then destroyed. All biological data, including 
tissue and blood samples, will be stored indefinitely for patient care 
purposes and future analysis as needed. A research report will be 
prepared by the PI and submitted for publication as well as to the funding 
agencies. Any study report by the Sponsor-Investigator should be copied 
to Genentech.  Additionally, any literature articles that are a result of the 
study should be sent to Genentech.  
 
 
6. 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP 
(see Section 4.9 of the guideline) require that records and documents 
pertaining to the conduct of clinical trials and the distribution of 
investigational drug, subject records, consent forms, laboratory test 


Protocol:  VISORB page 37 
 
04Feb2019 
results, and medication inventory records, must be retained for 2 years 
after the last marketing application approval in an ICH region or after at 
least 2 years have elapsed since formal discontinuation of clinical 
development of vismodegib.  All state and local laws for retention of 
records also apply.  
For studies conducted outside the United States under a U.S. IND, the 
Principal Investigator must comply with the record retention requirements 
set forth in the U.S. FDA IND regulations and the relevant national and 
local health authorities, whichever is longer. 


Protocol:  VISORB page 38 
 
04Feb2019 
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cisplatin and etoposide (CE) versus CE with either vismodegib (V) or 
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13. Epstein, E. H. Basal cell carcinomas: attack of the hedgehog. Nat Rev 
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14. Erivedge [package insert]. South San Francisco, CA: Genentech, Inc.; 
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22. Karhadkar, S. S., G. S. Bova, et al. Hedgehog signalling in prostate 
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26. Marks, R., D. Jolley, et al. The incidence of non-melanocytic skin cancers 
in an Australian population: results of a five-year prospective study. Med J 
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27. Miller, D. L. and M. A. Weinstock. Nonmelanoma skin cancer in the United 
States: incidence. J Am Acad Dermatol 1994;30:774-778. 
28. Online Mendelian Inheritance in Man. (2012). "#10940: Basal Cell Nevus 
Syndrome; BCNS."   Retrieved June 2012, from 
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29. Scales, S. J. and F. J. de Sauvage. Mechanisms of Hedgehog pathway 
activation in cancer and implications for therapy. Trends Pharmacol Sci 
2009;30:303-312. 
30. Sekulic, A., M. R. Migden, et al. Efficacy and safety of vismodegib in 
advanced basal-cell carcinoma. N Engl J Med 2012;366:2171-2179. 
31. Sloan, A.E., C.J. Nock et al. Targeting glioma stem cells in GBM ABTC-
0904: phase 0/II study of hedgehog pathway inhibitor GDC-0449, SNO 
Poster Presentation, 2012 
32. Tang, J. Y., J. M. Mackay-Wiggan, et al. Inhibiting the hedgehog pathway 
in patients with the basal-cell nevus syndrome. N Engl J Med 
2012;366:2180-2188. 
33. Thayer, S. P., M. P. di Magliano, et al. Hedgehog is an early and late 
mediator of pancreatic cancer tumorigenesis. Nature 2003;425:851-856. 
34. van Hattem, S., M. J. Aarts, et al. Increase in basal cell carcinoma 
incidence steepest in individuals with high socioeconomic status: results of 
a cancer registry study in The Netherlands. Br J Dermatol 2009;161:840-
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35. Von Hoff, D. D., P. M. LoRusso, et al. Inhibition of the hedgehog pathway 
in advanced basal-cell carcinoma. N Engl J Med 2009;361:1164-1172. 
36. Watkins, D. N., D. M. Berman, et al. Hedgehog signalling within airway 
epithelial progenitors and in small-cell lung cancer. Nature 2003;422:313-
317. 
37. Wolfe, C. M., W. H. Green, et al. Basal Cell Carcinoma Rebound After 
Cessation of Vismodegib in a Nevoid Basal Cell Carcinoma Syndrome 
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Protocol:  VISORB page 41 
 
04Feb2019 
 
APPENDICES 
 


Protocol:  VISORB page 42 
 
04Feb2019 
APPENDIX 1  
Study Flowchart 
 
 


 
Protocol:  VISORB page 43 
 
04Feb2019 
APPENDIX 2: Definition of Women of Non-Childbearing Potential 
Female patients who meet at least one of the following criteria are defined as women of 
non-childbearing potential: 
 
≥ 50 years old and naturally amenorrheic for ≥ 1 year 
 
Permanent premature ovarian failure confirmed by specialist gynecologist 
 
Previous bilateral salpingo-oophorectomy and/or hysterectomy 
 
XY karyotype, Turner’s syndrome, or uterine agenesis 
 
Female patients who do not meet at least one of the above criteria are defined as 
women of childbearing potential, and will be excluded from this study. 
Children of both genders will be excluded from this study, which includes pre-
menstrual as well as post-menarche girls. 
Women of childbearing potential who are excluded from this study will still be 
eligible to receive vismodegib per FDA-approved indications and standard of 
care. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol:  VISORB page 44 
 
04Feb2019 
APPENDIX 3: Material Safety Data Sheet (MSDS) 
 
The current Material Safety Data Sheet (MSDS) for ERIVEDGE Capsules (150 mg) is 
available at: 
http://www.gene.com/download/pdf/ErivedgeCapsules150mgMSDS.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The information in this safety data sheet is based on current scientific 
knowledge. It should not be taken as expressing or implying any 
warranty concerning product characteristics. 
 


 
Protocol:  VISORB page 45 
 
04Feb2019 
APPENDIX 4 
 
Table 16:  Schedule of Assessments 
 
 
 
 
Screen 
Initiation of 
Vismodegib 
Assessments  
(+/- 1 month
10) 
Study Visit (months) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12, -1/ +3 months ( 
or 1 month post-op 
following surgery)
12 
Withdrawal of 
vismodegib for 
surgical 
treatment (+/- 1 
month) 
Early withdrawal 
of vismodegib 
Informed Consent 
x 
Demographics 
x 
Medical History
1 
x 
 
Medical Exam
2, 
x 
x 
x 
 
x
10 
 
 
X
10 
   
 
   X
10 
 
 
X
10 
X
10 
X
10 
Ophthalmic 
oculoplastic exam
3 
x 
 
x 
 
x 
 
 
X 
 
 
x 
x 
x 
Standard clinical 
photos 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Visual Assessment 
Score (pre)
4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual Assessment 
Score (post)
5 
 
 
 
 
x 
 
x 
 
 
x 
 
 
x 
x 
x 
Biopsy for histologic 
diagnoses/evaluation 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI or CT scan
6 
x 
 
 
x 
 
 
 
X
13 
 
x 
X
11 
X
11 
CBC/Chemistry 
Labs
7 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
Biomarker Draw 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
x 
Response 
Evaluation
8 
 
 
x 
 
x 
 
x 
 
x 
x 
x 
AE assessment9 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


 
Protocol:  VISORB page 46 
 
04Feb2019 
Footnotes: 
 
1. Medical history including smoking history. Assessed by Ophthalmology team. 
2. Medical exam assessed by Med Onc team. 3 month supply of medication will be 
provided at the time of each standard 3-month visit. 
3. Ophthalmic exam should include visual acuity, slit lamp exam, eye motility and tearing.  
Assessed by Ophthalmology team. 
4. See Table 14 in the protocol.  Assessed by Ophthalmology team. 
5. See Table 15 in the protocol.  Assessed by Ophthalmology team. 
6. Additional MRI/CT will be for tumor measurements and assessments. Assessed by 
Ophthalmology team. 
7. CBC/Chemistry lab tests per Med-Onc team for SOC. 
8. Assessed by Ophthalmology team. 
9. Assessed by Med-Onc team. 
10. Visits may be scheduled more frequently per Med-Onc or Ophthalmology team 
discretion. Last medical exam will occur prior to surgery. Remaining medication and 
diary should be returned to Ophthalmology. 
11. Per the discretion of the Ophthalmologist. 
12. Subjects will be followed for 1 year or until surgery followed by one month post-
operative evaluation. 
13. 9-12 month window for CT-MRI imaging, as determined by the treating physician. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Protocol:  VISORB page 47 
 
04Feb2019 
 
 
 
 
 
 
 
APPENDIX 5 
 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-4630 
 
Genentech Study Number 
ML29160 
Principal Investigator 
Alon Kahana, MD, PhD 
Site Name 
Kellogg Eye Center/University of Michigan 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 
835-2555 
 


 
Protocol:  VISORB page 48 
 
04Feb2019 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT 
BEHIND THIS COVER SHEET