A Phase 2, Single-center, Single-arm, Open Label Trial of Vismodegib in Patients With Keratocystic Odontogenic Tumors
Phase: PHASE2
Conditions: Keratocystic Odontogenic Tumor
Sponsor: NYU College of Dentistry

CONFIDENTIAL
This is a Bluestone Center for Clinical Research 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 
Bluestone Center for Clinical Research.
PROTOCOL 
STUDY TITLE:
A phase 2, single-center, single-arm, open-label trial 
of vismodegib in patients with keratocystic 
odontogenic tumors
STUDY DRUG:
ERIVEDGE® (vismodegib)
SUPPORT PROVIDED BY:
Genentech, Inc.
SPONSOR-INVESTIGATOR:
Brian L. Schmidt, DDS, MD, PhD
Director, NYU Bluestone Center for Clinical 
Research
Professor, 
Department 
of 
Oral 
and 
Maxillofacial Surgery
421 First Avenue, Clinic 2W, 2nd Floor,
New York, New York 10010
Ph: (212) 998-9543; Fax: (212) 995-4843
IND NUMBER
126634 (Exempt IND)
STUDY NUMBER:
GENENTECH STUDY NUMBER:
15-00254
ML28859
PROTOCOL VERSION/DATE:
14 October 2016

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TABLE OF CONTENTS
1.
INTRODUCTION.............................................................................................................................................4
1.1
DISEASE BACKGROUND........................................................................................................................................4
1.2
RATIONALE FOR THE SELECTION OF VISMODEGIB ......................................................................................................4
1.3
CLINICAL EXPERIENCE, VISMODEGIB SAFETY AND EFFICACY.........................................................................................5
2.
STUDY OBJECTIVES......................................................................................................................................18
2.1
PRIMARY OBJECTIVES........................................................................................................................................18
2.2
SECONDARY OBJECTIVES ....................................................................................................................................19
3.
STUDY DESIGN ............................................................................................................................................19
3.1
DESCRIPTION OF THE STUDY ...............................................................................................................................19
3.2
STUDY PHASES.................................................................................................................................................20
3.3
SAFETY PLAN ...................................................................................................................................................20
3.4
COMPLIANCE WITH LAWS AND REGULATIONS.........................................................................................................20
4.
MATERIALS AND METHODS.........................................................................................................................21
4.1
SUBJECT SELECTION ..........................................................................................................................................21
4.2
STUDY TREATMENT...........................................................................................................................................23
4.3
CONCOMITANT AND EXCLUDED THERAPY..............................................................................................................26
4.4
STUDY ASSESSMENTS ........................................................................................................................................27
4.4.1
PHASE 1: SCREENING ....................................................................................................................................32
4.4.2
BASELINE VISIT.............................................................................................................................................33
4.4.3
PHASE 2: TREATMENT (1 YEAR) ......................................................................................................................35
4.4.4
PHASE 3: POST-TREATMENT (2 YEARS FOLLOW-UP): ..........................................................................................38
4.5
DISCONTINUATION OF PROTOCOL-SPECIFIED THERAPY.............................................................................................40
4.6
SUBJECT DISCONTINUATION ...............................................................................................................................40
4.7
STUDY DISCONTINUATION..................................................................................................................................41
4.8
STATISTICAL METHODS......................................................................................................................................41
4.9
DATA QUALITY ASSURANCE................................................................................................................................43
5.
REPORTING OF ADVERSE EVENTS................................................................................................................44
5.1
ASSESSMENT OF SAFETY.....................................................................................................................................44
5.2
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY VARIABLES..............................................................45
5.3
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE EVENTS..............................................................46
5.4
SAFETY REPORTING REQUIREMENTS FOR IND EXEMPT STUDIES.................................................................................50
5.5
STUDY CLOSE-OUT ...........................................................................................................................................50
6.
RETENTION OF RECORDS.............................................................................................................................51
7.
RESPONSIBILITIES........................................................................................................................................51
7.1 INVESTIGATOR RESPONSIBILITIES................................................................................................................................51
8.
CONFLICT OF INTEREST ...............................................................................................................................54
9.
PUBLICATION PLAN.....................................................................................................................................54
GENENTECH SUPPORTED RESEARCH.....................................................................................................62
Appendix A: Study Flowchart
Appendix B:  Definition of Women of Childbearing Potential and Acceptable and Unacceptable 
Forms of Contraception
Appendix C:  Gorlin Syndrome Diagnostic Criteria

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Appendix D:  NCI-CTCAE Grading System for Adverse Events Commonly Associated with 
Vismodegib Therapy
Appendix E:  Safety Reporting Fax Coversheet
Appendix F:  Material Safety Data Sheet (MSDS) 

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1.
INTRODUCTION 
1.1
Disease 
Background
The keratocystic odontogenic tumor (KCOT) is a benign odontogenic neoplasm that has 
destructive and infiltrative behavior [1]. KCOT can occur as part of nevoid basal cell 
carcinoma syndrome (NBCCS) or as a sporadic case. KCOTs are the most prominent 
feature of NBCCS and they are present in 65-100% of cases [2]. Four to five percent of 
KCOT patients have NBCCS [3]. Although KCOTs are benign, they tend to be aggressive, 
with local invasion of bony structures, extensive growth, and potential for substantial 
disfigurement  [4]. This condition has a high recurrence rate and it is estimated that after 
initial treatment with various procedures recurrence ranges from 2.5% to 62.5%[5];[6]. 
The only therapeutic option for patients affected by KCOT is surgery which can involve 
significant destruction of tissue; often multiple surgeries are required. Thus, the 
management of patients with KCOT has challenged and frustrated both patients and 
providers[6]. 
Research findings suggest that mutations in PTCH1 are frequent in both sporadic KCOT 
(29%) and NBCCS-associated KCOT (approximately 88%). Thus PTCH1 gene mutations 
may play a significant role in the pathogenesis of NBCCS and the related sporadic 
tumors  [7]. In this study, we plan to test GDC-0449 (Vismodegib) as novel treatment in 
two groups of patients: NBCCS-associated KCOT and sporadic KCOT cohort. The 
inclusion of this two-group cohort is based on the evidence that mutations of the 
hedgehog (Hh) pathway are present in both groups and consequently all patients 
affected by KCOT may benefit from a systemic Hh pathway antagonist. 
We hypothesize that an inhibitor of the sonic Hh can be an important therapeutic 
advancement in the treatment of KCOT. This study proposes to test GDC-0449 
(Vismodegib) for treating patients with KCOT. This drug has the potential to reverse 
KCOT proliferation. GDC-0449 may be useful as a neo-adjuvant prior to surgery in 
patients with KCOT or may be a surgery substitute in some cases. The use of GDC-
0449 prior to surgery may lead to tumor shrinkage and reduce the extent of required 
surgery or eliminate the need for surgery completely.
1.2
Rationale for the Selection of Vismodegib
GDC-0449 is a synthetic, small molecule inhibitor of the sonic Hh pathway, which is 
involved in tumorigenesis, thus providing a strong rationale for its use in the treatment of 
a variety of cancers. Phase I clinical trials in patients with advanced basal cell 
carcinoma (BCC) and medulloblastoma (MB) highlighted an objective response to GDC-
0449. Reported side effects were minor, with only one grade 4 adverse event. 
Phase II trials on GDC-0449 for the treatment of advanced BCC, metastatic colorectal 
cancer, ovarian cancer, MB and other solid tumors have recently been completed[8]. 
Because of its low toxicity and specificity for the Hh pathway, this drug has potential 

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advantages compared with conventional chemotherapy, and may also be used in 
combination treatments. 
On 30 January 2012, the U.S. Food and Drug Administration (FDA) approved 
ERIVEDGE® (vismodegib) capsules for the treatment of adults with metastatic basal 
cell carcinoma (mBCC), or with locally advanced basal cell carcinoma (laBCC) that has 
recurred following surgery or who are not candidates for surgery, and who are not 
candidates for radiation. On 12 July 2013, vismodegib was approved for the treatment 
of adult patients with symptomatic metastatic basal cell carcinoma and locally advanced 
basal cell carcinoma inappropriate for surgery or radiotherapy based on a conditional 
marketing authorization from the European Medicines Agency (EMA).
Recently it was reported that GDC-0449 was effective in treating recurrent KCOTs in a 
single patient [9]. The patient was a 55-year-old man with NBCCS. In addition to having 
multiple BCCs over a 25 year period the patient had three mandibular KCOTs that had 
been unsuccessfully treated with surgery, chemotherapy and radiation. The patient was 
started on daily oral GDC-0449 for control of his BCCs. In addition to having resolution 
of his BCCs at 12-week follow-up he had complete resolution of the three mandibular 
KCOTs, as documented by dental radiographs, after 2 years of GDC-0449 therapy.
The dose of Vismodegib chosen in this study is the same as the FDA-approved dosing 
for the treatment of adults with metastatic basal cell carcinoma since the expected 
activity of that drug dose and regimen against keratocystic odontogenic tumor is 
expected to be similar to basal cell carcinoma, and is consistent with doses under study 
in the above noted phase I and II studies of other types of cancers.
There is no prior clinical research experience using Vismodegib for the indication of 
KCOT.  Therefore, Vismodegib will be used according to the FDA approved dose of 150 
mg orally once daily.
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 (see 
the Vismodegib Investigator’s Brochure and the U.S. package insert for further details).

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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 BCC (mBCC) or 
locally advanced BCC (aBCC) to the drug [10]. Thirty-three patients with mBCC or 
locally aBCC 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%)
aBCC  advanced basal cell carcinoma.

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Table 2
SHH3925g Phase I Adverse Events in Patients with aBCC (n  33)
Grade 2
Grade 3
Grade 4
Clinical Event
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
NA
NA
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
aBCC  advanced basal cell carcinoma; NA  not applicable.
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 mBCC and those with locally aBCC 
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) [11]. 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 aBCC (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 (SAEs) were reported in 25% of 
patients. Seven deaths due to AEs were reported and none of the deaths were related 
to vismodegib.

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Based on the results of this pivotal trial, vismodegib was approved on 30 January, 2012 
by the US Food and Drug Administration (FDA) for the treatment of adults with mBCC, 
or with locally aBCC that has recurred following surgery or who are not candidates for 
surgery, and who are not candidates for radiation. [12].
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
Stable Disease
21 (64%)
15 (45%)
24 (38%)
15 (24%)
Progressive Disease
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
BCC  basal cell carcinoma; CI  confidence interval; DOR  duration of response; IRF  independent 
review facility; INV  investigator assessed; mos  months; ORR  overall response rate.

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Table 4: ERIVANCE Investigator Assessed Efficacy at the18-Month Update
Investigator Assessed
mBCC 
(n = 33)
locally aBCC 
(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 DOR, n (%)
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
BCC  basal cell carcinoma; CI  confidence interval; DOR  duration of response; laBCC  locally 
advanced BCC; mBCC  metastatic BCC; NA  not applicable; NE  not estimable; ORR  overall 
response rate; OS  overall survival; PFS  progression-free survival.

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Table 5: ERIVANCE  Safety Results at the 18-Month Update
Number (%) of Patients with Adverse Events
Metastatic 
BCC
(n = 33)
Locally 
Advanced BCC 
(n = 71)
All Patients with AEs
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%)
Adverse 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.
BCC - basal cell carcinoma
Table 6: Most Frequent Treatment Emergent Adverse Events (>10% of patients) at 
the 18-Month Update
NCI CTCAE Grade, (N = 104)
Number (%) of 
Patients with 
Adverse Event
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

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Number (%) of 
Patients with 
Adverse Event
NCI CTCAE Grade, (N = 104)
Total
1
2
3
4
5
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
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
NA  not applicable; NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse 
Events
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 aBCC or mBCC, 
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. 2012). The study has been completed following FDA approval and 
commercial availability of vismodegib.
Among 95 efficacy evaluable patients (56 patients with locally aBCC 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 locally aBCC (n = 56) and 30.8% (95% CI, 17.0%, 47.6%) for patients with mBCC 
(n = 39). CR, PR, and stable disease (SD) were observed in 10.7%, 35.7%, and 48.2%, 
respectively, of patients with locally aBCC; no patients in this cohort exhibited 
progressive disease (PD) as best response. For patients with mBCC, CR, PR, and SD 
rates observed were 5.1%, 25.6%, and 51.3%, respectively. In this cohort, 7.7% of 
patients exhibited PD as best response. Among patients with locally aBCC 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). 

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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 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
 
locally aBCC
(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)
aBCC  advanced basal cell carcinoma; CI  confidence interval; mBCC  metastatic basal cell carcinoma.

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Table 3
SHH4811g Vismodegib Expanded Access Study Common Treatment-
Emergent Adverse Events
NCI CTCAE Grade
TEAEs
(n  120)
Median Time 
to AE Onset, 
Days (95% CI)a
All AEs,
n (%)
1
n (%)
2
n (%)
3
n (%)
4
n (%)
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)
NA
NA
NA
Alopecia
87 (74-104)
69 (57.5)
57 (47.5)
12 (10.0)
NA
NA
NA
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)
–
–
–
AE  adverse event; NA  not applicable; NCI CTCAE  National Cancer Institute Common 
Terminology Criteria for Adverse Events; TEAE  treatment emergent adverse event.
a For those patients experiencing the TEAE
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 [13-15].  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.  AEs reported in   10% of patients are summarized in Table 9 See the 
Vismodegib Investigator’s Brochure and the U.S. package insert for additional details on 
nonclinical and clinical studies on vismodegib.

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Table 9: Phase II BCNS Study (SHH4685s) Adverse Events Reported in ≥10% of 
Patients
Number (%) of Patients 
with Grade 1 or 2 AEs
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
AE  adverse event; GI  gastrointestinal.
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 aBCC or 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 PD, unmanageable toxicities, or withdrawal from study (investigator/patient 
request) or termination by the Sponsor).
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 follow up 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 

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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 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.

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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. 
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 (95% CI: 28.0  80.0 days), 84.0 days (95% CI: 
27.0  120.0 days), and 60.0 days (95% CI: 55.0  86.0 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 PO in 
adult patients with medulloblastoma that was recurrent after or progressive while 
receiving standard (n=40) [16, 17]. 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.

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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)[18]. 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 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)[19]. The primary endpoint was improvement of PFS. The study failed 
to meet its primary endpoint of improved PFS vs. placebo (hazard ratio=0.79 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)[20]. 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 PO in patients 
with glioblastoma multiforme that was recurrent after or progressive while receiving 
standard treatment (n=40)  [21]. 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 

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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
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)[22]. The primary endpoint was improvement in PFS. The study failed 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)[23]. 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%)
2.
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives of the study are:
a. To evaluate the efficacy of GDC-0449 in reducing KCOT size (shrinkage) in 
NBCCS-associated KCOT and sporadic KCOT patients following 6 to 12 months 
of ingestion of 150 mg/day, up to 1 year of treatment and up to 2 years of post-
treatment follow-up.
b. To evaluate the safety of this dose of GDC-0449 in these patients. 
Tumor response (reduction in tumor volume and shrinkage) will be measured by 
volumetric CT scan.
Time Frame: Efficacy will be assessed at 1 year and 2 years after the study medication 
is stopped. Patients will undergo evaluation for 3 years (up to 1 year of treatment and 
up to 2 years of post-treatment follow-up). All patients will participate in the assessment 
of the safety and tolerability of the study drug. Safety monitoring will capture risks 
related to study participation and adverse events related to the study drug.

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2.2
Secondary Objectives
The secondary objectives of the study are:
a. To determine the time of response of a GDC-0449 anti-proliferative effect (i.e. 
tumor shrinkage) after administration of the drug up to one year or until treatment 
is stopped; 
b. To assay germ line PTCH1 mutations before treatment with GDC-0449 in 
patients with NBCCS-associated KCOT; 
If tumor removal is required, to assess tumor PTCH1 mutations before and after 
treatment with GDC-0449 in NBCCS-associated KCOT and sporadic KCOT in order to 
determine the correlation of tumor response and the presence of tumor PTCH1 
mutation.
3.
STUDY DESIGN
3.1
Description of the Study
This is a single-center, interventional, single-arm, open-label, two-cohort clinical trial. A 
total of 40 patients will be screened in order for 20 patients to be enrolled (10 with 
NBCCS-associated KCOT and 10 with sporadic KCOT) over a period of 2 years. This is 
a 3 year study where each patient will undergo up to 1 year of treatment and up to 2 
years of post-treatment follow-up. If a patient is experiencing an ongoing adverse event 
at the time of the study completion, he/she will be followed-up until resolution of the 
adverse event or until the condition has stabilized. The same applies to patients who 
are withdrawn from the study due to adverse events.
It is estimated that it will take approximately 2 years to recruit 20 patients for the study 
(10 with NBCCS-associated KCOT and 10 with sporadic KCOT). 
All patients will be assessed for safety and efficacy of the study drug GDC-0449 
(Vismodegib).

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3.2
Study Phases
There are 3 Phases in this study:
Phase 1/Screening
Baseline Visit 
Note: Study procedures and assessments during the baseline 
visit 
can 
be 
conducted 
over 
several 
visits 
until 
all 
inclusion/exclusion criteria are verified and patient is eligible to 
proceed with treatment (first study drug administration)
Phase 2/ Treatment (1 Year)
1 Month Visit (+/- 7 days from first study drug administration)
3 Month Visit (+/- 7 days)
6 Month Visit (+/- 7 days)
1 Year Visit - End of Treatment Phase (+/- 7 days)
Note: Visits for safety assessment will be conducted at 2, 4, 5, 
7, 8, 9, 10 and 11 months.
Phase 3/Post-Treatment (2 Year Follow-Up)                                                    
1 Month Visit (+/- 7 days from the end of the treatment phase)
1 Year Visit (+/- 7 days)
2 Year Visit - End of Follow-Up Phase
Note: Visits for safety assessment will be conducted at 2 and 3 
months
Study procedures and assessments for these visits are outlined in Section 4.5. A 
schedule of assessments is provided in Appendix A. 
3.3
Safety Plan
Patients will be evaluated at each study visit for the duration of their participation in the 
study (see Section 4.5 and Appendix A).
Specific potential safety issues for this trial are outlined below. 
Please refer to the Vismodegib Investigator’s Brochure for a detailed description of the 
safety profile of vismodegib.
See Section 5.1 for complete details of the safety evaluation for this study.
3.4
Compliance with Laws and Regulations
This study will be conducted in accordance with current U.S. FDA Good Clinical 
Practices (GCPs), and local ethical and legal requirements.

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4.
MATERIALS AND METHODS
4.1
Subject Selection
4.1.1 Inclusion Criteria
Patients are eligible to participate in the study if they meet the following criteria:
Males and females, 18 years of age and above at the time the informed consent 
form is signed;
Able to understand and sign the Informed Consent Form and other necessary 
paperwork prior to initiation of study procedures;
Able to communicate with the investigator/study site personnel, understand and 
comply with the study requirements, and willing to return for specified visits at the 
appointed time;
Patients who have received prior treatment for their KCOT and with a diagnosis 
of recurrent (maxillary or mandibular) sporadic KCOT or NBCCS-associated 
KCOT (single or multiple);
Diagnosis of KCOT will be done by past pathology report or by biopsy at the 
study site, if applicable;
Willingness to consent to biopsy of the lesion, if needed; 
Willingness to delay excision of the target tumor site, unless evidence of disease 
progression or lack of drug tolerability;
For female patients of childbearing potential, agreement to use two acceptable 
methods of birth control, including one barrier method during the study and 24 
months after discontinuation of study drug;
For males with female partners of childbearing potential, agreement to use a 
male condom (with spermicide) and to advise their female partners to use an 
acceptable method of birth control during the study and for 3 months after the 
discontinuation of the study drug;
Agreement not to donate blood/blood products during the study and for 24 
months after the discontinuation of the study drug;
For males not to donate sperm products or semen during treatment and for 3 
months after the discontinuation of the study drug;
Able and willing to swallow pill;

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No malabsorption syndrome or other condition that would interfere with enteral 
absorption;
At least 4 weeks since last chemotherapy, investigational therapy, radiotherapy 
or major surgical procedure and recovered from the first study drug 
administration;
KCOT measures at least 1 cm in one dimension on pretreatment volumetric CT 
scan;
No clinically significant abnormalities with clinical laboratory assessments;
4.1.2 Exclusion Criteria
Patients are excluded from participation if the following applies:
Concurrent anti-tumor therapy;
Completion of the most recent anti-tumor therapy (including Vismodegib) less 
than 4 weeks prior to the initiation of treatment (first study drug administration);
Uncontrolled medical illness;
Pregnancy or lactation; female patients who are planning to become pregnant for 
the duration of the study and 24 months post-treatment;
Inability or unwillingness to swallow capsules; 
Any medical or psychological illness or condition preventing adequate consent;
History of significant atherosclerotic disease, including the following:
o Coronary artery disease (i.e., myocardial infarction within the past year or 
unstable angina);
o Documented carotid atheroma;
Known HIV infection;
Current alcohol abuse;
History of resistance to vismodegib (patients who previous received vismodegib 
for BCC and had no clinical response will be excluded).

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4.1.3 Subject Recruitment and Screening
Clinicians and staff at the clinical study site will be made aware of the study and trained 
on the eligibility criteria, the enrollment procedures and study procedures. A study 
coordinator will be available at the site. All patients who arrive at the clinic should be 
considered potentially eligible. The study coordinator will review appointment schedules 
and information available at the time of the patient appointments to identify potential 
subjects and to rule out patients who do not fall into the defined study population. Either 
the clinician or the study coordinator will inform the potential subjects about the study 
and ask if they are interested in participating. Patients will be informed that their 
participation in the study, or not, will have no influence on their clinical management. If 
the patient expresses interest, then the clinician or study coordinator will assess the 
patient’s eligibility (screening for eligibility does not require any testing) and answer any 
questions the patient might have about the study. A signed consent form documenting 
informed consent for eligible subjects will be obtained prior to the start of any study 
procedures.  Advertisements such as flyer and web ad will be used in this study for 
recruitment of subjects.  Web ad will be posted on NYU Bluestone website. All 
advertisements will be approved by an Institutional Review Board prior to posting or 
dissemination.  A doctoral referral letter will be sent out via email and/or mail to oral and 
maxillofacial surgeons, asking for referral of eligible subjects who might be interested in 
the study.  A publically available directory will be used to obtain the contact information 
of the oral and maxillofacial surgeons.  A doctoral referral letter will be accompanied 
with the drug package insert, inclusion/exclusion criteria, and the study flyer.
4.2
Study Treatment 
This is a single-center, interventional, single-arm, phase II, open-label, two-cohort 
clinical trial. A total of 40 patients will be screened in order for 20 patients to be enrolled 
(10 with NBCCS-associated KCOT and 10 with sporadic KCOT) over a period of 2 
years. Only patients with a diagnosis of recurrent (maxillary or mandibular) sporadic 
KCOT or NBCCS-associated KCOT (single or multiple) will be recruited. All patients will 
receive 150 mg/day of GDC-0449 (Vismodegib) orally for 1 year.  All patients will be 
assessed for safety and efficacy of the study drug GDC-0449 (Vismodegib).
This is a 3 year study where each patient will undergo up to 1 year of treatment and up 
to 2 years of post-treatment follow-up.
The Sponsor Investigator of the study will ensure maintenance of complete and 
accurate records of the receipt, dispensation, and disposal or return of all Vismodegib in 
accordance with 21 Code of Federal Regulations (C.F.R.), Part 312.57 and 312.62 and 
Genentech requirements.
Vismodegib Dosage 

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The recommended dose of 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 v10, 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[24]. 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 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 [25, 26].  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 v10, 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 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 PO; 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: 

Page 25 of 63
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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. 
Vismodegib Packaging and Labeling 
Genentech, Inc., the manufacture of ERIVEDGE®, will label and package the study drug 
on behalf of the Sponsor Investigator for this clinical research study.  
Please refer to the Master Label Certification from Genentech, Inc. for detailed 
information about labeling and packaging for the study drug.
Preparation and Administration of Study Drug
Study drug will be supplied by Genentech, Inc in labeled 75cc HDPE bottle.  Each bottle 
will contain 32 hard capsules Vismodegib 150mg. The first dose of study drug will be 
given during a study visit and the subjects will be monitored for 6 hours after taking the 
drug for the first time. After the first administration, the study drug will be given to the 
study subjects to be taken at home.
Subject Compliance Monitoring
The study subjects will be given enough study drugs to last until the next visit. 
Dispensing records will document quantities received and quantities dispensed, lot 
number (if applicable), date dispensed, patient identifier number, and initials of the 
person dispensing the study drugs.  Subjects will bring back the study drug bottle with 
any unused study drug at each study visits to monitor their compliance.
Drug Accountability
Receipt of Drug Supplies
Upon receipt of the of the study treatment supplies, an inventory must be performed and 
a drug receipt log filled out and signed by the person accepting the shipment.  It is 
important that the designated study staff counts and verifies that the shipment contains 
all the items noted in the shipment inventory.  Any damaged or unusable study drug in a 
given shipment (active drug or comparator) will be documented in the study files.  The 
investigator must notify study sponsor of any damaged or unusable study treatments 
that were supplied to the investigator’s site.
Storage

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The boxes containing the study drug will be stored at room temperature under secured 
conditions with limited access. The study drug will be stored in room #236 in Bluestone 
Center for Clinical Research.  Room #236 is a limited card swipe access secure room 
with approximately 50 square feet of space and approximately 15 linear feet of 
countertop space for processing medication orders. Room #236 contains two security 
cameras which are under 24 hour surveillance by NYU College of Dentistry’s security 
team.
Dispensing of Study Drug
Regular study drug reconciliation will be performed to document drug assigned, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, and signed and dated by the study team.
Return or Destruction of Study Drug
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug 
reconciliation form, signed and dated.  Any discrepancies noted will be investigated, 
resolved, and documented prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files.
4.3
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 ofAEs 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 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 

Page 27 of 63
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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.
4.4
Study Assessments
Study assessments and procedures for efficacy and safety are detailed in Appendix A.  
Patients’ screening information will be recorded on the Screening and Enrollment Log. 
Clinical Laboratories and Vital Signs
Safety evaluations include clinical laboratory assessments as set forth in the Schedule 
of Study Assessments and Procedures in Appendix A. Safety and tolerability will be 
measured by adverse events, physical examination, complete blood count, vital signs, 
and oral cavity assessments.  Details of laboratory procedures are provided in the 
laboratory manual for the study. 
Samples of blood will be taken on selected visits (see Appendix A). 20 mL (inclusive) of 
blood will be obtained by venipuncture on each required visit. Approximately 100 mL of 
blood will be drawn over the course of the study (Screening through the completion of 
the Treatment Phase) for clinical laboratory assessments. Patients consenting to have a 
blood sample drawn for future DNA analysis will have an additional 7-10 mL of blood 
drawn at the baseline visit. Analysis of all clinical blood samples will be made at a 
central clinical laboratory. The investigator and clinical monitor will be provided with a 
list of the normal ranges used by the testing laboratory for all variables assayed during 
the study and a statement of accreditation (or similar) for the laboratory.
Complete blood count, serum pregnancy test, serum chemistry, coagulation time, and 
liver function will be assessed and include the following measures: white blood count, 
hemoglobin, platelets, glucose, uric acid, calcium, phosphorus, sodium, potassium, 
chloride, alkaline phosphatase, albumin, alanine transaminase (ALT), aspartate 
transaminase (AST), BUN and creatinine.
Female patients of childbearing potential will have a urine pregnancy test. A pregnancy 
test will be performed by the study center by use of a dipstick. All laboratory results will 
be reviewed and the reports signed by an investigator. 

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Any results considered to be of clinical significance must be dealt with and followed up 
as clinically appropriate. All laboratory results considered to represent an adverse event 
(AE) must be documented in the case report form (CRF). Repeat samples will be taken 
if required for clinical follow up or because the sample is lost or damaged. Any abnormal 
end of treatment clinical laboratory result of clinical significance must be repeated at 
regular intervals until it returns to normal, or until an investigator is satisfied that the 
abnormality is not related to the drug and needs no further investigation. 
Vital signs (blood pressure, heart rate and temperature) will be obtained for safety 
monitoring.
Optional Blood Sample for Future Genetic Testing
If a subject agrees to provide a blood sample for future genetic testing, an additional 
blood sample will be collected at Baseline and also at one year visit if subject has new 
tumor.  Human DNA will be extracted from the blood and stored at the Bluestone Center 
for Clinical Research for up to 10 years to be used for DNA sequencing as part of a 
future study related to KCOT. PCR amplification of exons encoding the open reading 
frame of genes associated with KCOT will be carried out using nested primers prior to 
sequencing PCR products in both the sense and antisense directions.  Identified 
mutations will be confirmed by an independent PCR and sequencing reaction.  The 
genetic testing will not include tests that can identify patients’ risks for other conditions. 
Only users authorized by the Bluestone Center for Clinical Research and Genentech 
would have access to the samples. The stored samples will be labeled with the subject 
code, diagnosis and/or location of the sample. The linking key between subject code 
and subject identity will be maintained by the PI.  The subject may withdraw their 
samples from storage and future use by providing a written request to the PI.
Oral Cavity Assessment, Head & Neck, & Physical Exam
At the scheduled time points, according to the Schedule of Study Assessments and 
Procedures in Appendix A, study personnel will perform a comprehensive oral exam 
consisting of an evaluation of oral hard and soft tissue structures for each patient. Oral 
hard tissue assessments will be performed with a dental mirror on the teeth and bony 
structures.  Oral soft tissues will be performed by examining each patient’s mouth and 
pharynx, including lips, tongue, floor of the mouth, palate, gingiva, alveolar mucosa, 
buccal mucosa, oropharynx, tonsils, uvula, and salivary glands using palpation 
techniques and visualization.  
A complete extraoral physical exam of the head and neck regions will also be noted by 
visualization and bi-manual palpation. This assessment will be performed during the 
baseline visit and the treatment and post-treatment phase of the study. 
In addition to the oral hard tissue assessments, extraoral and head and neck 
examinations, a complete physical exam will be done during the baseline and treatment 

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phase of the study. This exam will include the examination of the cardiovascular, 
pulmonary, abdomen and nervous system.
Dermatologic Assessments
A thorough skin examination will be performed by a study investigator for NBCCS-
associated KCOT patients at different time points (see Appendix A for more details). 
The purpose of this exam will be to identify any suspicious lesions. Patients with 
suspicious findings will be referred to a dermatologist as per standard of care. 
Photographs of the lesions will be taken and all findings will be recorded on the relevant 
CRF. Follow-up visits with a dermatologist will be conducted for patients with suspicious 
lesions as per standard of care. All findings by a dermatologist will be kept with the 
study records.
Any abnormal findings will be documented.  Any abnormalities noted at the Baseline 
visit, may be reason to exclude a patient from the study.  At the time of the first study 
drug administration or post-dose, should an adverse event be reported, the investigator 
will determine which safety assessments should be performed.  All findings will be 
recorded on the respective CRF.  
Any clinically significant signs or symptoms that are present at, or during the Baseline 
visit, and that worsen during or after study drug administration, will be recorded as 
adverse events on the adverse event CRF. Non-significant clinical abnormalities will 
also be recorded on the relevant CRF.
Photography
When applicable, any suspicious lesions which are discovered during the skin 
examination will be photographed and filed in the patient’s study chart. Photographs will 
only contain images of the suspicious lesion. The patient’s face will not be visible in the 
photograph.
Panoramic Radiograph and Volumetric CT Scan
Tumor volume will be measured at baseline, and tumor response (reduction in tumor 
volume and recurrence) will be measured during the treatment phase and post-
treatment phase by Panoramic Radiograph and Volumetric CT scan. The use of 
Panoramic Radiograph and Volumetric CT scan to measure the tumor volume are 
obtained for clinical assessment purposes only. No additional scans will be performed 
for research purposes. Disease progression during the treatment phase will be 
classified by an increase of at least 20%, with an absolute change greater than 5 mm in 
tumor size after 3 months of treatment.  KCOTs grow within the bone.  CT scan and 
panoramic radiograph are superior, with regard to sensitivity and specificity, in terms of 
evaluating bone involvement.  
Biopsy and Analysis of the Tumor

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If the patient had a previous biopsy performed, a tissue slide will be obtained for study 
purposes and confirmation of KCOT diagnosis.  If clinically indicated, an additional 
biopsy of the tumor will be done and if the patient agrees, the leftover tissue from the 
tumor biopsy will be stored for future genetic analysis related to KCOT. The storing of 
tumor for future genetic analysis is optional and will be stored for 10 years.  These 
additional biopsies will be flash-frozen in liquid nitrogen (LN2) and stored in LN2 at the 
Bluestone Center for Clinical Research. 
The future genetic testing will not include tests that can identify patients’ risks for other 
conditions. Only users authorized by the Bluestone Center for Clinical Research and 
Genentech would have access to the samples. The stored samples will be labeled with 
the subject code, diagnosis and/or location of the sample. The linking key between 
subject code and subject identity will be maintained by the PI.  The subject may 
withdraw their samples from storage and future use by providing a written request to the 
PI.
Assessment of Gene Mutations and Gene Expression in Tumor Specimens: The 
additional fresh-frozen tumor specimens will be subjected to gene mutation and gene 
expression analysis. If no additional fresh-frozen specimen is obtained, the initial biopsy 
samples, which are formalin-fixed, paraffin-embedded (FFPE), will be used instead. 
FFPE tissue scraped from serially cut slides will be deparaffinized using Envirene 
reagent (Hardy Diagnostics, Santa Maria, CA, USA) before isolation of RNA using the 
Roche High Pure FFPE RNA Micro Kit (Roche Diagnostics, Indianapolis, IN). RNA will 
be extracted from fresh-frozen tissue using the High Pure RNA Tissue Kit (Roche 
Diagnostics, Indianapolis, IN). RNA will be reversed transcribed using the High-Capacity 
cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA) with 
random primers. PCR will be carried out using the Taqman Universal PCR Master Mix 
(Applied Biosystems), with the following cycling conditions: 50°C for 2 min; 95°C for 10 
min; 40 cycles of 95°C for 15 s, 60°C for 1 min. qRT-PCR profiling of genes associated 
with KCOT will be performed For analyses, gene expression from the genes of interest 
will be normalized to the average cycling threshold (Ct) of three housekeeping genes 
(GUSB, SDHA, and  UBC).
For gene mutation analysis, DNA will be extracted from the fresh-frozen or formalin-
fixed paraffin-embedded (FFPE) tissue sections. PCR amplification of exons encoding 
the open reading frame of genes associated with KCOT will be carried out using nested 
primers prior to sequencing PCR products in both the sense and antisense directions.  
Identified mutations will be confirmed by an independent PCR and sequencing reaction. 
Potential Risks to Participants 
Information on potential risks to patients participating in this study is as follows:
•
Oral Examinations/Head and Neck Examination:  

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The oral examination will involve procedures that are routinely performed in dental 
practice.  A licensed dentist/hygienist will perform the procedures. The risks from the 
oral examination include minor discomfort or minor pain during the procedures.
•
Biological Sample Collection:  
Urine (if female of child bearing potential) will be collected. This collection processes 
minimal risk to the patient.  
•
Blood Sampling Collection:
Peripheral blood sampling will be performed by a trained phlebotomist, nurse, dentist or 
physician utilizing standard venipuncture techniques.  
Patients may have some 
discomfort and/or bruising at the site of needle entry.  There is a very small risk of 
fainting.  Infection in the area of the needle insertion is rare.  Preventive measures will 
be used during sample collection to reduce the risk of these rare side effects.
•
GDC-0449 Administration: 
Vismodegib is a previously studied drug. Our knowledge of adverse events related to 
vismodegib results from clinical trials. Adverse reactions and the associated incidence 
related to vismodegib are documented. Participants will be closely monitored for 
previously-reported and unrecognized adverse events. Tumor growth in participants on 
the drug is possible; however, participants will be monitored with both clinical and 
radiographic examination to identify such growth. Participants on vismodegib might 
avoid surgery and the morbidity (i.e., loss of bone and teeth) associated with surgery.
GDC-0449 (Vismodegib) capsule is a Hh pathway inhibitor indicated 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 radiation. 
The most common adverse reactions (incidence ≥ 10%) are muscle spasms, alopecia, 
dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, 
arthralgias, vomiting and ageusia. In clinical trials, a total of 3 of 10 pre-menopausal 
women developed amenorrhea while receiving GDC-0449. Treatment-emergent Grade 
3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients 
(4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%).
The safety and efficacy of vismodegib in pediatric patients has not been established. 
Studies in animals indicate that oral Hh pathway inhibitors pose a substantial risk of 
developmental defects during the post-natal period, which includes irreversible effects 
on growing teeth or bones and male reproductive organs. The occurrence of premature 
epiphyseal fusion has been identified on routine pharmacovigilance through literature 
review and from serious adverse events (SAEs) reported in an Investigator Sponsored 
Trial (IST) of pediatric patients receiving vismodegib therapy. In some cases, fusion 
progressed after drug discontinuation.
In this study, the safety and efficacy of oral GDC-0449 in the management of NBCCS-
associated KCOT and sporadic KCOT will be examined. The recommended dose is 
150mg taken orally once daily until disease progression or until unacceptable toxicity. 
The capsule has a pink opaque body and a grey opaque cap with “150 mg” printed on 
the capsule body and “Vismo” printed on the capsule cap in black ink. It can be taken 

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14 Oct 2016
with or without food and capsules should not be opened or crushed. If patients miss a 
dose, they will be advised not to make up that dose but instead to resume dosing with 
the next scheduled dose. 
Pregnancy status prior to the initiation of GDC-0449 will be verified with a serum 
pregnancy test. Male and female patients will be advised of the risks of embryo-fetal 
death and severe birth defects and the need for contraception during and after 
treatment.
In addition, patients must agree not to donate blood or blood products during the study 
and for 24 months after discontinuation of vismodegib.
If a patient experiences unacceptable drug toxicity, he/she will be allowed a treatment 
break lasting for at least one month, up to three months. If the patient is unable to 
resume treatment after an 3 month treatment break, he/she will be discontinued from 
the study.
A potential risk of treatment of KCOT with vismodegib is disease progression, i.e. tumor 
growth. Participants will be closely monitored with clinical and radiographic examination 
for evidence of disease progression. The natural history of KCOTs is that the tumors 
grow and expand slowly relative to the proposed examination schedule. Therefore, it is 
highly unlikely that unanticipated growth in participants on vismodegib would be 
encountered.
The potential benefit of treatment of KCOT with vismodegib is decreased tumor 
recurrence and reduced surgical morbidity. Currently the management of KCOT is 
surgical. The surgical options include:  1. resection, 2. enucleation with or without 
treatment of the bony cavity using tissue fixatives or liquid nitrogen, or 3. surgical 
decompression. The morbidity of surgical resection and enucleation involves the loss of 
bone and teeth. In some cases the sensory nerve in the proximity of the tumor is 
removed leaving the patient with paresthetia or anesthesia in the distribution of the face 
or tongue. Replacement of bone and teeth is extremely difficult and in many cases not 
possible. Decompression involves placement of a drain into the tumor cavity followed by 
irrigation of the bony cavity three times a day for 12 to 24 months. Often after this 
treatment eventual removal of the tumor is required. A potential benefit for participants 
treated with vismodegib is that they might avoid the morbidity associated with the 
above-described surgery. 
4.4.1 Phase 1: Screening  
Potential patients (10 with NBCCS-associated KCOT and 10 with sporadic KCOT, 
males and females, ≥18 years) will be recruited from the Department of Oral and 
Maxillofacial Surgery at NYU College of Dentistry, NYU Langone Medical Center and 
Bellevue Hospital, as all these institutions represent major referral sources for head and 
neck pathology. Patients will also be recruited from other private and academic oral and 
maxillofacial surgery practices both in the New York area and other parts of the country 

Page 33 of 63
14 Oct 2016
by referral.  Investigator will present this study during society meetings so that other 
surgeons can refer KCOT patients to this study. 
Before a patient’s participation in the study, the investigator will be responsible for 
obtaining written ICF from the patient, after adequate explanation of the aims, methods, 
anticipated benefits and potential risks of the study and before any protocol specific 
screening procedure is performed or the study drug is administered. The patient will be 
given ample time to consider the information provided and ask questions before giving 
written consent.
The acquisition of informed consent will be thoroughly documented in the patient’s chart 
and the informed consent form with be personally signed and dated by both the patient 
and the person who conducted the informed consent discussion. A patient will be 
considered enrolled in the study, once the informed consent form is signed. The original 
informed consent will be retained and a copy will be provided to the patient. The same 
process will be followed for the consenting for optional future genetic testing on blood 
and on the tumor. 
4.4.2 Baseline Visit
The following procedures will be performed at Baseline visit (study procedures and 
assessments during the baseline visit can be conducted over several visits until all 
inclusion/exclusion criteria are verified and patient is eligible to proceed with treatment 
(first study drug administration).
After obtaining written Informed Consent for a potential subject, a unique Screening 
number will be assigned and the following evaluations will be performed to screen for 
eligibility:  

Informed Consent and Screening

Review of Inclusion/Exclusion Criteria

Review of Medical Records, if applicable

Medical/Dental History 

Concomitant Medications
o
All 
prescription, 
non-prescription 
medicines, 
vitamins 
and 
herbal 
supplements will be recorded at the baseline visit in the concomitant 
medication CRF. Throughout the study, any changes in concomitant 
medication must be recorded by the investigator.

Demographics (including height and weight)
o
In addition to the height and weight, the following information will be 
collected: date of birth, gender and race.

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14 Oct 2016

Serum Pregnancy Test (if female patient of child bearing potential):
o
Female patients of reproductive potential are required to use two forms of 
acceptable contraception during therapy and for 24 months after completing 
therapy. See appendix B for definition of reproductive potential and 
acceptable contraception. Male patients must use condoms at all times, 
even after a vasectomy, during sexual intercourse with female partners of 
reproductive potential during treatment with vismodegib and for 2 months 
after the last dose to avoid exposing a pregnant partner and unborn fetus to 
vismodegib.
o
If 7 days have passed between the patient’s enrollment in the study (date 
the ICF was signed) and the first study drug administration, the serum 
pregnancy test will be repeated.

Oral Cavity Assessment (soft & hard tissues, extraoral, head & neck)

Physical Exam 

Clinical Laboratories
o
Complete blood count, serum pregnancy test, serum chemistry, coagulation 
time, and liver function will be assessed: white blood count, hemoglobin, 
platelets, glucose, uric acid, calcium, phosphorus, sodium, potassium, 
chloride, alkaline phosphatase, albumin, alanine transaminase (ALT), 
aspartate transaminase (AST), BUN and creatinine
o
All laboratory results will be reviewed and the reports will be signed by the 
investigator. Any results considered to be of clinical significance must be 
dealt with and followed up as clinically appropriate. All laboratory results 
considered to represent an AE must be documented in the CRF. Repeat 
samples will be taken if required for clinical follow up or because the sample 
is lost or damaged. Any abnormal end of treatment clinical laboratory result 
of clinical significance must be repeated at regular intervals until it returns to 
normal, or until the investigator is satisfied that the abnormality is not 
related to the study drug and needs no further investigation.

Genetic Testing of blood for PTCH1 mutation

Genetic Testing of the tumor (if biopsy on excision is required for PTCH1 mutation)

Vital Signs (blood pressure, heart rate, temperature)

Verification of KCOT Diagnosis
o
If a patient had an outside biopsy, then a copy of the pathology report and 
slides confirming the KCOT diagnosis will be obtained. For patients with 
multiple KCOTs associated with NBCCS, the pathology report and slides 
associated with each of the lesions will be obtained. If a patient has a lesion 
that is suspicious for KCOT, but no biopsy, then a biopsy will be performed 
as a standard of care. If a patient has multiple KCOTs associated with 

Page 35 of 63
14 Oct 2016
NBCCS but there is no biopsy of any of the lesions, then a biopsy will be 
performed on selected lesions.
o
The investigator will review the patient’s medical records to confirm that the 
patient was treated with the standard of care and that the KCOT is 
recurrent.

Biopsy of the Tumor, if applicable

Panoramic Radiograph

Volumetric CT Scan
o
Once the diagnosis of recurrent KCOT is confirmed a baseline volumetric 
CT scan will be obtained. The baseline CT will include the jaws and the 
brain. Patients must have at least one lesion measuring at least 1 cm in 
dimension to be enrolled.

Skin Examination (for  NBCCS-associated KCOT patients)
o
The entire skin will be examined and basal cell carcinomas, if present, will 
be mapped by location and size

Photographs of Skin Lesions, if applicable

Study Drug Administration – First Dose
o
Once the baseline visit assessments are complete and eligibility is 
confirmed, all patients will receive the same treatment (150 mg/day of 
GDC-0449 orally for 1 year). After the first study drug administration, 
patients will be observed and monitored by the investigator for 6 hours. 
Patients will maintain the medication regimen until they are required to 
discontinue the study drug due to disease progression, or unacceptable 
toxicity, as assessed by the investigator.

Study Drug Dispense until next visit

Adverse Events
Upon discharge from the clinic, specific instructions will be given to patients regarding 
the use of the medication, as well as adequate study drug supplies until their next visit. 
Patients will be instructed the following:
o
Not to donate blood or blood products while receiving GDC-0449 and for 
at least 24 months after the last dose of the study drug.
o
Not to get pregnant during the study and for 24 months after the last dose 
of the drug (see more details in Appendix 2)
o
To take 150 mg of GDC-0449 orally once daily with or without food and to 
swallow capsules whole. Capsules should not be opened or crushed.

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14 Oct 2016
o
If a dose is missed, not to make up that dose but to resume dosing with 
the next scheduled dose.
o
To notify the investigator immediately if they notice any changes with their 
health status or if they become pregnant.
4.4.3 Phase 2: Treatment (1 Year)
1 Month, 3 Month, 6 Month and 1 Year Visit (+/- 7 Day Window)

Continuance Criteria: patients will be released from study participation for the 
following reasons: 
o
non-compliance with study procedures
o
development of a medical condition or taking a medication which would 
affect the study outcome, as covered in the exclusion criteria 
o
disease progression or unacceptable toxicity of study drug, as assessed 
by the investigator
o
pregnancy
o
withdrawal of patient consent
o
protocol violation
o
lost to follow-up
 

Review of Medical Records, if applicable

Medical/Dental History update

Concomitant Medications update

Urine Pregnancy Test (if female of child bearing potential)

Oral Cavity Assessment (soft & hard tissues, extraoral, head & neck)

Physical Exam 

Clinical Laboratories (at 3 month, 6 month and 1 year visit)

Genetic Testing for Blood (at 1 year visit)

Genetic Testing for the Tumor (at 1 year visit)

Vital Signs (blood pressure, heart rate, temperature)

Panoramic Radiograph

Volumetric CT Scan (at 6 month and 1 year visit)

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14 Oct 2016

Skin Examination for NBCCS-associated KCOT patients at 6 month and 1 year 
visit

Photographs of Skin Lesions, if applicable

Compliance with Study Drug
o
Compliance with study drug will be checked by counting the capsules that 
were returned to the site versus the capsules that were administered to 
patient at the end of the last visit. Any discrepancy will be documented in 
the patient’s chart and in the drug accountability log. Study reminders 
regarding compliance will be reviewed with the patient in order to 
maximize the proper use of the study drug.

Study Drug Dispense until next visit

Adverse Events
Upon discharge from the clinic, specific instructions will be given to patients regarding 
the use of the medication, as well as adequate study drug supplies until their next visit. 
Patients will be instructed the following:
o
Not to donate blood or blood products while receiving GDC-0449 and for 
at least 24 months after the last dose of the study drug.
o
Not to get pregnant during the study and for 24 months after the last dose 
of the drug (see more details in Appendix B)
o
To take 150 mg of GDC-0449 orally once daily with or without food and to 
swallow capsules whole. Capsules should not be opened or crushed.
o
If a dose is missed, not to make up that dose but to resume dosing with 
the next scheduled dose.
o
To notify the investigator immediately if they notice any changes with their 
health status or if they become pregnant.
2 Month, 4 Month, 5 Month, 7 Month, 8 Month, 9 Month, 10 Month and 11 Month Visit 
(+/- 7 Day Window)

Continuance Criteria: patients will be released from study participation for the 
following reasons: 
o
non-compliance with study procedures
o
development of a medical condition or taking a medication which would 
affect the study outcome, as covered in the exclusion criteria 
o
disease progression or unacceptable toxicity of study drug, as assessed 
by the investigator
o
pregnancy
o
withdrawal of patient consent
o
protocol violation
o
lost to follow-up

Page 38 of 63
14 Oct 2016
 

Review of Medical Records, if applicable

Medical/Dental History update

Concomitant Medications update

Urine Pregnancy Test (if female of child bearing potential)

Compliance with Study Drug
o
Compliance with study drug will be checked by counting the capsules that 
were returned to the site versus the capsules that were administered to 
patient at the end of the last visit. Any discrepancy will be documented in 
the patient’s chart and in the drug accountability log. Study reminders 
regarding compliance will be reviewed with the patient in order to 
maximize the proper use of the study drug.

Study Drug Dispense until next visit

Adverse Events
Upon discharge from the clinic, specific instructions will be given to patients regarding 
the use of the medication, as well as adequate study drug supplies until their next visit. 
Patients will be instructed the following:
o
Not to donate blood or blood products while receiving GDC-0449 and for 
at least 24 months after the last dose of the study drug.
o
Not to get pregnant during the study and for 24 months after the last dose 
of the drug (see more details in Appendix B’)
o
To take 150 mg of GDC-0449 orally once daily with or without food and to 
swallow capsules whole. Capsules should not be opened or crushed.
o
If a dose is missed, not to make up that dose but to resume dosing with 
the next scheduled dose.
o
To notify the investigator immediately if they notice any changes with their 
health status or if they become pregnant.
4.4.4 Phase 3: Post-Treatment (2 Years Follow-up):   
7 Month, 1 Year and 2 Years Post-Treatment Visits (+/- 7 Day Window)

Continuance Criteria: patients will be released from study participation for the 
following reasons: 
o
non-compliance with study procedures
o
development of a medical condition or taking a medication which would 
affect the study outcome, as covered in the exclusion criteria 

Page 39 of 63
14 Oct 2016
o
disease progression or unacceptable toxicity of study drug, as assessed 
by the investigator
o
pregnancy
o
withdrawal of patient consent
o
protocol violation
o
lost to follow-up

Review of Medical Records, if applicable

Medical/Dental History update

Concomitant Medications update

Urine Pregnancy Test (if female patient of child bearing potential)

Oral Cavity Assessment (soft & hard tissues, extraoral, head & neck)

Vital Signs (blood pressure, heart rate, temperature)

Panoramic Radiograph

Volumetric CT Scan (at 1 year and 2 year post-treatment visit)

Skin Examination for NBCCS-associated KCOT patients at 1 year post-treatment 
visit

Photographs of Skin Lesions, if applicable

Adverse Events

Study Completion/Discharge (at 2 year post-treatment visit)
During the 2 year post treatment phase and visits, patients will be reminded of the 
following:

Not to donate blood or blood products while receiving GDC-0449 and for at least 
24 months after the last dose of the study drug.

Not to get pregnant during the study and for 24 months after the last dose of the 
drug (see more details in Appendix B)

To notify the investigator immediately if they notice any changes with their health 
status or if they become pregnant
Should a patient decide to withdraw from the study or is discontinued by the investigator 
(see continuance criteria in phase 1 and 2), all efforts will be made to complete the 
discontinuation visit procedures and assessments (see Appendix A). 

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1 Month, 2 Month and 3 Month Post-Treatment Visits (+/- 7 Day Window)

Continuance Criteria: patients will be released from study participation for the 
following reasons: 
o
non-compliance with study procedures
o
development of a medical condition or taking a medication which would 
affect the study outcome, as covered in the exclusion criteria 
o
disease progression or unacceptable toxicity of study drug, as assessed 
by the investigator
o
pregnancy
o
withdrawal of patient consent
o
protocol violation
o
lost to follow-up
 

Review of Medical Records, if applicable

Medical/Dental History update

Concomitant Medications update

Urine Pregnancy Test (if female of child bearing potential)

Adverse Events
4.5
Discontinuation of Protocol-Specified Therapy
No dose reductions will be allowed in this study. Treatment with vismodegib may 
only be interrupted for up to:

Two consecutive weeks if a patient becomes temporarily unable to 
swallow capsules

Two consecutive weeks in case of an intolerable toxicity finding
A total up to eight weeks of dose interruptions (e.g., 4 x 2-week interruptions, 8 x 
1-week interruptions, etc.) is allowed during the Treatment Phase. 
Protocol-specified therapy may be discontinued for any of the following reasons:

Progressive disease (PD)

Unacceptable toxicity

Patient election to discontinue therapy (for any reason)

Physician’s judgment

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4.6
Subject Discontinuation
Study subjects may be discontinued from the study for any of the following reasons: 
o
non-compliance with study procedures
o
development of a medical condition or taking a medication which would 
affect the study outcome, as covered in the exclusion criteria 
o
disease progression or unacceptable toxicity of study drug, as assessed 
by the investigator
o
pregnancy
o
withdrawal of patient consent
o
protocol violation
o
lost to follow-up
Should a patient decide to withdraw from the study or is discontinued by the 
investigator, all efforts will be made to complete the discontinuation visit procedures and 
assessments (see Appendix A). 
In the event that a subject becomes pregnant during the study, the subject will be 
withdrawn from the study immediately upon confirmation of pregnancy. These subjects 
will be required to return to the study site to undergo discontinuation visit assessments. 
In addition, any documented pregnancy will be tracked and followed through outcome. 
4.7
Study Discontinuation
The Genentech Study Center and the Principal Investigator have 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

Data recording are inaccurate or incomplete

Study protocol not followed
Both the investigator and Genentech, Inc. reserve the right to terminate the study at any 
time.  Should this be necessary, both parties will arrange discontinuation procedures.  In 
terminating the study, both the investigator and Genentech, Inc. will assure that 
adequate consideration is given to the protection of the patients’ interests.  All patients 
will undergo an exit examination if the study is terminated prematurely.
Patient’s medical information obtained as a result of this study is considered confidential 
and disclosure to third parties other than those noted below is prohibited.  Patients will 
receive written copies of all laboratory data, and radiographs to bring to their health care 
provider.  All reports and communications relating to patients in this study will identify 
each patient only by their initials and number.  Medical information resulting from a 
patient’s participation in this study may be given to the patient’s personal physician or to 

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the appropriate medical personnel responsible for the patient’s welfare.  Data generated 
as a result of this study are to be available for inspection on request by FDA or other 
government regulatory agency auditors, Genentech’s medical monitor (or designee), 
and the Institutional Review Board (IRB).
4.8
Statistical Methods
a. Analysis of the Conduct of the Study
Accrual rates and sampling bias will be determined by computing the recruitment rate 
from among those identified as eligible.
Retention and compliance will be evaluated as the proportion of completers at the four 
primary time points: after 6 and up to 12 months of treatment, and then 1 and 2 years 
after treatment. We will detail and tabulate reasons for loss to follow-up and relate 
retention to baseline age, KCOT severity and between NBCSS-associated and 
sporadic cohorts. 
b. Efficacy Analysis
i.
Primary Endpoint
The effect of GDC-0449 will be evaluated (at a significance level of 5% and controlling 
the false discovery rate) using Wilcoxon signed rank tests to compare the mean KCOT 
volume at baseline to those acquired at 6, 12, 24,36 and 48 months. These 
comparisons will also be accomplished using paired t-tests. 
ii. Subject population for this analysis. As a primary intention to treat (ITT) analysis, we 
will analyze data from all randomized subjects who complete Phase 1.  For these 
analyses, Phase 1 values will be substituted for missing observations. Should more 
than 20% of the data be missing at any observation interval, analysis of that interval will 
be abandoned. Deviations from this plan, for example, emergent interest in the analysis 
of the all-treated or protocol-compliant subjects, will be transparently pursued and 
reported. 
iii. Treatment of missing data. Two secondary effectiveness analyses will either carry 
the last observation forward into missing cells, or use maximum likelihood estimates of 
those values. We expect the best estimate of efficacy is likely to lie within the limits set 
by these conservative (ITT) and liberal (LOCF, ML) treatments of missing data.
iv. Secondary Endpoints
Secondary analysis will quantify the proportion of patients achieving minimal clinically 
significant changes in their tumors and comparing that to a theoretical expectation of 
5% improvement with a Fisher exact test, and the effect of the PTCH1 mutation on 
tumor volume reduction will be assessed with an independent samples t-test. These 
analyses will use the same population as the primary endpoint.
All analyses will be done using IBM SPSS Version 21.

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v. Sample size determination. Twenty subjects will be recruited. Analysis of the primary 
endpoint is capable of detecting changes in tumor volume in the Wilcoxon tests of 
approximately 1.0 and .68 SD, assuming a 2-tailed type 1 error of 5% and power of 80% 
and then assuming either n=10 (separate analysis of the NBCSS-associated and 
sporadic cohorts) or n=20 (combined analysis of both cohorts), respectively (G*Power, 
v3.1).
c. Safety Analysis
All safety-related interventions, events, and findings will be summarized by incidence 
and duration and event classification. An adverse event will be considered treatment 
emergent if the onset date and time occur on or after the recorded clock time of the 
administration of study drug. Adverse events will be coded to preferred terms and 
system organ classes according to the Medical Dictionary for Regulatory Activities 
(MedDRA®). The severity of each adverse event will be determined from the World 
Health Organization (WHO) Toxicity Criteria or by protocol specified criteria. In addition, 
all adverse events will be assessed as to whether the onset of the event was related to 
the study drug or not and they will be followed to final resolution. Other safety 
assessments include vital signs, oral cavity examinations, and complete blood count. In 
the unlikely event that treatment is associated with increasing tumor size, tumor area, 
determined from panoramic radiographs acquired at each visit, will be compared to 
baseline.
4.9
Data Quality Assurance
Accurate, consistent, and reliable data will be ensured through the use of standard 
practices and procedures.

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5.
REPORTING OF ADVERSE EVENTS
5.1
Assessment of Safety
Specification of Safety Variables 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and 
serious adverse events (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 period, including signs or symptoms associated with KCOT 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.

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).

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Data Safety Monitoring Plan

The principal investigator will be responsible for data and safety monitoring of this 
single site study.  Adverse events, serious adverse events, unanticipated problems, and 
subject status will be reviewed at least annually after enrollment begins.  Both the 
investigator and Genentech, Inc. reserve the right to terminate the study, if the 
incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to subjects.  Should this be necessary, both parties will arrange 
discontinuation procedures.  
In terminating the study, both the investigator and 
Genentech, Inc. will assure that adequate consideration is given to the protection of the 
patients’ interests.  All patients will undergo an exit examination if the study is 
terminated prematurely.  Data safety monitoring summary will be submitted to the IRB 
at the time of annual continuation review.   
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 FDA, appropriate IRB(s), 
and Genentech, Inc. 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 study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is 
earlier. After this period, investigators should only report SAEs that are attributed to 
prior study treatment. All AEs occurring from the start of study treatment through to 
study completion, whether or not they are related to the study, will be recorded in the 
subject chart. 
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 

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discontinuation of vismodegib or dose reduction and, if applicable, reappears upon re-
challenge
No
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 current 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 should 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), 
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 

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reported as the 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
If a female subject becomes pregnant while receiving the study drug or within 24 
months after the last dose of study drug, a report should be completed and 
expeditiously submitted to Genentech. 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 weeks after the expected date of 
delivery, and at 3, 6, and 12 months of the infant’s life).

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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 quaterly 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.”
h. 
AEs of Special Interest (AESIs)
There are no Adverse Events of Special Interest (AESIs)for vismodegib. 
I. 
Instructions for Reporting Adverse Events
Serious Adverse Events Reporting
Investigators must report all SAEs and AESIs to Genentech within the timelines 
described below. The completed MedWatch/case report should be faxed immediately 
upon completion to Genentech Drug Safety at:
(650) 225-4682 or
 (650) 225-4630

Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available.

Serious AE reports that are related to vismodegib and AEs of Special Interest 
(regardless of causality) will be transmitted to Genentech within fifteen (15) calendar 
days of the Awareness Date.
Non-Serious Adverse Events
Bluestone Center for Clinical Research will forward a copy of the Final Study Report to 
Roche upon completion of the Study.
Special Situations Reports
In addition to SAEs, pregnancy reports, and AESIs, the following Special Situations 
Reports should be collected and transmitted to Roche even in the absence of an 
Adverse Event within thirty (30) calendar days:

Data related to product usage during pregnancy or breastfeeding

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
Data related to overdose, abuse, misuse, inadvertent/erroneous administration, 
medication error or occupational exposure, with or without association with an 
AE/SAE unless otherwise specified in the protocol

Lack of therapeutic efficacy

Suspected Transmission of an Infectious Agent (STIAMP) by the study drug
–
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected.
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 each 
investigational product 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 (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 an 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 the following website:
http://www.fda.gov/medwatch/getforms.html

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5.4
Safety Reporting Requirements for IND Exempt Studies
For Investigator-Sponsored IND-Exempt Studies, there are some reporting 
requirements for the FDA in accordance with the guidance set forth in 21 CFR 314.80.
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 AE is one that is not already 
described in the Investigator’s 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 Drug Safety 
Fax:
(650) 225-4682 or (650) 225-4630
Please use the safety reporting fax cover sheet in the appendices of this protocol for 
your fax transmission.
Questions Related to Safety Reporting
For questions related to safety reporting, please contact Genentech Drug Safety:  
Tel:  (888) 835-2555
Fax:  (650) 225-4682 or (650) 225-4630
5.5
Study Close-Out
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech.  This includes all IND annual reports and the Clinical Study Report (final 
study report).  Additionally, any literature articles that are a result of the study should be 
sent to Genentech. 
Copies of study reports should be mailed to the assigned Clinical Operations contact for 
the study:
Vismodegib (GDC0449) Protocols:
Email: hedgehog-gsur@gene.com
Fax: 866-741-3639

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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 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.
7.
RESPONSIBILITIES
7.1 Investigator Responsibilities
7.1.1 Compliance with Good Clinical Practice 
The Sponsor-Investigator will ensure this study is conducted in accordance with the 
basic principles of “Good Clinical Practice,” as outlined in 21 CFR 312, subpart D, 
“Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, part 54, and part 56, 
as well as applicable requirements of the International Conference on Harmonization 
(ICH) Guideline of Good Clinical Practice (ICH E6) and the Health Insurance Portability 
and Accountability Act of 1996 (HIPAA).
7.1.2 Institutional Review Board (IRB) 
This protocol, any protocol amendments and any study related materials (such as 
advertisements, patient information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted to the IRB.  Approval from the IRB must be 
obtained before starting the study and documented in a letter to the investigator 
specifying the protocol number, if applicable, protocol version, documents reviewed, 
and date on which the IRB granted the approval.  
All unexpected SAEs related to study participation will be reported to the IRB within 5 
business days.  
7.1.3 Informed Consent
Informed Consent for patients ≥ 18 years of age:
For inclusion of patients 18 years or older, the investigator will obtain written informed 
consent from each individual participating in this study after adequate explanation of the 
aims, methods, objectives, and potential hazards of the study and prior to undertaking 

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any study-related procedures.  The investigator will utilize an IRB-approved consent 
form.  
Each ICF will be signed and dated by the individual participating in the study and the 
person obtaining the consent.  By signing the ICF, the patient agrees to complete all 
evaluations unless the patient withdraws consent or is terminated from the study for any 
reason.
As part of the informed consent, the investigator will obtain HIPAA compliant 
authorization from patients to use and disclose relevant protected health information 
(PHI) and permission for authorized representatives of Genentech Inc., or regulatory 
authorities including the FDA, to review in confidence any records identifying patients in 
the clinical study.
Recruitment efforts may precede obtaining informed consent; however, informed 
consent must be obtained prior to any protocol specific procedures being performed.
The investigator will communicate any new information on safety to patients who 
consent to participate in this study in accordance with IRB requirements.  The ICF will 
be updated, if necessary. 
7.1.4 Confidentiality
The investigator will assure that patients’ anonymity will be strictly maintained and that 
their identities will be protected from unauthorized parties.  Only patient initials and an 
identification code (i.e., not names) will be recorded on any form submitted to the 
sponsor or IRB.  
The investigator agrees that all information received from Genentech, Inc., including but 
not limited to the Investigator’s Brochure, the study drug, and any other study 
information, are the sole and exclusive property of Genentech Inc.  This information is 
not to be disclosed to any third party (except employees or agents directly involved in 
the conduct of the study or as required by law) without prior written consent from 
Genentech Inc.  
The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into 
the public domain.
7.1.5 Study Files and Retention of Records
The investigator will maintain adequate and accurate records that fully document the 
conduct of the study and enable study data to be verified.  These documents should be 
classified into separate categories:  1) investigator’s study file (regulatory binder) and 2) 
patient clinical source documents.

The investigator’s study file (regulatory binder) includes the original protocol, 
protocol amendments, CRFs and query forms, IRB approval with correspondence, 

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approved informed consent forms, drug records, staff curriculum vitae (CV) and 
authorization forms, and other appropriate documents and correspondence.

Patient clinical source documents include, but are not limited to, the patient’s 
medical/dental records, laboratory reports, radiographs, pathology and special 
assessment reports, consultant letters, screening and enrollment log, as applicable.  
The investigator will make the source documents for this study available for inspection 
to Genentech, Inc. or its representatives, or to regulatory or health authority inspectors.  
The investigator will retain all study documents for at least two years after the last 
approval of a marketing application in an International Conference on Harmonisation 
(ICH) region (i.e., United States, Europe, or Japan), and until there are no pending or 
contemplated marketing applications in an ICH region.  If no application is filed or if the 
application is not approved for such indication, the investigator will retain all study 
documents for at least two years after the investigation is discontinued and regulatory 
authorities have been notified.  
If no application is filed or if the application is not approved for such indication, the 
investigator will retain all study documents for at least two years after the investigation is 
discontinued and regulatory authorities have been notified.  The investigator may retain 
documents longer if required by applicable regulatory requirements or by agreement 
with Genentech, Inc.
7.1.6 Case Report Forms 
The investigator is responsible for the completeness and accuracy of information 
collected on the CRFs for each individual enrolled.  The investigator will review and 
approve all CRFs; document the reason that a patient withdraws from the study on the 
appropriate CRF and attempt to obtain termination assessments; and continue follow-up 
to document the outcome of any adverse event.

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7.1.7 Drug Accountability
The investigator is responsible for ensuring adequate accountability of all used and 
unused study drug, including acknowledgment of receipt of each shipment of study 
products (quantity and condition) and patient dispensing records.  Dispensing records 
will document quantities received and quantities dispensed, lot number (if applicable), 
date dispensed, patient identifier number, and initials of the person dispensing the study 
drugs.
Unused study drug must not be discarded or destroyed by the investigator until 
requested in writing by the sponsor.  The sponsor may request in writing that study drug 
inventory be destroyed in compliance with their institutional requirements.
7.1.8 Inspections
The investigator will make the source documents for this study available to Genentech, 
Inc. or its authorized designee, or to the regulatory or health authority inspectors.
8.
Conflict of Interest
The Sponsor-Investigator does not participate in any financial arrangement with the 
funding sponsor, Genentech other than for this study and its associated usual and 
customary fees; has no proprietary interest in this product or significant equity interest in 
Genentech; and was not and is not the recipient of significant payments of other sorts 
(as defined in 21 CFR 54.2(f)) 
9.
Publication Plan
Neither the complete nor any part of the results of the study carried out under this 
protocol, nor any of the information provided by the sponsor for the purposes of 
performing the study, will be published or passed on to any third party without the 
consent of the study sponsor.  Any investigator involved with this study is obligated to 
provide the sponsor with complete test results and all data derived from the study.

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1.
Bhargava, D., A. Deshpande, and M.A. Pogrel, Keratocystic odontogenic tumour (KCOT)--a cyst to a 
tumour. Oral Maxillofac Surg, 2012. 16(2): p. 163-70.
2.
Gorlin, R.J., Nevoid basal-cell carcinoma syndrome. Medicine, 1987. 66(2): p. 98-113.
3.
Gorlin, R.J. and R.W. Goltz, Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A 
syndrome. The New England Journal of Medicine, 1960. 262: p. 908-12.
4.
Goldberg, L.H., et al., Resolution of odontogenic keratocysts of the jaw in basal cell nevus syndrome 
with GDC-0449. Arch Dermatol, 2011. 147(7): p. 839-41.
5.
Bell, R.B. and E.J. Dierks, Treatment options for the recurrent odontogenic keratocyst. Oral Maxillofac 
Surg Clin North Am, 2003. 15(3): p. 429-46.
6.
Kaczmarzyk, T., I. Mojsa, and J. Stypulkowska, A systematic review of the recurrence rate for 
keratocystic odontogenic tumour in relation to treatment modalities. Int J Oral Maxillofac Surg, 2012. 
41(6): p. 756-67.
7.
Sun, L.S., X.F. Li, and T.J. Li, PTCH1 and SMO gene alterations in keratocystic odontogenic tumors. J 
Dent Res, 2008. 87(6): p. 575-9.
8.
De Smaele, E., E. Ferretti, and A. Gulino, Vismodegib, a small-molecule inhibitor of the hedgehog 
pathway for the treatment of advanced cancers. Curr Opin Investig Drugs, 2010. 11(6): p. 707-18.
9.
Goldberg, L.H., et al., Resolution of odontogenic keratocysts of the jaw in basal cell nevus syndrome 
with GDC-0449. Archives of dermatology, 2011. 147(7): p. 839-41.
10.
Von Hoff, D.D., et al., Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J 
Med, 2009. 361(12): p. 1164-72.
11.
Sekulic, A., et al., Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med, 
2012. 366(23): p. 2171-9.
12.
Erivedge [package insert], 2015, Genentech, Inc.: South san Francisco, CA.
13.
Gorlin, R.J., Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore), 1987. 66(2): p. 98-113.
14.
Gorlin, R.J. and R.W. Goltz, Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A 
syndrome. N Engl J Med, 1960. 262: p. 908-12.
15.
Tang, J.Y., et al., Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N 
Engl J Med, 2012. 366(23): p. 2180-8.
16.
Gajjar, A.J., S. Gururangan et al, A prospective phase II study to determine the efficacy of GDC 0449 
(vismodegib) in adults with recurrent medulloblastoma (MB): A Pediatric Brain Tumor Consortium 
study (PBTC 25B). ASCO Poster Presentation, 2013.
17.
Asklund, T., et al., Early and persisting response to vismodegib in a patient with bone metastasizing 
medulloblastoma. Acta Oncol, 2013. 52(4): p. 862-6.
18.
Berlin, J., et al., A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI 
and bevacizumab in patients with previously untreated metastatic colorectal cancer. Clin Cancer Res, 
2013. 19(1): p. 258-67.
19.
Kaye, S.B., et al., A phase II, randomized, placebo-controlled study of vismodegib as maintenance 
therapy in patients with ovarian cancer in second or third complete remission. Clin Cancer Res, 2012. 
18(23): p. 6509-18.
20.
Catenacci, D.V.T., N. Bahary et al, Final analysis of a phase Ib/Randomized phase II study of 
Gemcitabine plus Placebo or Vismodegib, a Hedgehog pathway inhibitor, in patients with metastatic 
pancreatic cancer: A University of Chicago Phase II Consortium Study 2013. ASCO Poster 
Presentation, 2013.
21.
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.
22.
Cohen, D.J., P. Christos et al, A randomized phase II study of vismodegib, a hedgehog pathway 
inhibitor, combined with FOLFOX in patients with advanced gastric and gastroesophageal junction 
carcinoma: A New York Cancer Consortium led study. ASCO Poster Presentation, 2013.
23.
Belani, C.P., S.E. Dahlberg et a, Three-arm Randomized phase II study of cisplatin and etoposide (CE) 
versus CE with either vismodegib (V) or cixutumumab (Cx) for patients with extensive stage-small cell 
lung cancer (ES-SCLC). ASCO Poster Presentation, 2012.
24.
Graham, R.A., et al., Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in 
patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. 
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Lorusso, P.M., et al., Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib 
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LoRusso, P.M., et al., Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients 
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APPENDIX B
Definition of Women of Childbearing Potential and Acceptable and 
Unacceptable Forms of Contraception 
Definition of 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 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.
Additionally, the parent or guardian of young female patients who have not yet started 
menstruation should verify that menstruation has not begun.  If a young female patient 
reaches menarche during the study, she is to be treated as a woman of childbearing 
potential from that time forward.
Acceptable contraception
Women of child-bearing potential must use two methods of acceptable contraception 
including one highly effective method and a barrier method during Erivedge therapy and 
for 9 months after the final dose.
Acceptable forms of barrier contraception include the following:

Latex, non-latex, or any other male condom (always used with spermicide)

Diaphragm (always used with spermicide)
Acceptable forms of secondary contraception, when used with a barrier method, include the 
following:

Combination hormonal contraceptives, hormonal patch, or hormonal intramuscular 
contraceptives (subcutaneous hormonal implant, medroxyprogesterone acetate depot)

Tubal sterilization
Other acceptable forms include the following:

100% commitment to abstinence from sexual intercourse (for medical or personal 
reasons)

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Unacceptable contraception
The following are unacceptable forms of contraception:

IUD progesterone T 

Progestin-only contraceptives

Female condom

Natural family planning (rhythm method) or breastfeeding

Fertility awareness

Withdrawal

Cervical shield

Vaginal contraceptive ring
NOTE: Patients should be counseled on the use of contraception before beginning 
treatment with vismodegib.  As appropriate, the treating physician should refer the 
subject to her gynecologist or other healthcare provider to ensure proper understanding 
of the use of her chosen contraceptive method.

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APPENDIX C
Gorlin Syndrome Diagnostic Criteria (if applicable)
Major Criteria
Minor Criteria
More than two histologically confirmed BCCs, 
or one under the age of 20 years
Macrocephaly determined after adjustment for 
height
Keratocystic odontogenic tumors (KOT) of the 
jaw proven by histology
Congenital 
malformations 
such 
as 
the 
following: cleft lip or palate, frontal bossing, 
strabismus, “coarse face,” or moderate or 
severe hypertelorism
Three or more palmar and/or plantar pits
Skeletal abnormalities such as the following: 
Sprengel’s 
deformity, 
marked 
pectus 
deformity, marked syndactyly of the digits, 
scoliosis
Bilamellar calcification of the falx cerebri (if 
less than 20 years old)
Radiological 
abnormalities 
such 
as 
the 
following: bridging of the sella turcica; 
vertebral anomalies such as hemivertebrae, 
fusion or elongation of the vertebral bodies, 
modeling defects of the hands and feet, or 
flame-shaped lucencies of the hands or feet
Fused, bifid, or markedly splayed ribs
Ovarian fibroma
First- degree relative with BCCNS
Medulloblastoma, menengioma
PTCH1 gene mutation in normal tissue
Note: Diagnostic criteria are adapted from Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical 
manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 
1997;69:299-308.

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APPENDIX D
NCI-CTCAE Grading System for Adverse Events 
Commonly Associated with Vismodegib Therapy
Adverse 
event
Grade 1
Grade 2
Grade 
3
Grade 
4
Grade 
5
Alopecia
Hair loss of < 50% of 
normal for that individual 
that is not obvious from a 
distance but only on 
close 
inspection; 
a 
different hair style may 
be required to cover the 
hair loss but it does not 
require a wig or hair 
piece to camouflage
Hair loss of ≥ 50% normal 
for that individual that is 
readily apparent to others; 
a wig or hair piece is 
necessary if the patient 
desires 
to 
completely 
camouflage the hair loss; 
associated 
with 
psychosocial impact
–
–
–
Dysgeusia
Altered 
taste 
but 
no 
change in diet
Altered taste with change 
in 
diet 
(e.g., 
oral 
supplements); noxious or 
unpleasant taste; loss of 
taste
–
–
–

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APPENDIX E 
SAFETY REPORTING FAX COVER SHEET
Genentech Supported Research
AE / SAE FAX No: (650) 225-4682
Alternate Fax No: (650) 225-4630
Genentech Study Number
Principal Investigator
Site Name
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
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER 
SHEET.
Page 1 of ___ 

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APPENDIX F
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