Clinical trial NCT01700049
Conditions: Basal Cell Carcinoma
Keywords: advanced BCC high risk locally advanced
Sponsor: Mayo Clinic
Start date: 2013-01-14; Completion date: 2018-07-03
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the safety and effectiveness of oral vismodegib therapy in the treatment of different 'histologic subtypes' of basal cell skin cancer (BCC). The term 'histologic subtype' refers to how the cells and tumor tissue looks under the microscope. Three different 'histologic subtypes' of basal cell skin cancer (infiltrative/morpheaform, nodular and superficial) will be examined in this study.

Detailed description:
The purpose of this study is to investigate the safety and effectiveness of oral vismodegib therapy in the treatment of different 'histologic subtypes' of basal cell skin cancer (BCC). The term 'histologic subtype' refers to how the cells and tumor tissue looks under the microscope. Three different 'histologic subtypes' of basal cell skin cancer (infiltrative/morpheaform, nodular and superficial) will be examined in this study. Each subtype has a characteristic look under the microscope, which is related to how the tumor will behave and grow.

ERIVEDGE (oral vismodegib capsule) has been approved for use in the United States for treatment of metastatic BCC tumors (mBCC), tumors that have spread further into the skin, bones or other tissues, or spread to other parts of the body and locally advanced basal cell skin cancer (laBCC), cancers that have come back after surgery or that the healthcare provider thinks cannot be treated with surgery or radiation. It works by blocking the signal, called Hedgehog, which basal cell skin cancer cells need to grow. It has been given to about 800 people during clinical trials.

Data from previous studies is mostly based on a subtype of BCC made up of little round collections of cancer cells, called "Nodular". There is almost no data on the use of vismodegib in other subtypes of BCC that that tend to extend deep into the skin ("Infiltrative" subtype), or spread widely near the surface of the skin ("Superficial" subtype).

A total of 36 subjects will be enrolled in the study. All study participants will receive oral vismodegib treatment.

At the Week 12 visit, skin biopsies will be performed to give the investigators more information on how the tumor is responding to vismodegib. If there is no evidence of tumor on the biopsy, the subject will be eligible to end treatment early and enter the Observation period. During this time the subject will be followed clinically every 3 months for up to 1 year.

For all other subjects, if any evidence of tumor is seen on biopsy at week 12, the subject will continue treatment for the full 24 weeks. At week 24 visit, skin biopsies will be performed again to see if there is any tumor left. If there is no evidence of tumor on the biopsy, the subject will be eligible to end treatment early and enter the Observation period. If there is tumor left, the subject will be referred for surgery or other standard of care treatment to remove the tumor.

Arms: arm 1: This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy and safety of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell carcinoma (BCC). A total of 36 subjects with infiltrative/morpheaform, nodular, or superficial BCC will be enrolled in the study.
Interventions: intervention 1: vismodegib (150 mg PO daily)
Intervention descriptions: intervention 1: Biopsies will be performed on all participants at baseline, week 12 and week 24.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Phase 2B single-site, open-label, 
nonrandomized study evaluating the 
efficacy of oral vismodegib in various 
histologic subtypes 
(infiltrative/morpheaform, nodular and 
superficial) of high risk and/or locally 
advanced basal cell carcinoma 
 
NCT# 01700049 
 
January 21, 2017 


STUDY PROTOCOL - ML28485 
SLU IRB # 22355 
 
Protocol Title: 
Phase 2B single-site, open-label, nonrandomized study  
evaluating the efficacy of oral vismodegib in various histologic  
subtypes (infiltrative/morpheaform, nodular and superficial) of 
high risk and/or locally advanced basal cell carcinoma. 
 
Version: 
3.1 
 
Issue Date: 
June 21, 2012 - Revised January 14, 2013 and July 11, 2013 
 
Revised May 20, 2016 
 
Revised January 27, 2017 
 
Study Short name:  Vismo Histo 
 
Prepared by: 
Scott W. Fosko, M.D. and Melinda B. Chu, M.D. 
 
Reviewed and Approved by Saint Louis University IRB 
 
Protocol Author:  
 
Medical Monitor/Medical Director: 
Scott W. Fosko, M.D. 
 
Scott W. Fosko, M.D. 
Professor and Chairman 
Saint Louis University 
Department of Dermatology 
1402 S. Grand Blvd. 
Saint Louis, MO 63104 
phone: (314) 256-3430 
 
Biostatistician 
 
Clinical Data Management 
Eric S. Armbrecht, Ph.D. 
 
Rosemary King 
Assistant Professor 
 
Research Coordinator 
Saint Louis University 
 
Saint Louis University 
School of Public Health 
 
Department of Dermatology 
 
 
Phone: (314) 256-3436 
 
 
Fax: (314) 256-3451 
 
Project Coordination 
 
Study Coordinator 
 
 
Rosemary King, PA-C 
                  Rosemary King, PA-C 
 
 
 
Research Coordinator 
 
 
 
Saint Louis University 
 
 
 
Department of Dermatology 
 
 
 
Phone: (314) 256-3436 
 
 
 
Fax: (314) 256-3451 
 


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v.3.1 January 27,2017 
This document contains confidential information.  Do not copy, disclose, or circulate 
without written authorization from Dr. Scott Fosko.


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v.3.1 January 27, 2017  
Table of Contents_ 
 
1. 
BACKGROUND INFORMATION ....................................................................................... 7 
1.1 
INTRODUCTION ............................................................................................................ 7 
1.2 
RATIONALE ................................................................................................................... 8 
1.3 
POTENTIAL RISKS and BENEFITS ............................................................................. 9 
2. 
STUDY OBJECTIVES ......................................................................................................... 10 
2.1 
Primary Objectives ......................................................................................................... 10 
2.2 
Secondary Objectives ..................................................................................................... 10 
3. 
STUDY DESIGN.................................................................................................................. 10 
4. 
SUBJECT SELECTION ....................................................................................................... 11 
4.1 
Inclusion Criteria ......................................................................................................... 11 
4.2 
Exclusion Criteria ........................................................................................................ 12 
5. 
INFORMED CONSENT .................................................................................................... 132 
6. 
STUDY METHODOLOGY ................................................................................................. 13 
6.1 STUDY PROCEDURES .................................................................................................. 13 
6.1.1 
Pre-study Screening visit ........................................................................................ 13 
6.1.2 Treatment Initiation Visit (Baseline/Day 1) ................................................................ 15 
6.1.2 
Interval Visits ........................................................................................................ 165 
6.1.3 
Intra-treatment Tissue Histopathologic Evaluation ................................................ 17 
6.1.4 
End of Treatment visit (Week 24) .......................................................................... 18 
6.1.5 
Early Termination ................................................................................................... 20 
6.1.6 
Surgery visit ............................................................................................................ 20 
6.1.7 
Study Exit Visit (Post-Surgery Visit) ..................................................................... 21 
6.1.8 
Observation period .................................................................................................. 21 
6.2 
Methods of Assessment ................................................................................................ 22 
6.2.1 
Measurement of Target Tumor ............................................................................... 22 
6.2.2 
Clinical response evaluation of target lesion .......................................................... 22 
6.2.3 
Measurement of Wound Size ................................................................................ 221 
6.2.4 
Photographs of Target Tumor ............................................................................... 221 
6.3 
Histopathologic evaluation ........................................................................................ 221 
6.3.1 
Histologic Subtype Definitions ............................................................................... 22 
6.3.2 
Pre-study Screening Visit biopsy specimens .......................................................... 23 
6.3.3 
Week 12 and Week 24 Visit biopsy specimens ...................................................... 24 


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6.3.4 
Surgical Excision specimen .................................................................................. 243 
6.4 
INTERCURRENT DISEASE TREATMENT AND CONCOMITANT 
MEDICATIONS ....................................................................................................................... 25 
6.4.1 
Intercurrent Disease Treatment ............................................................................... 25 
6.4.2 
Concomitant Medications ..................................................................................... 254 
6.5 
SUBJECT COMMITMENT TO STUDY ................................................................ 254 
6.6 
SUBJECT WITHDRAWAL OR DISCONTINUATION ....................................... 254 
6.6.1 
Subject Stopping Criteria ........................................................................................ 25 
6.6.2 
Other Withdrawal or Discontinuations ................................................................... 26 
6.7 
TREATING OVERDOSE............................................................................................ 265 
6.8 
PREGNANCY ............................................................................................................ 265 
7. 
REPORTING OF ADVERSE EVENTS ............................................................................ 276 
7.1 
Assessment of Safety .................................................................................................. 276 
7.1.1 
Adverse Events ..................................................................................................... 276 
7.1.2 
Serious Adverse Events .......................................................................................... 28 
7.2 
Methods and Timing for Assessing AND Recording Safety variables ........................ 287 
7.2.1 
Adverse Event Reporting Period .......................................................................... 287 
7.2.2 
Assessment of Adverse Events ............................................................................... 29 
7.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events .......................... 298 
7.3.1 
Eliciting Adverse Events....................................................................................... 298 
7.3.2 
Specific Instructions for Recording Adverse Events .............................................. 29 
7.3.3 
MedWatch 3500A Reporting Guidelines.............................................................. 310 
7.3.4 
Additional Reporting Requirements for IND Holders ............................................ 32 
IND Annual Reports ........................................................................................................... 332 
7.4 
Data Safety Monitoring Plan ........................................................................................ 332 
8. 
Materials and Supplies .......................................................................................................... 34 
8.1 
Study Drug ..................................................................................................................... 34 
8.2 
Study Drug Labeling .................................................................................................... 343 
• 
Protocol ID Number ............................................................................................................ 343 
• 
Investigator Name ............................................................................................................... 343 
8.3 
Study Drug Inventory and Storage ................................................................................. 35 
9. 
DATA ANALYSIS AND STATISTICAL PROCEDURES .............................................. 354 
9.1 
Sample Size Determination ....................................................................................... 354 
9.2 
Subject sub-group Assignment ................................................................................. 365 


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v.3.1 January 27, 2017  
9.3 
PARAMETERS TO BE MEASURED:.................................................................... 365 
9.3.1 
Primary Endpoints ................................................................................................ 365 
9.3.2 
Secondary Endpoints ............................................................................................ 376 
9.3.3 
Efficacy Analysis .................................................................................................. 376 
9.4 
SAFETY ANALYSES ................................................................................................. 398 
9.4.1 
Adverse Events ..................................................................................................... 398 
9.4.2 
Vital Signs and Dermatological Examination Data ................................................ 38 
10. 
Data Security & Confidentiality Plan ................................................................................ 38 
10.1 
Hard-Copy Data Forms .............................................................................................. 39 
10.2 
Electronic Data ........................................................................................................... 40 
10.3 
Confidentiality Security Plan...................................................................................... 40 
11. 
Final Study Report ........................................................................................................... 400 
12. 
Administrative Procedures ............................................................................................... 400    
12.1 Ethical Approval .............................................................................................................. 400 
12.2 
Regulatory Approval ................................................................................................ 410 
12.3 
STUDY PERSONNEL ............................................................................................. 410 
12.4 
Participant compensation and ESEARCH-RELATED COSTS:.............................. 410 
12.5 
PRESTUDY DOCUMENTATION REQUIREMENTS.......................................... 410 
12.6 
COMPLETION AND RETURN OF CASE REPORT FORMS.............................. 410 
12.7 
STUDY MONITORING .......................................................................................... 421 
Source data verification will be performed by the clinical monitor at each monitoring visit. ... 421 
12.8 
Quality Assurance Procedures .................................................................................. 421 
12.9 
AMENDMENT TO PROTOCOL ............................................................................ 421 
12.10 
DEPARTURE FROM PROTOCOL FOR INDIVIDUAL SUBJECTS................... 421 
12.11 
RECORDS OF STUDY ........................................................................................... 432 
13. 
REFERENCES ................................................................................................................ 454 
14. 
APPENDICES ................................................................................................................. 510 
14.1 
Appendix 1:  NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines) Basal Cell and Squamous Cell Skin Cancers ................................................. 521 
14.2 
Appendix 2: ‘Mask Areas’ of Face: high risk anatomic areas ........................... 532 
14.3 
Appendix 3:  ECOG Performance Status............................................................. 543 
14.4 
Appendix 4:  Required Elements of Informed Consent ...................................... 554 
14.5 
Appendix 5:  Treatment Algorithms ..................................................................... 576 
14.6 
Appendix 6:  Study Procedures Flowchart .......................................................... 598 
14.7 
Appendix 7:  SKINDEX-16 .................................................................................... 621 


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v.3.1 January 27, 2017  
14.8 
Appendix 8:  Instructions for study participants ................................................ 632 
                   use of study medication ...............................................................................................  
14.9 
Appendix 9:  FACT-G (Version 4) ........................................................................ 643 
14.10 
Appendix 10:  TARGET LESION ASSIGNMENT EXAMPLES ..................... 665 
14.11 
Appendix 11.  NCI Common Terminology Criteria for Adverse Events 
(CTCAE) v.4 .......................................................................................................................... 676 
 
 
 


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v.3.1 January 27, 2017  
1. 
BACKGROUND INFORMATION 
1.1 
INTRODUCTION 
Basal cell carcinoma (BCC) is the most common type of skin cancer, with almost 3 million cases 
diagnosed each year in the United States. (Skin Cancer Foundation 2011, Rogers et al 2010)  The 
incidence of BCC is increasing 10% each year worldwide and its prevalence is expected to equal 
that of all other cancers combined in the near future. (Madan et al 2010)   
 
Though extremely rare, some patients have progressive mutilating metastatic BCC (mBCC) or 
locally advanced BCC (laBCC), which can be fatal.  Most BCCs are not life-threatening, but 
they are still quite morbid as they commonly occur on the head and neck.  Some BCC lesions 
grow very quickly and are associated with poorer outcomes. Features of these ‘high risk’ BCC 
(hrBCC) lesions were defined by the National Comprehensive Cancer Network (NCCN) and this 
hrBCC cohort was highlighted as one of particular concern. (See Appendix 1, NCCN 2011).  
Since hrBCC tumors are much more common, they actually represent a much bigger public 
health problem than mBCC or laBCC. 
 
Due to its superior cure rate, Mohs micrographic surgery (MMS) is widely accepted as the gold 
standard for treatment for the majority of BCC tumors, especially laBCC and hrBCC. (Mikhail 
and Mohs 1993, NCCN 2011)  Even with the utilization of the Mohs tissue preservation 
technique, surgery can be quite extensive resulting in significant disfigurement, depending on the 
size and anatomic location of the lesion.   
 
While size of tumor is a predictive factor of patient outcomes, visual examination can frequently 
be deceiving and local microscopic invasion may be much more extensive than initially thought.  
In some cases, tumor seen at the skin surface may only represent one fifth of its microscopic 
spread. (Batra and Kelley 2004)   Since many tumors exhibit significant subclinical extension, 
the resulting surgical defect after tumor clearance can be considerably larger than the presenting 
lesion, often necessitating complex, costly, and time-consuming repairs, compromising the final 
cosmetic appearance or function.    
 
Adjuvant therapies aiding in the removal of primary or recurrent tumors could lessen the risk of 
cosmetic disfigurement by decreasing tumor burden prior to surgery.  Topical therapies, such as 
imiquimod, have been investigated in the past for this purpose.  They are not widely used due to 
concern that the variable penetration of topical therapy may lead to noncontiguous response, 
leading the clinician to incorrectly believe that the tumor has been completely cleared. (Harting 
et al 2007)  An oral agent, that hypothetically would be distributed to the tumor uniformly, may 
be better suited for neoadjuvant treatment of BCC prior to surgery.  In fact, in selected lesions, 
oral treatment could possibly even lead to complete eradication of tumor tissue, thereby 
eliminating the need for surgery altogether.  Vismodegib is an orally delivered small Hedgehog 
pathway inhibitor (HPI) that shows promise in the management of BCC.  Vismodegib was 
granted priority review and was recently approved by the U. S. Food and Drug Administration 
for the treatment of adults with metastatic basal cell carcinoma or with locally advanced basal 
cell carcinoma that has recurred following surgery or who are not candidates for surgery, and 
who are not candidates for radiation. 
 


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v.3.1 January 27, 2017  
1.2 
RATIONALE 
Vismodegib has been shown to have an anti-tumor effect on BCC in preclinical and clinical 
studies.  It exerts its effect by blocking the Hedgehog (Hh) pathway directly, disrupting the 
development of cancers that are due to PTCH mutations or SMO mutations, like those seen in 
the majority of BCCs. (Lorusso et al 2011, Von Hoff et al 2009)  An estimated 90% of BCC 
tumors have mutations in the Hh signaling pathway, either an inactivation of the PTCH mutation 
(loss-of function mutation) or an activation of the SMO15 mutation (gain of function), that 
disrupt normal signaling between cells and lead to a proliferation of basal cells and the 
development of BCC. (Rubin and De Sauvage 2006, Hopper and Scott 2006)  For this reason, 
inhibiting the Hh signaling pathway has been identified as a therapeutic target in the treatment of 
BCC. 
 
Though many BCCs possess the same mutation in the Hh pathway, BCC is a very heterogeneous 
tumor type when considering all of the known histologic subtypes.  Twenty-three subtypes of 
BCC have been recorded in the literature, but for practical purposes these have been combined 
and three subtypes (infiltrative/morpheaform, nodular and superficial) are used clinically. 
(Sexton et al 1990, Wade and Ackerman 1978, Rippey 1998)  The most common type of BCC is 
nodular (70%). (Weedon 2009, Mosterd et al 2011)  Superficial subtypes comprise around 10-
15% of BCCs.  About 10-15% of BCCs are categorized as infiltrative/morpheaform subtype for 
clinical management and considered to be an “aggressive” subtype of BCC.  Infiltrative BCCs 
and morpheaform BCC have different appearances histologically, but are considered together for 
management due to their similar aggressive clinical course.   
 
Histologic features are well known to impact tumor biologic behavior and response to treatment.  
Treatment options for BCC are often curative when considering clinical and histologic features, 
the latter a more powerful prognostic factor with laBCCs and hrBCCs. (Walling et al 2004)  For 
example, it is well recognized that infiltrative/morpheaform tumors are associated with increased 
rates of recurrence and poorer prognosis since their tumor characteristics make it difficult to 
obtain clear margins during surgery. (Walling et al 2004)  These BCC subtypes frequently have 
tumor nests outside of the tumor bulk.  During surgery, tumor remnants may go undetected by 
conventional means and continue to grow.  If a histological response to vismodegib in aggressive 
subtypes can be demonstrated pre-operatively, clinicians may possess greater confidence that all 
tumor nests have been eradicated and clear margins have been obtained during surgery, leading 
to improved patient outcomes. Conversely, superficial BCCs are considered to have non-
aggressive tumor behavior and are also more likely than other subtypes to be located on the low-
risk locations of the trunk and extremities. (Weedon 2009)  These tumors, which typically 
undergo simple excisions, nonetheless can require significant circumferential margins of normal 
tissue to ensure complete removal, again impacting cosmesis, function and or cost.  
 
It is unknown if BCC histologic subtype impacts tumor response to vismodegib.  Data from 
previous studies, where inclusion was open to all subtypes of basal cell skin cancer, is 
predominantly based on nodular subtype.  Most currently recruiting studies investigating 
vismodegib in BCC do not specify a tumor subtype for inclusion, but if one is specified for 
inclusion, it is nodular subtype only.  (ClinicalTrials.gov Identifier NCT01201915)  No previous 
or ongoing studies have stipulated inclusion of other histological subtypes of BCC.   
 


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v.3.1 January 27, 2017  
The goal of this study is to identify the cohorts of patients that will most likely benefit from 
treatment with vismodegib.  In the new era of cancer therapeutics, matching treatment modality 
with specific tumor features contributes to better patient outcomes. This investigation will assist 
in providing a greater understanding of the efficacy of vismodegib in BCCs of aggressive 
subtypes and of other histologic subtypes.  This study may provide better guidance for targeted, 
individualized information about a patient’s unique tumor biology and optimize management of 
BCCs in our patients.  
 
 
1.3 
POTENTIAL RISKS AND BENEFITS 
The safety, preliminary efficacy, and pharmacokinetics of vismodegib in mBCC and laBCC were 
assessed in an open-label, multicenter, two-stage Phase I trial. Patients with solid tumors 
refractory to standard therapy were treated until disease progression, intolerable toxicities, or 
withdrawal from the study.  Thirty-three patients with mBCC or laBCC were included in 
analysis and followed over a 20-month period.  Assessment using the RECIST criteria version 
1.0 was completed if tumors had radiologically measurable disease. Otherwise, pre-defined 
clinical response measures were employed.  An overall response rate of 58% was observed. (Von 
Hoff et al 2009)  The most common response, in 17 of 33 cases, was partial response. Complete 
response was seen in 2 cases. Stable disease was observed in 12 cases. (Von Hoff et al 2009) No 
dose-limiting toxic events or grade 5 events were observed with a single grade 4 adverse event 
(asymptomatic hyponatremia) reported. The more significant and frequent adverse events were 
GI related with dysgeusia and muscle spasm reported. 
 
Further evidence of the efficacy of vismodegib in the treatment of BCC was shown in the pivotal 
ERIVANCE trial, a Phase II single-arm, non-randomized trial of single-agent vismodegib at 150 
mg/day to progression or intolerance with 104 patients enrolled: (33 mBCC, 71 LA BCC).  The 
study met its primary endpoint overall response rate (ORR) by an independent review facility 
(IRF) and showed shrinkage of tumors in a pre-defined percentage of patients8.  A preliminary 
safety assessment showed the most common adverse events were consistent with previous 
experience with vismodegib. The most common adverse events were muscle spasms, hair loss, 
altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. A detailed 
safety assessment is ongoing. 
 
Therapy with vismodegib has the potential to significantly decrease morbidity of the patients’ 
BCC either through complete clearance of tumor or by substantially decreasing the morbidity of 
surgery.  Though BCC expected to respond favorably to treatment with vismodegib, surgical 
excision by MMS will occur within 6 months of initial consultation; this study will not adversely 
affect the current standard of care in the management of BCC in non-responders. 
 
In a recent Phase 2 trial, vismodegib was also reported to slow the development of BCCs in 
patients with Basal Cell Nevus Syndrome (BCNS), a rare genetic disorder which causes patients 
to develop hundreds of large BCCs.  (Tang et al 2011).  Further studies are needed, but 
vismodegib may slow the progression of BCC in patients without BCNS. 
 
 


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v.3.1 January 27, 2017  
2. 
STUDY OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVES 
 To compare the efficacy of vismodegib in various histologic subtypes of high risk 
and/or locally advanced basal cell skin cancer 
 
2.2 
SECONDARY OBJECTIVES  
 To evaluate the onset of efficacy of vismodegib during 24 weeks of treatment in 
various histologic subtypes of high risk and/or locally advanced basal cell skin cancer  
 
 To evaluate the safety and tolerability of vismodegib over 24 weeks of treatment in 
subjects with high risk and/or locally advanced basal cell skin cancer  
 
 To evaluate patient reported outcome (PRO) measures during 24 weeks of treatment 
with vismodegib in subjects with high risk and/or locally advanced basal cell skin 
cancer  
 
 
3. 
STUDY DESIGN 
This is a Phase 2B two-site, open-label, nonrandomized 24-week study of the efficacy and safety 
of vismodegib (150 mg PO daily) in subjects with high risk and/or locally advanced basal cell 
carcinoma.  A total of 36 subjects with infiltrative/morpheaform, nodular, or superficial BCC 
will be enrolled in the study.  Each subtype group will have a minimum of 10 subjects.  No 
group will have more than 16 subjects. 
 
 
 
 
At Treatment Initiation Visit (Baseline/Day 1), eligible subjects will begin a 24-week treatment 
regimen with vismodegib 150 mg daily.  Clinical assessments will be performed every 4 weeks 
during treatment.  Intra-treatment tissue histopathologic evaluation will be conducted at Week 
12.  Subjects will be eligible to discontinue treatment early and enter the Observation period if 
there is no histologic evidence of tumor on Week 12 pathology specimens.  Post-treatment 
histopathologic evaluation will be performed at Week 24 (End of Treatment visit).  Subjects will 
be eligible to enter the Observation period in lieu of surgery if their target lesion displays 
complete histologic response on biopsy specimens obtained at Week 24 visit.  For subjects with 
histologic evidence of disease on pathology at Week 24 visit, surgical excision or Mohs surgery 
on the target lesion will be performed within 4 weeks of the last dose of study drug.  Patient 
Reported Outcomes (PRO) data will be collected at baseline visit, during treatment, end of 
treatment/early termination visit, surgical visit, and study exit (post-surgery) visit, and at first 
Observation period visit (when applicable)  Safety assessments including adverse event (AE) 
monitoring and concomitant medications will be performed at each visit. 
 
The rationale for using 24-week treatment schedule was based on previous data from pilot 
studies.  Data from a previous trial of 33 subjects with advanced BCC, demonstrated that 94% 
(17/18) of responders responded by 24-weeks. (Von Hoff et al 2009)  In non-responders, 
treatment beyond 24 weeks may unnecessarily endanger the patient and allow their basal cell 
skin cancer to progress potentially negatively affecting clinical outcome.   
 


11 
v.3.1 January 27, 2017  
4. 
SUBJECT SELECTION 
A total of 36 subjects with histologically-confirmed basal cell skin cancer who meet all 
eligibility criteria will be enrolled.  Patients with mBCC will be excluded. 
 
 
4.1 
INCLUSION CRITERIA 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Evidence of a personally signed and data informed consent document indicating that the 
subject (or legally acceptable representative) has been informed of all pertinent aspects of 
the trial. 
2. Subjects who are willing to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
3. Be 18 years of age or older at the time of informed consent. 
4. Has one or more clinically suspicious lesions for BCC at Pre-Study screening Visit that 
is/has: 
a. a diameter ≥ 6 mm if located on the “mask areas” of face (central face, eyelids, 
eyebrows, periorbital, nose lips [cutaneous and vermillion], chin, mandible, 
preauricular and postauricular skin/sulci, temple, ear), genitalia, hands, or feet 
(See Appendix 2 for Figure of “mask areas” of face) 
b. a diameter ≥ 10 mm if located on cheeks, forehead, scalp, or neck 
c. a diameter ≥ 20 mm if located on trunk and extremities 
 
or has a lesion suspicious for locally advanced BCC defined as a lesion that: 
a. is ≥ 10 mm, 
b. has recurred following surgery or surgical resection would result in substantial 
deformity, and 
c. has been deemed not appropriate for radiation. 
 
5. Have a histologically-confirmed BCC prior to first dose of study drug at Treatment 
Initiation Visit (Baseline/Day 1). 
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less at 
Baseline/Day 1 visit.  (See Appendix 3, ECOG Performance Status) 
7. Males and females must agree that they have no desire or plan to conceive children in the 
future 
8. Female of reproductive potential must use 2 effective methods to avoid pregnancy during 
therapy and for 9 months after completing therapy. Effective methods must be used for 1 
month before initiating therapy. 
9. Male patients must use effective measures to avoid pregnancy in their partner at all times, 
even after vasectomy, during treatment and for 3 months after the last dose.  
10. Agreement not to donate blood or blood products during the study and for 9 months after 
the last dose. 
11. Subjects with Basal Cell Nevus Syndrome are eligible for enrollment. 
 
 


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v.3.1 January 27, 2017  
4.2 
EXCLUSION CRITERIA 
 
Subjects presenting with any of the following will not be included in the study: 
1. Women who are pregnant or lactating, or planning pregnancy while enrolled in the study. 
2. History of prior treatment with vismodegib or any Hh Pathway Inhibitor 
3. Have evidence of clinically significant and unstable diseases or conditions such as 
cardiovascular, immunosuppressive, hematologic, hepatic, neurologic, renal, endocrine, 
collagen-vascular, or gastrointestinal abnormalities.  Subjects with clinically stable 
chronic medical conditions including, but not limited to, controlled hypertension, 
diabetes mellitus type II, hypercholesterolemia, or osteoarthritis, will be allowed to enter 
the study. 
4. Have any dermatological disease at treatment site that the investigator thinks may be 
exacerbated by treatment with vismodegib or cause difficulty with examination (e.g., 
psoriasis, eczema). 
5. The target lesion identified at Pre-study Screening visit has been determined to be mBCC  
by radiological assessment prior to first dose of study drug. 
6. Inability or unwillingness to swallow capsules. 
7. Have a history of infection requiring hospitalization, parenteral antimicrobial therapy, or 
as otherwise judged to be clinically significant by the investigator within 4 weeks prior to 
first dose of study drug. 
8. Have a history of infection requiring antimicrobial therapy within 2 weeks prior to first 
dose of study drug. 
9. Have a history of alcohol of substance abuse, unless in full remission for greater than 6 
months prior to first dose of study drug 
10. Known to be infected with human immunodeficiency virus (HIV), hepatitis B or hepatitis 
C viruses. 
11. Participation in other study using an investigational or experimental therapy or procedure 
within 4 weeks or 5 half-lives (whichever is longer) before the study begins and/or during 
study participation.  Subjects cannot participate in studies of other investigational or 
experimental therapies or procedures at any time during their participation in this study. 
12. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study. 
13. Subjects who are investigational site staff members or subjects who are Sponsor 
employees directly involved in the conduct of the trial. 
14. A subject who, in the opinion of the investigator or sponsor, will be uncooperative or 
unable to comply with study procedures. 
15. Subjects (male and female) who desire to conceive in the future 
 
 


13 
v.3.1 January 27, 2017  
5. 
INFORMED CONSENT 
 
Prior to entering the study, the investigator or designated assistant will explain to each subject or 
legally acceptable representative, the nature of the study, its purpose, procedures, expected 
duration, and the benefits and risks involved in study participation.   
 
Alternative therapies for treatment of BCC (e.g. surgical excision, Mohs surgery, radiation 
therapy, imiquimod topical treatment, 5-fluorouracil topical therapy, electrodessication and 
curettage, cryotherapy and photodynamic therapy) will be discussed with the subject.  Subjects 
will be informed that declining to participate or withdrawal after enrollment in trial will in no way 
affect the management or care of the patient. 
 
Each subject will be given an information and consent document and the opportunity to ask 
questions; and will be informed of his/her right to withdraw from the study at any time without 
prejudice.  After this explanation and before any study-specific procedures have been performed, 
the subject, or legally acceptable representative, will voluntarily sign and date an informed 
consent statement.  Prior to participation in the study, the subject or his/her legally acceptable 
representative should receive a copy of the written informed consent form and any other written 
information provided to the subject.  (See Appendix 4 for information on required elements of 
informed consent.) 
 
 
6. 
STUDY METHODOLOGY 
 
6.1 STUDY PROCEDURES 
 
The following sections describe in detail all study procedures.  A flow chart of study procedures 
is presented at the end of the protocol (Appendix 6). 
 
 
6.1.1 
Pre-study Screening visit  
Subjects will be screened within 4 Weeks (+/-3 days) prior to the Treatment Initiation 
(Baseline/Day 1) visit to confirm that they meet the entrance criteria for the study. The study 
investigator or sub-investigator will discuss with each subject the nature of the study, its 
requirements, and its restrictions. Written informed consent must be obtained prior to 
performance of any protocol-specific procedures. 
 
The following procedures will be performed at Pre-study Screening visit, within 4 weeks prior to 
Treatment Initiation (Baseline/Day 1, Visit 2) visit 
 
 Confirmation of inclusion criteria, excluding histologic confirmation of basal cell skin 
cancer of target lesion. 
 Identification of skin lesion(s) clinically suspicious for basal cell skin cancer. 
 Recording of medical history. (Medical history is defined as a disease or syndrome that is 
ongoing at or stopped before Informed Consent.) 


14 
v.3.1 January 27, 2017  
 Recording of history of alcohol and drug use, smoking status (current smoker, current 
heavy smoker >20 cigarettes per day), and average weekly alcohol consumption 
(units/week), where a unit contains 12 g of pure alcohol, an amount equivalent to that 
contained in 5 oz (a glass or 148 mL) of wine, 12 oz (355 mL) of beer, or 1.5 oz (44 mL) 
of 90 proof of spirits. (The intent is to monitor the subject’s alcohol consumption during 
the study to determine if it has impact on the efficacy, disease state and any co-
morbidities.  It is the PI’s discretion to determine acceptable levels of consumption or 
abuse.  Alcohol and/or substance abuse are exclusionary.)   
 Recording of current medications and all other drugs (including non-prescription drugs, 
vitamins, and dietary supplements) taken within 4 weeks prior to Screening. 
 Complete physical examination including full-body skin exam. 
o Physical examination includes: height, weight, general appearance, skin (other 
than primary diagnosis), HEENT (head, eyes, ears, nose and throat), heart 
(auscultation), lungs (auscultation), abdomen (palpation and auscultation), lower 
extremities (peripheral edema), neurologic (mental status, station, gait, reflexes, 
motor and sensory function, coordination) and lymph nodes. 
 Vital signs [blood pressure (BP); heart or pulse rate; and oral, tympanic, or temporal 
temperature]. 
 Males are reminded that they must use effective measures to avoid pregnancy in their 
partner at all times, even after vasectomy, for 3 months after the last dose.  
 Females are reminded that they must use 2 effective methods to avoid pregnancy for 1 
month prior to start of study medication, during therapy, and for 9 months after 
completing therapy.  
 For  women who do not want to conceive in the future but are still women of 
childbearing potential: 
o Two negative pregnancy tests with a sensitivity of at least 25 mIU/mL at least 19 
days apart  
o For patients with regular menstrual cycles, the second pregnancy test should be 
done during the first 5 days of the menstrual period immediately preceding the 
beginning of therapy and after the patient has used 2 effective measures to avoid 
pregnancy for 1 month. 
o For patients with amenorrhea, irregular cycles, or using a contraceptive method 
that precludes withdrawal bleeding, the second pregnancy test must be done 
immediately preceding the  beginning of therapy and after the patient has used 2 
effective measures to avoid pregnancy for 1 month. 
 Laboratory evaluation at baseline to evaluate abnormalities in hematocrit/platelet counts, 
renal or hepatic function and electrolytes. 
 
6.1.1.1 
Target lesion selection 
 If multiple lesions are deemed to be suspicious for basal cell skin cancer on visual 
inspection, up to 4 lesions will be considered for investigation and designated “potential 
target lesions”.  Potential target lesion(s) will be selected at clinician discretion using 
clinical and dermoscopic findings and in consideration of patient preference.  
 Measurement pre- and post-biopsy and high resolution digital photography of potential 
target lesion(s). 


15 
v.3.1 January 27, 2017  
 Template map drawing of clinically evident tumor margins and local landmarks using a 
permanent marker on a clear plastic overlay.  
 To confirm diagnosis of BCC and to designate histologic subtype, up to three 
representative 2-mm or three representative 3-mm punch biopsies will be performed on 
each potential target lesion. 
o Skin biopsies performed at Pre-study Screening visit will comprise no more than 
10% of visible lesion surface area.  
o Skin biopsies must be performed at least 1 mm from peripheral margin of visible 
lesion. 
 Biopsy of each potential target lesion will be performed in area that clinically appears to 
be thickest by inspection at palpation.  If the potential target lesion appears to be 
homogenous, the biopsy will be performed at the center of the lesion. 
 Post-biopsy pre-treatment lesion area will also be recorded and template drawn.   
 
 
6.1.2 Treatment Initiation Visit (Baseline/Day 1) 
 
The objective of this visit is to ensure that subjects who will enter the study continue to meet all 
inclusion and exclusion criteria and to perform baseline evaluations of the biopsy-confirmed 
BCC target lesion site.   
 
For subjects with >1 histologically-confirmed BCC identified at Pre-study Screening Visit, target 
lesion assignment for primary endpoint analysis is described in Section 9.2.1  Target lesion 
assignment. 
 
The study visit should occur within 4 weeks of Pre-study Screening visit.   
 
The following procedures will be performed at Treatment Initiation Visit (Baseline/Day 1) after 
confirmation that the subject has met all inclusion criteria and has no exclusion criteria present: 
 Assessment of any changes (deletions, additions, or dose modifications) to medications. 
 Complete physical examination including general appearance, skin exam, and visual 
inspection of target lesion. 
 Vital signs (BP; heart or pulse rate; and oral, tympanic, or temporal temperature). 
 Weight and height measurements.  
 Urine pregnancy test (α--hCG) for women who are of childbearing potential. 
Photography and measurement of target lesion(s) with ruler visible in photographic field 
 Template map drawing of clinically evident tumor margins and local landmarks using a 
permanent marker on a clear plastic overlay.  
 Complete an evaluation of target tumor, including: 
 Tumor measurement/dimensions Photograph target lesion  
 Adverse Event (AE) Monitoring. 
 Subjects will complete the Patient Reported Outcomes (PRO) questionnaire: SKINDEX-
16 to obtain baseline information.  (Appendix 6) 
 Dispense study drug bottles. 
 Provide appropriate training and specific written instructions for study drug (capsules) 
self-administer by subject. 


16 
v.3.1 January 27, 2017  
 Observe subject administer first dose of study drug (on Day 1 only) 
 Review subject diary and instructions on completion for daily dosing/drug accountability. 
The subject will be instructed to begin data diary recording at home. 
 Reminder to use effective measures to avoid pregnancy 
 Subject will be a given written instructions for adverse event monitoring, measures to 
avoid pregnancy and avoiding of blood production products (Appendix 7.) 
 
 
6.1.2 
Interval Visits 
 
The objectives of these interval visits are to provide a systematic and objective evaluation of the 
target tumor, and to monitor subject safety while ensuring continued compliance with study 
procedures.  Every attempt should be made to have individual subject assessments performed by 
the same physician (investigator or equally qualified physician listed on FDA form 1572), 
preferably on the same day of the week for each visit. 
 
The following procedures will be performed at all visits during treatment: 
 Assessment of any changes (deletions, additions, or dose modifications) to medications. 
 Complete physical examination including general appearance, skin exam, and visual 
inspection of target lesion(s). 
 Vital signs (BP; heart or pulse rate; and oral, tympanic, or temporal temperature). 
 Weight and height measurements.  
 Urine pregnancy test (α--hCG) only for women who are of childbearing potential.  
 laboratory evaluation to evaluate abnormalities in hematocrit/platelet counts, renal or 
hepatic function and electrolytes if deemed necessary by the investigator. 
 Photography and measurement of target lesion with ruler visible in photographic field 
 Template map drawing of clinically evident tumor margins and local landmarks using a 
permanent marker on a clear plastic overlay.  
 Adverse Event (AE) Monitoring. 
 Review subject dosing dairy and conduct accountability of used and unused study drug 
returned by the subject to determine study drug dosing regimen compliance. 
 Collect unused study drug and re-dispense study drug 
 Observe subject administer doses of study drug and document in the dosing diary. 
 Clinical Response Evaluation by investigator (See below Section 6.2.2, Clinical response 
evaluation of target lesion for instructions) 
 Reminder to use effective measures to avoid pregnancy 
 Remind subjects to bring all unused drug supplies with them to their next scheduled visit. 
 
Week 8, 16, and 24, Surgery Visit, Study Exit Visit (Post-Surgery Visit): PRO questionnaires 
will be performed by the subject (SKINDEX-16 and Functional Assessment of Cancer Therapy – 
General (FACT-G).  (Appendix 7 and 9.)   
 
At week 12, Intra-treatment tissue histopathologic evaluation will be performed to assess 
histologic response.  For subjects with apparent clinical complete response at Week 12 and no 
histologic evidence of disease is observed, subjects will enter the observation period and be 
followed clinically every 3 months up to one year (See Appendix 5, Figure 3 for more 


17 
v.3.1 January 27, 2017  
information).  Sample diagrams demonstrating the sites of screening biopsies and Week 12 
biopsies for a tumor is seen in Section 6.1.3.   
 
 
6.1.3 
Intra-treatment Tissue Histopathologic Evaluation 
 
All subjects will undergo intra-treatment Tissue Histopathologic Evaluation at Week 12 visit.  
For lesions that display complete clinical response, histologic presence or absence of tumor on 
biopsy determines whether or not the subject is eligible to end treatment early and enter the 
Observation period (See Appendix 5 , Figure 3).  Subjects with clinical partial response or stable 
disease at Week 12 visit will continue treatment for the full duration of 24 week regardless of 
pathology on sampling biopsy (See Appendix 5, Figure 2). 
 
Tumors Exhibiting Complete Clinical Response 
For lesions that the investigator has determined to show complete clinical response at Week 12 
visit, sampling biopsy will be performed at the farthest edge(s) of pre-biopsy lesion compared to 
location of initial punch biopsy/biopsies at Pre-study Screening Visit (See Figure 1 A).  Up to 
three 2-mm or three 3-mm punch biopsies will be performed on the area of tumor clearance at 
Week 12 when possible. Tumor biopsies may comprise no more than 10% of visible lesion seen 
at screening visit. 
 
 
Figure 1.  Site of Week 12 biopsies for tumors with exhibiting complete clinical response. 
 
 
For lesions that display partial clinical response or stable disease by clinical response evaluation, 
“Residual Tumor Assessment” and “Area of Tumor Clearance Assessment” will be performed 
(See Figure 2.).   
 
 
Residual Tumor Assessment 


18 
v.3.1 January 27, 2017  
A single 2-mm or 3-mm punch biopsy or up to three 2-mm or three 3-mm sampling punch 
biopsies will be performed on the residual tumor. 
 Biopsy must be performed in area not previously biopsied. 
 Biopsy of residual tumor should be performed at least 1 mm from the peripheral margin 
of visible or palpable lesion 
  Tumor biopsies performed at Week 12 visit will comprise no more than 10% of visible 
lesion surface area.  
 
 
Area of Tumor Clearance Assessment 
Up to three 2-mm or three 3-mm punch biopsies will be performed on the area of tumor 
clearance at Week 12 when possible.  
 
 
 
Figure 2.  Site of Biopsies at Pre-study Screening Visit and Week 12 visit for tumors exhibiting clinical partial response or  
  stable disease. 
 
 
6.1.4 
End of Treatment visit (Week 24) 
Any unused study drug will be collected.   
 
After 24 weeks of treatment, all subjects will undergo sampling biopsy/biopsies.  If residual 
histologic disease is detected, surgical excision will be performed within 4 weeks of last dose of 
study drug.  If no histologic evidence of disease is observed, subjects will enter the observation 
period and be followed clinically every 3 months up to one year.  (See Appendix 5, Figure 1 and 
Figure 2.) 
 
Biopsies at Week 24 visit will be performed in similar manner as performed at the Week 12 visit.   
 


19 
v.3.1 January 27, 2017  
For lesions that the investigator has determined to show complete clinical response at Week 24 
visit, sampling biopsy will be performed at the farthest edge(s) of pre-biopsy lesion compared to 
location of initial punch biopsy/biopsies at Pre-study Screening Visit and sites of biopsies 
performed at Week 24 visit (See Figure 3).  Up to three 2-mm or three 3-mm punch biopsies will 
be performed on the area of tumor clearance at Week 24 when possible. Tumor biopsies may 
comprise no more than 10% of visible lesion seen at screening visit. 
 
Figure 3.  Site of biopsies for tumors displaying clinical complete response at Week 24 visit. 
 
 
For lesions that display partial clinical response or stable disease by clinical response evaluation, 
“Residual Tumor Assessment” and “Area of Tumor Clearance Assessment” will be performed 
(See Figure 4) 
 
 
Residual Tumor Assessment 
A single 2-mm or 3-mm punch biopsy or up to three 2-mm or three 3-mm sampling punch 
biopsies will be performed on the residual tumor. 
 Biopsy must be performed in area not previously biopsied. 
 Biopsy of residual tumor should be performed at least 1 mm from the peripheral margin 
of visible or palpable lesion 
  Tumor biopsies performed at Week 24 visit will comprise no more than 10% of visible 
lesion surface area.  
 
 
Area of Tumor Clearance Assessment 
Up to three 2-mm or three 3-mm punch biopsies will be performed on the area of tumor 
clearance at Week 24 when possible.  
 
 


20 
v.3.1 January 27, 2017  
Figure 4.  Site of biopsies for tumors that display partial response or stable disease at Week 24 visit. 
 
 
 
6.1.5 
Early Termination 
If a subject discontinues from the study early (due to patient decision to discontinue or disease 
progression), the study procedures will be completed as described for Week 24. 
 
 
6.1.6 
Surgery visit 
Subjects that are found to have histologic evidence of disease on biopsies performed at Week 24 
visit will undergo surgical excision.  This visit should be scheduled to occur with 4 weeks of last 
dose of study drug and will be performed as standard of care treatment. 
 
For lesions that display clinical partial response or stable disease and that show histologic 
evidence of disease on sampling biopsy at Week 24 visit, residual visible or palpable tumor of 
target lesion will be removed using the standard Slow Mohs micrographic surgery, margin-
controlled excision with rush permanent sections.  Two types of specimens will be surgically 
removed at the time of surgical excision. First, the area of known BCC will be excised and will 
include the pre-biopsy area.  This specimen will be labeled the tumor “debulking” specimen. 
 
Second, marginal tissue will be excised in an attempt to completely remove the tumor until clear 
surgical margins are obtained, providing the patient the known standard of care.  This tissue will 
be labeled “tumor margins” specimen. Peripheral and deep margins will be examined and 
recorded if positive or negative.  If either peripheral or deep margins is positive, additional 
surgical excisions will be done in the Mohs tissue orientation fashion  until no tumor cells are 
observed and surgical margins are deemed negative, as is standard of care.  In the event that only 
superficial BCC (sBCC) remains at the surgical margin, it will be at the discretion of the 
managing physician if further surgery, an alternative treatment modality, or observation will 
occur. 


21 
v.3.1 January 27, 2017  
For lesions that were deemed by investigator to exhibit complete clinical response at week 24 
visit, but were found to have residual disease on the sampling biopsy at week 24 visit, the 
debulking specimen will include area of known BCC as seen on histology. 
 
 
6.1.7 
Study Exit Visit (Post-Surgery Visit) 
This study visit should be scheduled to occur within 4 weeks of surgical excision or Mohs 
surgery, performed as standard of care treatment. 
 
The following procedures will be performed: 
 Assessment of any changes (deletions, additions, or dose modifications) to medications 
(noting exclusions, restrictions, and prohibited medications)  
 Complete physical examination including general appearance, skin exam, and visual 
inspection of surgical site of target lesion(s). 
 Vital signs (BP; heart or pulse rate; and oral, tympanic, or temporal temperature). 
 Weight and high measurements. 
 Urine pregnancy test (α-hCG) only for women who are of childbearing potential.  
 Surgical site photography  
 Adverse Event (AE) Monitoring. 
 
6.1.8 
Observation period 
All subjects will be followed for the observation period of 1 year after discontinuation of study 
medication. 
 
During the observation period the subjects will followed every 3 months for 1 year after last 
dose. 
 
The following study procedures during observation period: 
 Assessment of any changes (deletions, additions, or dose modifications) to medications. 
 Complete physical examination including general appearance, skin exam, and visual 
inspection of target lesion(s) area. 
 Vital signs (BP; heart or pulse rate; and oral, tympanic, or temporal temperature). 
 Weight and height measurements.  
 Urine pregnancy test (α--hCG) only for women who are of childbearing potential for 
visits within 7 months of last dose of study drug.  
 Photography and measurement of target lesion area  
 Adverse Event (AE) Monitoring. 
 Reminder to use effective measures to avoid pregnancy (for women who are of child 
bearing potential for visits within 7 months of last dose of study drug).  
 PRO questionnaires will be performed by the subject (SKINDEX-16 and Functional 
Assessment of Cancer Therapy – General (FACT-G) at first visit during Observation 
period (3 months after discontinuing treatment).   
 
If a subject is noted to have a recurrence of target lesion or new lesions suspicious for BCCs on 
any part of the body, biopsy will be performed to confirm diagnosis.  If pathology is consistent 
with basal cell carcinoma, the subject will exit the Observation period and all treatment options 


22 
v.3.1 January 27, 2017  
will be discussed with the subject.  If Mohs micrographic surgery is determined to be the best 
therapeutic option, surgical excision and study procedures will be performed as described in 
Section 6.1.6.   
 
Subjects who underwent surgical excision of the target lesion may elect to be followed by phone 
contact every 3 months to provide information on the status of the surgical site and occurrence of 
any adverse events. 
 
 
6.2 
METHODS OF ASSESSMENT 
 
6.2.1 
Measurement of Target Tumor  
 
At the treatment initiation visit, the baseline size of the target tumor will be determined by 
measuring the 2 largest perpendicular diameters of the target tumor. Target tumor size will be 
measured at each visit 
  
6.2.2 
Clinical response evaluation of target lesion 
Measurements of longest length and perpendicular diameter of target lesion(s) will be recorded 
at each interval visit and compared template map drawn treatment initiation visit.  
 
Complete response will be defined as the disappearance of a palpable or visible tumor. 
 
Partial response will be defined as a reduction of more than 50% in the diameter of a 
palpable or visible tumor.  
 
Stable disease will be defined as no change in diameter of palpable or visible tumor or a 
reduction of up to 50% in the diameter of a palpable or visible tumor. 
 
Disease progression will be defined as increase of 20% in either perpendicular diameter 
of a palpable or visible tumor. 
 
6.2.3 
Measurement of Wound Size  
 
 
Wound size will be measured post-excision to all subjects.  
 
6.2.4 
Photographs of Target Tumor 
 
Photographs of the target tumor will aid in tracking the changes in the tumor.  Photographs of the 
target tumor should be taken at the pre-study screening visit before and after biopsy, at the 
treatment initiation visit, at each interval visit, at the Mohs surgery visit, and at study exit visits. 
 
 
6.3 
HISTOPATHOLOGIC EVALUATION 
 
6.3.1 
Histologic Subtype Definitions 
 


23 
v.3.1 January 27, 2017  
Histologic subtypes will be assigned according to the standard classification into 
infiltrative/morpheaform, nodular, or subtypes (Sexton et al, 1990.)  Tumors with more than one 
subtype (i.e. “mixed” subtype) will be categorized by the most aggressive subtype.  The tumor 
subtypes will also be recorded by their percentage comprising the BCC tumor. 
 
Histologic subtypes will be defined as Table 1. 
 
 Histologic subtype 
                                                     Definition 
 
Nodular (70%) 
Large and small, well-circumscribed nests of basaloid cells in the dermis, 
accompanied by slit-like retraction from surrounding stroma 
 
 
Superficial (10-15%) 
Proliferation of atypical basaloid cells parallel and superficially confined to the 
epidermis with slit-like retraction of the palisaded basal cells from subjacent 
stroma 
 
 
Morpheaform (5-10%) 
One to two cells thick columns of basaloid cells enmeshed in a dense collagenized 
stroma containing proplastic fibroblasts.  The tumors are poorly demarcated, 
showing widespread invasion of the reticular dermis and penetration in the 
subcutaneous tissue 
 
Infiltrative (5-10%) 
 
Irregularly sized and shaped nests of tumor cells with sharp angulation of their 
peripheral contours and occasional foci of slit-like retraction; frequently fibrotic 
stroma with plumb desmoplastic stromal fibroblasts. 
 
       Table 1.  Histologic classification of BCC (Adopted from Mosterd et al 2011.) 
 
 
6.3.2 
Pre-study Screening Visit biopsy specimens 
Biopsy specimens will be processed by Saint Louis University Department of Dermatology’s 
Dermatopathology Laboratory for hematoxylin and eosin (H&E) assessment and 
immunohistochemical staining.  Histologic assessment will be performed by a board-certified 
Dermatopathologist.  If pathology of the target lesion does not demonstrate basal cell skin 
cancer, the subject will be excluded from the study.   
 
Breslow depth or “invasion index” of deepest basal cell skin cancer cells will be recorded.  This 
may include small nests of cells outside of the bulk of the tumor.   
 
The thickness of the tumor will be measured from below the stratum corneum to the bottom of 
the deepest tumor nest using an ocular micrometer (Pierre Verniers method) to the precision of 
0.1 mm.  Tumor thickness and investigation of disease-free deep margin will be defined as at 
least 0.1 mm of tumor-free tissue.  
 
If more than one sampling biopsy was performed on a target lesion, the most aggressive subtype 
and the depth of the deepest tumor cells on any biopsy will be recorded. 
 
In tumors with multiple subtypes, a diagram will be created to denote areas of each histological 
subtype to determine anatomic location of cells of different subtypes and depth of tumor cells of 
different histological subtype. 
 


24 
v.3.1 January 27, 2017  
Photography of pathologic slide will be performed. 
 
Immunohistochemical evaluation of tumor tissue will also be performed in order to estimate the 
cellular density and composition of the pre-treatment lesion.  
 
 
6.3.3 
Week 12 and Week 24 Visit biopsy specimens 
 Week 12 and Week 24 biopsy specimens will be processed and examined in the manner 
outlined for biopsies performed during the screening visits.   
 
 Residual tumor 
o Evidence of any histologic change in residual tumor tissue compared to pre-
treatment biopsy specimens  
o Estimate of changes in cellular density and composition compared to screening 
visit 
 
 Area of Tumor Clearance 
o Assessment of histologic clearance in areas of apparent clinical tumor clearance 
 
Additional immunohistochemical staining with anticytokeratin (AE1/AE3) and Ber-EP4 will be 
performed to delineate tumor from inflammation when necessary.   
 
 
6.3.4 
Surgical Excision specimen 
Pathologic evaluation of “debulking” specimen and “tumor margins” specimen will be 
performed in the manner of the biopsy and Week 12 specimens.  Breslow depth of area this 
measurement will be used to determine quantitative histological response of deepest part of 
lesion.  Histopathologic subtype(s) will be recorded, and comment made as to tissue location of 
each subtype noted.  Photography of surgical specimens will also be performed.   In a manner as 
performed on biopsy specimen, diagram will be created to include tracing of different areas of 
histological subtype.  Depth of deepest tumor cells will be recorded.  A percentage estimate will 
be determined as to the histologic subtypes of the majority of tumor cells within the surgical 
specimen.   
 
FUTURE USE OF BLOOD, TISSUE OR DATA 
The investigator will request permission from subjects to allow tissue to be used in the future for 
research purposes.  Subjects may decline future use of tissue. The specimens taken during the 
tissue collection as specified for this research study include the sample to be used in the future. 
No extra tissue will be taken for future research purposes. 
 
 The tissue may be used to further evaluate Basal Cell Skin Cancer.  All tissue specimens will be 
labeled with a study ID code, and study assigned pathology number.  The investigator will 
maintain a list of the participants and code numbers in a locked file with access limited to the 
study team. 
 


25 
v.3.1 January 27, 2017  
The investigator may share the tissue (with code only) with other researchers at Saint Louis 
University and at other research centers. Other investigators will not have access to identifying 
information.   
   
All specimens will be kept indefinitely, and will be maintained in the Biospecimens 
Accessioning and Processing (BAP) Core Lab at Mayo Clinic Florida. .   
 
 
6.4 
INTERCURRENT DISEASE TREATMENT AND CONCOMITANT 
MEDICATIONS 
 
6.4.1 
Intercurrent Disease Treatment 
 
Subjects who develop additional tumors during the study may receive conventional forms of 
treatment for the non-target tumors during the treatment and follow-up periods if the following 
criteria are met: 
 
 The tumor(s) are sufficiently distal from the target tumor to prevent interference with the 
target tumor (at least 5 cm) 
 The treatment is not listed in Exclusion Criteria  
 The treatment will not affect the target lesion(s) 
 
6.4.2 
Concomitant Medications 
 
The investigator will record any medications given in treatment of AEs on the appropriate CRF 
page.  Any medication taken by the subject during the course of the study should also be 
recorded on this form.  Local anesthetics used for pre-study biopsies and target tumor excisions 
need not be recorded.  Over-the-counter medicinal products (dietary supplements, herbal 
medications, etc) should also be recorded.  Data recorded will include name of the medication, 
dose, unit, frequency, route, indication, and start and stop dates. 
 
6.5 
SUBJECT COMMITMENT TO STUDY 
 
The duration of each subject’s participation in the study will be approximately 28 weeks.  
Subjects will be expected to visit the clinic for 10 scheduled study visits.  Up to 12 (three 
sampling biopsies on 4 possible target lesions) will be performed at the pre-study screening visit, 
12  punch biopsies at Week 12 visit and a complete Mohs excision may be performed at the 
target tumor site at the Mohs procedure visit within 4 weeks after the end-of-treatment visit.  
Subjects are expected to adhere to daily administration of medication during 24 weeks of 
treatment and take appropriate measures to avoid pregnancy and avoid donation of blood up to 9 
months after last dose. 
 
6.6 
SUBJECT WITHDRAWAL OR DISCONTINUATION 
 
6.6.1 
Subject Stopping Criteria 
 


26 
v.3.1 January 27, 2017  
The following objective measures have been defined as subject stopping criteria. If a subject 
presents with any of these characteristics, treatment with vismodegib will be stopped before 24 
weeks: 
1) Pregnancy 
2) 20% increase in target lesion tumor size 
 
 
6.6.2 
Other Withdrawal or Discontinuations 
 
Subjects may withdraw themselves or have the investigator withdraw them from the study at any 
time without prejudice to their future medical care.  Any subject who does not comply with the 
inclusion/exclusion criteria will be withdrawn from further participation in the study.  Subjects 
may also be discontinued if the investigator has determined that the subject has AEs of severe 
intensity or duration to warrant discontinuation.  If a subject discontinues due to AE, the subject 
will be followed until the AE has resolved. 
  
Any subject who receives study medications or placebo must complete EOT procedures 
including the Mohs surgical excision, and the investigator must complete the end-of-study 
Subject Status form. 
 
The investigator is encouraged to carefully select subjects who are likely to complete all study 
procedures. 
 
6.7 
TREATING OVERDOSE 
 
Overdose is unexpected due to the dose level administered with oral administration.   There is no 
information on overdosage in humans. In clinical trials, vismodegib capsule was administered at 
540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 
 
6.8 
PREGNANCY 
 
Vismodegib is teratogenic. As clinical studies of vismodegib have not been conducted in 
pregnant humans, subjects who become pregnant during the study must inform the investigator 
immediately of their pregnancy, and agree to provide follow-up information regarding the 
outcome of the pregnancy. In addition, there is the unknown potential irreversible affect on 
fertility with data showed in earlier studies of amenorrhea.  Subjects (male and female) who 
desire to conceive in the future are excluded from the study. 
 
Females of reproductive potential must use effective measures to avoid pregnancy during therapy 
and for 1 month prior to the start of the study medication, and for 9 months after completing 
therapy.  Male patients must use effective measures to avoid pregnancy in their partner, even 
after vasectomy, during sexual intercourse with females during treatment and for 3 months after 
the last dose to avoid exposing a pregnant partner and the unborn fetus to vismodegib. 
Vismodegib is contraindicated in nursing mothers during treatment and for 9 months after the 
last dose. In addition, subjects will be instructed not to donate blood or blood products while on 
treatment and for 9 months after the last dose of vismodegib.   


27 
v.3.1 January 27, 2017  
 
The anticipated pregnancy prevention program includes the following measures for women of 
childbearing potential: 
a) two negative pregnancy tests with a sensitivity of at least 25 mIU/mL at least 19 days 
apart  prior to starting study medication.  For patients with regular menstrual cycles, the 
second pregnancy test should be done during the first 5 days of the menstrual period 
immediately preceding the beginning of therapy and after the patient has used 2 forms of 
contraception for 1 month. For patients with amenorrhea, irregular cycles, or using a 
contraceptive method that precludes withdrawal bleeding, the second pregnancy test must 
be done immediately preceding the  beginning of therapy and after the patient has used 2 
forms of contraception for 1 month. 
b) Urine pregnancy test at each visit. 
c) Female patients must use 2 effective methods to avoid pregnancy for 1 month prior to 
start of study medication, during therapy, and for 9 months after completing therapy.  
 
Male patients must use effective measures to avoid pregnancy in their partner at all times, even 
after vasectomy, for 3 months after the last dose(condom with spermicide is the effective method 
of contraception per approved labeling for vismodegib). 
a) Study medication will NOT be dispensed at each visit until the results of pregnancy have 
been reviewed by the study investigator. 
b) Reminder to use effective measures to avoid pregnancy will be performed throughout the 
study treatment for both men and women 
 
Female patients do not have to follow the aforementioned measures to avoid pregnancy IF they 
agree to abide to the following conditions: 
• have stopped having their period for 12 months in a row (menopause) and their doctor 
says they are in menopause or clinically fit the criteria for menopause 
• had both of their ovaries or uterus taken out by surgery 
• their ovaries do not work and they cannot get pregnant (confirmed by their doctor) 
 
7. 
REPORTING OF ADVERSE EVENTS 
 
7.1 
ASSESSMENT OF SAFETY 
 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) that are considered related to study drug, all events of death, and any 
study specific issue of concern. 
 
7.1.1 
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: 


28 
v.3.1 January 27, 2017  
• AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with Basal Cell Carcinoma that 
were not present prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
 
7.1.2 
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). 
 
7.2 
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). 
 
7.2.1 
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.  Any subject 
who has an adverse event deemed related to the study treatment in this trial, will be followed 
until reversibility is established. This may occur after study completion at the subject’s 
regular clinic follow-up visits.  
 


29 
v.3.1 January 27, 2017  
7.2.2 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through general skin 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 
study drug, 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 study 
drug; and/or the AE abates or resolves upon discontinuation of study drug or dose reduction and, 
if applicable, reappears upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than the study drug (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has 
no plausible temporal relationship to study drug administration (e.g., cancer diagnosed 2 days 
after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator 
Brochure (I.B.) or not identified. This includes adverse events for which the specificity or 
severity is not consistent with the description in the P.I. or I.B. For example, under this 
definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated 
hepatic enzymes or hepatitis. 
 
7.3 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
 
7.3.1 
Eliciting Adverse Events 
 
A consistent methodology for eliciting AEs at all subject evaluation time points 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?”  
 
7.3.2 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
 


30 
v.3.1 January 27, 2017  
7.3.2.1 
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 ok to report the 
information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
 
7.3.2.2 
Deaths 
All deaths that occur during the protocol-specified AE reporting period regardless of attribution, 
will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death”. 
 
7.3.2.3 
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”). 
 
7.3.2.4 
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. 
 
7.3.2.5 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 9 months 
after the last dose of VISMODEGIB, a report should be completed and expeditiously submitted 
to the Genentech, Inc. 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 the VISMODEGIB should be reported as an SAE. 
 


31 
v.3.1 January 27, 2017  
7.3.2.6 
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.  
 
7.3.2.7 
Reconciliation of Study Drug Supply 
Investigators should conduct reconciliation for the product. Genentech and the investigator will 
agree to the reconciliation periodicity and format, but agree at minimum to exchange monthly 
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. 
 
7.3.2.8 
SAE Reporting 
Investigators must report all SAEs 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) 225-5288 
 
• Relevant follow-up information should be submitted to Genentech Drug Safety as soon as 
it becomes available. 
• Serious AE reports that are related to study drug will be transmitted to Genentech within 
fifteen (15) calendar days of the Awareness Date. 
• Serious AE reports that are unrelated to study drug will be transmitted to Genentech 
within thirty (30) calendar days of the Awareness Date. 
• Additional Reporting Requirements to Genentech include the following: 
• Any reports of pregnancy following the start of administration with VISMODEGIB will 
be transmitted to Genentech within thirty (30) calendar days of the Awareness Date.  
• All Non-serious Adverse Events originating from the Study will be forwarded, at most, 
on a quarterly report to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
 
7.3.3 
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 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 


32 
v.3.1 January 27, 2017  
• 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 and adverse event was reported. For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative noted above or the 
MSL assigned to the study. Relevant follow-up information should be submitted to Genentech 
Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
7.3.4 
Additional Reporting Requirements for IND Holders 
For Investigator-Sponsored IND Studies, some additional reporting requirements for the FDA 
apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
 
7 Calendar Day Telephone or Fax Report: 
The 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 study drug. An 
unexpected adverse event is one that is not already described in the study drug Investigator 
Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech within 7 
calendar days of first learning of the event. 
 
 
15 Calendar Day Written Report: 
The Investigator is also required to notify the FDA and all participating investigators, in a written 
IND Safety Report, of any serious, unexpected AE that is considered reasonably or possibly 
related to the use of study drug. An unexpected adverse event is one that is not already described 
in the study drug investigator brochure. 
 


33 
v.3.1 January 27, 2017  
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32. All safety reports previously filed by the investigator with the IND 
concerning similar events should be analyzed and the significance of the new report in light of 
the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a Medwatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
Genentech Drug Safety: Fax: (650) 225-4682 or (650) 225-5288 
 
And to the Site IRB:  
Saint Louis University 
Institutional Review Board 
3556 Caroline Street 
Caroline Building C110 
St. Louis, MO 63104 
Phone: 314-977-7744 
Fax: 314-977-7730  
 
For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 
IND Annual Reports 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. Copies of such reports should be faxed to Genentech Drug Safety: Fax: (650) 225-
4682 or (650) 225-5288 
 
 
7.4 
Data Safety Monitoring Plan  
Due to the potential risk of adverse side effects, patients will be monitored closely during the 
study period as described in protocol Section 6, 7.1, 7.2 and section 12.7.  Study participants will 
be able to contact one of the study physicians at any time with questions and concerns. All 
adverse events will be recorded, scored for severity and for relationship to the study as described 
in Section 7.3. Adverse event data will be reviewed periodically by the study team. All serious 
and unexpected adverse events will be reported to the IRB and regulatory authority as described 
in Section 7.3.  


34 
v.3.1 January 27, 2017  
8. 
MATERIALS AND SUPPLIES 
 
8.1 
STUDY DRUG 
 
Study drugs will be provided by Genentech or a designated facility working under contract for 
Genentech to Saint Louis University, Department of Dermatology.  
 
Study drug should be taken at approximately the same time each day, with or without food.  
Capsules must be swallowed whole and must not be opened under any circumstances.  If a 
patient misses a dose (e.g., due to emesis), he or she should be instructed not to take or make up 
that dose and to resume dosing with the next scheduled dose.  Missed doses will not be made 
up.  Patients will be instructed to bring all unused capsules to each study visit for assessment of 
compliance. 
 
Sufficient drug supplies for 36 subjects will be packaged, and labeled.  Drug supplies will be 
numbered in sequential order.  The study center should assign study drug in sequential order.  
The remaining supplies will be made available should additional subjects or study centers be 
required to reach the enrollment goal of 36 total subjects. 
 
Small, resealable plastic bags will be given to each subject for returning used and opened 
medication to the clinic.  Resealable bags will be dispensed at the same time medication is 
dispensed. 
 
At the Treatment Initiation Visit (Baseline/Day 1), and at the monthly interval, the study center 
will dispense a bottle of study drug to be used until the next interval visit at which drug will be 
dispensed.   
 
At each time medication is dispensed: 
• Dispense a resealable plastic bag  
• Write the date dispensed on both sides of the 2-part label, located on the carton 
• Affix the detachable portion of the 2-part label to the appropriate CRF page 
 
All medication, both used and unused will be destroyed according to standard operating 
procedure at Saint Louis University at the completion of the study. 
 
8.2 
STUDY DRUG LABELING 
 
Clinical supplies will be labeled with the following minimum information: 
• Protocol ID Number 
• Investigator Name 
• Drug name (or description) 
• Drug strength 
• Dosage form 
• Quantity per container 
• Instructions for use 
• Keep out of the reach of children 
• Storage conditions 


35 
v.3.1 January 27, 2017  
• Expiration date 
• Investigational drug caution statement(s) 
• Subject number 
• Date dispensed (to be written in) 
• Subject initials (to be written in) 
 
Each time study drug is dispensed, study center personnel should write the date the drug is 
dispensed and the subject initials on both the permanent and detachable labels of the bottle.  The 
study center should also complete the Drug Inventory Form each time study drug is dispensed. 
 
8.3 
STUDY DRUG INVENTORY AND STORAGE 
 
The investigator will take the following actions with regard to study drugs in concurrence with 
international regulatory requirements. 
 
1. Upon receipt of clinical study materials the investigator or designated individual on the study 
team will check the details of the supplies and document receipt on invoice and DAR. 
2. The investigator will keep study drugs in a locked and secure storage facility, accessible only 
to those individuals authorized by the investigator to dispense this study drug. All study drug 
will be stored separately from any other medications. 
3. The investigator or designee will maintain a temperature log to ensure that study drug is 
stored at manufacturer recommended room-temperature at all times. 
4. The investigator or designated individual will maintain an inventory.  This will include the 
description and quantity of study drug received during the course of this study, as well as a 
record of the materials that are dispensed and returned (how much, to whom, and when).  
This inventory record shall indicate the quantity and description of all study drugs on hand at 
any time during the course of the study.   
5. At the conclusion or termination of this study, the investigator agrees to conduct a final drug 
supply inventory, to record the results of this inventory and destroy all remaining study drug 
on site by IDS. 
6. The investigator agrees not to supply study drug to any person except study personnel and 
subjects in this study. 
 
9. 
DATA ANALYSIS AND STATISTICAL PROCEDURES 
 
9.1 
SAMPLE SIZE DETERMINATION 
This is a pilot study to investigate efficacy of vismodegib in different histologic subtypes of 
BCCs.  A total of 36 subjects will be enrolled into the study.  The sample size for this study was 
selected to allow a sufficient number of subjects of histologic subtypes other than nodular BCC, 
the most common subtype presenting in clinical practices.  Superficial BCC and 
infiltrative/morpheaform subtypes have similar presentation rates.  The enrollment method 
provides assurances that that evaluable data will be available for at least 36 subjects across three 
subtype groups: infiltrative/morpheaform, superficial, and nodular. Refer to Section 9.2 for 
details on subgroup type assignment.  A sample size of 16 in the nodular group yields a 95% 
confidence interval of 54%-96% for an observed partial response rate.  The nodular group is 


36 
v.3.1 January 27, 2017  
included as part of the pilot study, in part, to assess the overall viability of the study.  It is 
important to note that response rate of approximately 75% is anticipated in the nodular group, 
based on the published literature; the sample size of 16 the nodular group is sufficient to detect 
this level of efficacy.  A sample size of 10 for the infiltrative/morpheaform and superficial BCC 
groups yields a 95% confidence interval of 10%-70%. Although the confidence intervals are 
wide, the sample sizes are sufficient to detect a response rate greater the null rate (0%), the 
expected efficacy level if the treatment had no effect in these histologic subtypes.  
 
9.2 
SUBJECT SUB-GROUP ASSIGNMENT 
A total of 36 subjects with infiltrative/morpheaform, nodular, or superficial BCC will be enrolled 
in the study.   For patients with multiple BCC lesions, one “target lesion” will be identified and 
used for subject sub-group assignment for the purposes of enrollment and followed for primary 
endpoint analysis.  For scientific purposes, data from BCC tumors other than “target lesion” will 
also be collected.  The lesion(s) biopsied at Screening Visit will be reviewed and each subject 
will be assigned to a subtype group as detailed below and in Figure 5.    
 
Step 1.  Infiltrative/morpheaform subtype lesion will be 
given priority in subject sub-group assignment.  
 
Step 2.  If a potential subject does not have a possible target 
lesion that is infiltrative/morpheaform subtype and has a 
superficial BCC, then the subject will be assigned to the 
superficial BCC subtype group.  
  
Step 3.  If no infiltrative/morpheaform BCC or superficial 
BCC are identified, then nodular BCC will be eligible for 
enrollment. 
  
 
 
 
 
 
 
 
       Figure 5.  Target Lesion Assignment Algorithm 
If there are two lesions that may be eligible for target lesion assignment based on histologic 
subtype, then the lesion with larger clinical dimensions will be designated the “target lesion”.  
See Appendix 10, Target Lesion Assignment Examples for more information. 
 
This “Target Lesion Assignment Algorithm” will continue in this fashion until any two of the 
subtype groups reaches 26.  This is to ensure that each subgroup has at least 10 subjects.  At this 
point, subjects enrolled must have at least 1 BCC of the remaining subtype group.  
 
9.3 
PARAMETERS TO BE MEASURED:   
 
9.3.1 
Primary Endpoints 
Efficacy of vismodegib in treatment of target lesion(s) by clinical and histologic response 
evaluation. 
 
9.3.1.1 
    Clinical Response  
 Comparison of number of target lesions in each of the following groups: 
o Complete response, partial response, stable disease, or disease progression as 
defined above  


37 
v.3.1 January 27, 2017  
 Overall response rate and best overall response rate 
 Comparison of maximum diameter and lesion area of target lesion(s) post-biopsy and at 
End of Treatment visit 
 Comparison of dimensions of tumor within “debulking” specimen at surgery visit with 
dimensions of pre-biopsy tumor 
 
9.3.1.2 
Histologic response (at Week 12 and Week 24/Surgical Visit) 
 Residual tumor 
o Evidence of any histologic change in residual tumor tissue compared to pre-
treatment biopsy specimens  
o Estimate of changes in cellular density and composition at Week 12 and Week 
24/Surgical Visit 
 
 Area of Tumor Clearance 
o Assessment of histologic clearance in areas of apparent clinical tumor clearance at 
Week 12 and Week 24, and/or Surgical Visit 
 
 Comparison of deepest “invasion index” on biopsy specimen, at Week 12 biopsy, and 
“debulking” specimen or “tumor margins” specimen” at Surgery visit 
 Histologic subtypes observed on pathologic specimens (Screening visit and Week 12 and 
Surgical excision specimen) Location and depth of specific tumor cells of each histologic 
subtype on biopsy, week 12 biopsy, and Surgical excision specimens 
 Percentage of each histologic subtype in tumor specimen on biopsy, Week 12 biopsy and 
surgical excision specimens 
 
9.3.2 
Secondary Endpoints 
 
9.3.2.1 
Onset of efficacy 
 Onset of efficacy during 24 weeks of treatment by clinical and histologic response 
o Histologic response measured at 12 weeks and after 24 weeks of treatment 
 Interval to best overall response during 24 weeks of treatment by clinical response 
 
9.3.2.2 
      Safety and Tolerability 
Monitoring of adverse effects, onset of specific adverse effects and adverse effects that lead to 
early termination of treatment. 
 
9.3.2.3 
      Patient Reported Outcomes/Quality of Life 
Evaluation of patient reported outcome (PRO) measures before, during 24 weeks of treatment 
with vismodegib through SKINDEX-16 and FACT-G questionnaires. (See Appendix VI and 
VIII.) 
 
9.3.3 
Efficacy Analysis 
 
9.3.3.1 
Analysis of Primary Endpoints 
 


38 
v.3.1 January 27, 2017  
9.3.3.1.1 
Clinical Response  
Comparison of dimensions of tumor within debulk specimen at surgery visit with dimensions of 
post-biopsy tumor as drawn on template at screening visit will be assessed by a t-test for 
independent samples.   
 
Sub-group analyses by histologic subtype will be conducted by demographic factors including: 
gender, race, and anatomic location of target lesion will also assessed for any independent 
association with clinical response.  Statistical significance was defined by alpha 0.05.  All 
analysis was performed using SPSS (PASW) version 18.  
 
Analysis of the following subgroups will be performed: 
 Nonaggressive subtypes vs. Aggressive subtypes  
 Clinical subtypes (infiltrative/morpheaform, nodular, and superficial) 
 
9.3.3.1.2 
Histologic response 
 
Chi-square analysis will be performed to assess histologic response of residual tumor and area of 
tumor clearance for all tumors and by histologic subtype.   
 
Comparison of the “invasion index” on biopsy specimen and excision specimen will be assessed 
by a t-test for independent samples. 
 
Histologic subtypes observed on biopsy specimen and excision specimen will be depicted in a 
frequency table and proportions of each histologic subtype will be compared using a t-test for 
dependent samples. 
 
Size estimate of tumor based on biopsy specimen to actual size of tumor specimen on day of 
surgical excision or Mohs surgery will be assessed by a t-test for independent samples. 
 
Location and depth of specific tumor cells of each histological subtype on biopsy and surgical 
specimen. 
 
9.3.3.2 
Analysis of Secondary Endpoints 
 
9.3.3.2.1 
Onset of Efficacy 
For each target lesion, interval to clinical response and best overall response will be recorded and 
a histogram depicting response to treatment will be created.  For subjects who discontinue 
treatment early due to disease progression or personal preference, interval of treatment will be 
recorded. 
 
9.3.3.2.2 
Safety and Tolerability 
Graded adverse events (number and percent) will be reported according to the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (version 4.0).  (See Appendix X.)   
Adverse events that lead to early discontinuation of treatment will also be tabulated. 
 


39 
v.3.1 January 27, 2017  
Percentage of patients able to complete 24-week treatment regimen will be recorded.  For 
patients that are unable to complete 24-week treatment regimen, average and median time of 
treatment will be assessed. 
 
9.3.3.2.3 
Patient Reported Outcomes 
Quality of life (QoL) during study participation and patient impression of adverse effect 
tolerability will be assessed. 
QoL will be assessed using patient reported outcomes (PRO) questionnaires at Baseline, Week 8, 
Week 16, and Week 24 study visit/End of treatment visit using the following validated measures: 
- 
FACT-G (v. 4), Functional Assessment of Cancer Therapy-General (Appendix VIII) 
- 
Skindex-16, a quality-of-life measure for patients with skin disease (Appendix VI.) 
 
9.4 
SAFETY ANALYSES 
All safety measures will be analyzed using the ITT data set.  For all statistical tests, an overall 
test will be done first to compare the safety measures among all groups 
 
9.4.1 
Adverse Events 
Adverse events will be summarized by using the NCI Common Terminology criteria for AE, 
version 4 (Appendix IX).  The incidence of AEs (percent of subjects reporting the AE at least 
once).  A separate tabulation of incidences will display only AEs coded as “probably” or 
“possibly” related to treatment. 
 
9.4.2 
Vital Signs and Dermatological Examination Data 
Dermatological Examination findings and vital signs will be tabulated.  Any clinically significant 
changes in either will be discussed in the study report. 
 
10. 
DATA SECURITY & CONFIDENTIALITY PLAN 
Clinical data will be collected at the time of enrollment from the patient’s medical record.  
Data will be entered into the study electronic database. The Study Coordinator will also use hard 
copy forms as worksheets.  The paper worksheets will be retained at the Dermatology Clinic in a 
locked file cabinet within a locked office until the study is complete and all study analyses and 
publications have been accomplished. These paper worksheets will be subject to site safety 
monitoring reviews. 
 
The data elements obtained and recorded when a patient is enrolled into the study are described 
in section 11 of the protocol. 
 
When the subject is enrolled in the study, a study number will be automatically provided. The 
research team will recode the dates of enrollment and birth to calculate the subject’s age, in days, 
and the resulting analytical database fulfills the definition of a de-identified database according 
to HIPAA definitions. 
 


40 
v.3.1 January 27, 2017  
10.1 
HARD-COPY DATA FORMS  
The investigators have a dedicated, locked research room within the Dermatology offices, and 
the building has 24 hour on-site security guards. Data forms will include the aforementioned data 
points, and will be kept in research binders in a locked cabinet. 
 
10.2 
ELECTRONIC DATA 
User authentication is maintained with user/group domain-level security, centralized to desktop 
computers that are password-protected. There will be no transfer of data over public networks.  
The de-identified electronic database, which contains raw research data will also be pass-word 
protected and maintained on the Saint Louis University Dermatology department’s secured 
server. Once the data is ready for analyses, it will be coded and locked. Analytical files will 
contain no identifiers and will contain accumulated data for report of findings. 
 
10.3 
CONFIDENTIALITY SECURITY PLAN 
The investigators and research staff are fully committed to the security and confidentiality of all 
data collected this study. All personnel involved in this study have signed confidentiality 
agreements concerning all data encountered in the study clinic. All personnel involved with this 
study have completed Human Subjects Protection and HIPAA education. 
 
11. 
FINAL STUDY REPORT 
 
A final study report will be prepared by the Principal Investigator at Saint Louis University, 
Department of Dermatology. 
 
12. 
ADMINISTRATIVE PROCEDURES 
 
12.1 
ETHICAL APPROVAL 
An IRB should safeguard the rights, safety, and well being of all study subjects.  The investigator 
is responsible for providing the IRB with all necessary documents for review.  This may include 
the following: 
• Study protocol/amendment(s) 
• Written subject information/informed consent form and updates 
• Subject recruitment procedures (e.g., advertisements) 
• Investigator brochure/product information 
• Information about payments and compensation available to subjects 
• Investigator’s current curriculum vitae and/or other documentation evidencing qualifications 
 
This study will only be undertaken when full approval has been obtained from the appropriate 
IRB and a copy of the approval is received by Genentech.  The approval letter or notice by the 
IRB must contain: 
• Name and address of IRB 
• Date of meeting 
• Sufficient information to identify the version of both the protocol and subject 
information/informed consent documents 
• Sufficient information to identify all other documents reviewed 
 


41 
v.3.1 January 27, 2017  
The investigator must submit all subsequent protocol amendments to IRB for approval, 
according to local practice.  The IRB should also be notified of any administrative changes made 
to the protocol. 
 
12.2 
REGULATORY APPROVAL 
This study requires application to the FDA for approval under the Investigational New Drug 
(IND) -application. 
 
12.3 
STUDY PERSONNEL 
The investigator should maintain a list of appropriately qualified persons to whom he/she has 
delegated significant study-related duties.  In addition, he/she should maintain a signature sheet 
to document signatures and initials of all persons authorized to make entries and/or corrections 
on study related documentation, including CRFs. 
 
12.4 
PARTICIPANT COMPENSATION AND ESEARCH-RELATED COSTS:   
There will be no cost for procedures that are a result of study participation while in the trial.  
Procedures (skin biopsies and surgical excision) that are standard of care will be billed to the 
patient’s insurance company.  Compensation for subject time and inconvenience is $30 for each 
study visit.  If all 10 scheduled visits are kept, a subject will receive a total of $300.  A prorated 
amount will be provided for subjects who do not complete every study visit.  Payment will be 
issued 4-6 weeks after study completion or study termination.   
 
12.5 
PRESTUDY DOCUMENTATION REQUIREMENTS 
Before shipment of study drug, the investigator must provide Genentech with the following 
documents: 
1. Final version of this protocol including any amendments in place before study initiation. 
2. Curriculum vitae or other statement of qualification of the principal investigator.  The 
minimum information to be included is name, address, appointment, qualifications, and 
previous and current work experience. 
3. IRB approval letter. 
4. Signed and dated contract and/or research agreement between Genentech and the 
investigator. 
 
12.6 
COMPLETION AND RETURN OF CASE REPORT FORMS 
The investigator is responsible for the quality of the data recorded in the CRF.  The data recorded 
should be a complete and accurate account of the subject’s record collected during the study. 
 
The investigator and study monitor will identify any data that will be recorded directly on the 
CRF and considered as source data (i.e., no prior written or electronic record of the data).   
All CRF entries should be made in black ink for duplication purposes.  The investigator must 
review all entries for completeness and correctness.  When changes or corrections are made on 
any CRF, the investigator or authorized persons must draw a single line through the error then 
initial and date the correction as well as stating the reason for the error, except when due to a 
transcription error.  The original entry should not be obscured. 
 


42 
v.3.1 January 27, 2017  
The investigator agrees to complete and sign CRFs in a timely fashion after completion of each 
subject and make them available to the study monitor for full inspection.  In addition, any data 
queries prepared after the original CRFs have been completed should be answered promptly. 
 
Before acceptance, the clinical monitor will review the CRFs for completeness and adherence to 
the protocol.   
 
12.7 
STUDY MONITORING 
The study will be monitored by qualified personnel from the Department of Dermatology at the 
Saint Louis University. A data monitoring plan will be developed prior to study initiation.  
 
The investigator or designated person should adhere to regulatory requirements and institutional 
policies for research records documentation and agree, as a minimum requirement, to record the 
following information in the subject source notes: 
• Protocol ID number, brief description or title of study 
• Statement that subject has given written consent 
• All visit dates 
• All AEs 
• All concomitant medications 
• Primary efficacy details (as defined by the protocol) 
 
Source data verification will be performed by the clinical monitor at each monitoring visit. 
 
12.8 
QUALITY ASSURANCE PROCEDURES 
Quality assurance activities undertaken during this study include monitoring and source data 
validation by the study monitor (see Section 13.6).  
 
12.9 
AMENDMENT TO PROTOCOL 
The investigator will not amend this protocol unless agreed upon in advance by Genentech. 
Approval of the amendment by the IRB must be obtained before implementation, with 2 
exceptions: 
 
1. When necessary to eliminate apparent immediate hazard to the subject. 
2. When the change involves logistical or administrative aspects of the study. 
 
   
12.10 
DEPARTURE FROM PROTOCOL FOR INDIVIDUAL SUBJECTS 
Deviations from a written protocol for individual subjects are inherent to clinical research and 
can be categorized as either departure from protocol or minor deviations.  A “Departure From 
Protocol” is a deviation of such magnitude as to affect the evaluability of the subject or to 
potentially compromise the statistical analysis.  A departure is usually an emergency or other 
circumstance that requires a decision be made as to whether the subject should be withdrawn 
from the study.  When a protocol departure or suspected departure occurs; it will be only for that 
subject.  The investigator will contact the study monitor or medical monitor by telephone to 
report the departure.  In the event they are not available, the following emergency number is in 
operation at all times: 


43 
v.3.1 January 27, 2017  
Saint Louis University Hospital  
(on-call Dermatology Resident) 
314-577-8000 
 
The investigator must complete a “Departure From Protocol” CRF entry for each departure. 
 
Minor deviations address procedural issues that do not affect subjects’ adherence to protocol 
requirements to the extent it could compromise their continued participation in the study, or the 
results of the study.  Minor deviations observed for a specific subject, or involving several 
subjects, must be recorded as a comment on the appropriate CRF page(s) for each involved 
subject. 
 
12.11 
RECORDS OF STUDY 
The investigator should retain essential documents until at least 2 years after the last approval of 
a marketing application in an International Conference on Harmonization (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with Genentech.   
 
Records to be retained by the investigator include, but are not restricted to the following: 
• Signed and dated study protocol and amendments 
• Investigator’s brochure and any updates 
• Investigator agreement, including financial agreement 
• Signed and dated informed consent documents 
• Copy of all versions of subject information documents (as appropriate) 
• Application(s) to IRB 
• Copy of approved advertisements 
• IRB approval letter(s) 
• IRB composition 
• Curriculum vitae of all study personnel 
• Pre-study and Follow-up Financial Disclosure Forms 
• Clinical laboratory normal ranges and any updates 
• Clinical and/or pathology laboratory accreditation certificate or certification of established 
quality control (QC) and/or external QA or other validations 
• Instructions on handling study supplies and study related material (if not included in 
protocol) 
• Details of study material/supplies shipment dates, batch numbers, method of shipping, etc 
• Treatment allocation 
• Study Initiation monitoring report 
• CRFs and source data and primary records upon which they are based 
• Serious AE reports 
• Notification by  Genentech  and/or investigator to regulatory authorities/IRB of serious AEs 
including causality assessments 
• Report on any interim reviews done 


44 
v.3.1 January 27, 2017  
• Subject identification log 
• Subject screening/enrollment log 
• Drug accountability logs 
• Signature log of persons authorized to make entries and/or corrections on CRFs 
• Records of any retained samples (if applicable) 
• Interim/Final report(s) to the IRB (as appropriate) 
• Signed, final study report (if applicable) 
• Manuscript/publications of the study 
• Correspondence relating to the study monitor (if different from sponsor) 
• Correspondence with the study sponsor 
• Correspondence with the IRB 
 
 


45 
v.3.1 January 27, 2017  
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v.3.1 January 27, 2017  
14. 
APPENDICES 
 
 
APPENDIX 1: NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY (NCCN  
                         GUIDELINES) BASAL CELL AND SQUAMOUS CELL SKIN CANCERS 
 
 
APPENDIX 2: ‘MASK AREAS’ OF FACE: HIGH RISK ANATOMIC AREAS 
 
 
APPENDIX 3:  EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE  
                          STATUS 
 
APPENDIX 4:  REQUIRED ELEMENTS OF INFORMED CONSENT 
 
APPENDIX 5:  TREATMENT ALGORITHMS 
 
APPENDIX 6:  STUDY PROCEDURES FLOWCHART 
 
APPENDIX 7:  SKINDEX-16 
 
APPENDIX 8:  INSTRUCTIONS FOR STUDY PARTICIPANTS 
 
APPENDIX 9:  FACT-G (VERSION 4) 
 
APPENDIX 10:  TARGET LESION ASSIGNMENT EXAMPLES   
 
APPENDIX 11:  NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS    
                           (CTCAE) V.4 
 
 
 


52 
v.3.1 January 27, 2017  
14.1 
APPENDIX 1:  NCCN CLINICAL PRACTICE GUIDELINES IN 
ONCOLOGY (NCCN GUIDELINES) BASAL CELL AND SQUAMOUS 
CELL SKIN CANCERS 
 
http://www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf 
 
 


53 
v.3.1 January 27, 2017  
14.2 
APPENDIX 2: ‘MASK AREAS’ OF FACE: HIGH RISK ANATOMIC 
AREAS 
 
 
 
 
 


54 
v.3.1 January 27, 2017  
14.3 
APPENDIX 3:  EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS 
 
http://ecog.dfci.harvard.edu/general/perf_stat.html 
 
 


55 
v.3.1 January 27, 2017  
14.4 
APPENDIX 4:  REQUIRED ELEMENTS OF INFORMED CONSENT 
 
The Informed Consent must address the following information in simple language, easily 
understood, and translated when appropriate: 
 
1. Statement that the study involves research. 
2. Purpose(s) of the research. 
3. Expected duration of subject’s participation. 
4. Procedures to be followed and identification of any procedures which are experimental. 
5. Reasonable foreseeable risks or discomforts to the subject. 
• Risks/discomfort from study procedures Foreseeable risks associated with 
vismodegib, which include AEs listed in the Investigator’s Brochure or package insert 
6. Benefits to the subject or to others which may reasonably be expected from the research, 
including amount and stipulations of monetary compensation. 
7. Appropriate alternative procedures or courses of treatment, if any that might be advantageous 
to the subject. 
8. Extent to which confidentiality of records identifying the subject will be maintained. 
• Possibility that representatives of  Genentech and the FDA may inspect the records 
• Information on the confidential follow-up form will be held and treated with strict 
confidentiality, and will be used only in the event that long-term follow-up is needed 
9. Compensation and medical treatment available if injury occurs. 
“Genentech will pay medical expenses due to any medical problems caused by vismodegib 
as specified in the protocol.  However one of the risks that you assume by participating in 
this study is the possibility that the study drug will not be effective for you and will not treat 
or improve the condition for which you sought treatment.  If you suffer from any medical 
problems from the failure of vismodegib to effectively treat or improve your condition, 
Genentech will not pay your medical expenses unless another successful treatment was 
specifically discontinued for this study.” 
10. Whom to contact for answers to pertinent questions about the research and research subject’s 
rights. 
11. Whom to contact in the event of research-related injury to the subject. 
12. Participation is voluntary. 
• Refusal to participate will involve no penalty or loss of benefits to which the subject 
is otherwise entitled 
• Subject may discontinue participation at any time without penalty or loss of benefits 
to which subject is otherwise entitled 
 
 
 
 
 
 
 
 
 
 


56 
v.3.1 January 27, 2017  
 
 
ADDITIONAL ELEMENTS OF INFORMED CONSENT 
 
When appropriate, one or more of the following elements of information shall also be provided 
to each subject: 
 
13. Particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, 
if the subject may become pregnant) which are currently unforeseeable. 
14.  Anticipated circumstances under which subject’s participation may be terminated by the 
investigator without regard to subject’s consent. 
15. Additional costs to the subject that may result from participation in the research. 
16. Consequences of subject’s decision to withdraw, and procedures for orderly termination by 
the subject. 
17. Significant new findings developed during the course of the research, which may relate to the 
subject’s willingness to continue participation, will be provided to the subject. 
18. Approximate number of subjects involved in the study. 
 
 


57 
v.3.1 January 27, 2017  
14.5 
APPENDIX 5:  TREATMENT ALGORITHMS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. 


58 
v.3.1 January 27, 2017  
 
 
 
Figure 3. 
 
 


59 
v.3.1 January 27, 2017  
14.6 
APPENDIX 6:  STUDY PROCEDURES FLOWCHART 
 
Subjects with partial response or stable disease after 24 weeks of treatment and undergo  
surgical excision within 4 weeks of last dose of study drug. 
  
Pre-study 
Screening 
Visit 
Treatment 
Initiation 
Visit 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 8 
Study 
Exit 
Visit3 
  
Day 0 
Baseline / 
Day 1 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Surgery 
Visit 
30 days 
after 
surgery 
Procedure 
  
  
  
  
  
  
  
  
  
  
Sign & Date Informed 
Consent 
X 
  
  
  
  
  
  
  
  
  
Collect Medical History 
X 
  
  
  
  
  
  
  
  
  
Review InclusionExclusion 
Criteria 
X 
X 
  
  
  
  
  
  
  
  
Review Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Adverse Events 
(AEs) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Target lesion identification 
X 
  
  
  
  
  
  
  
  
Lesion measurement (pre-
biopsy) 
X 
  
  
  
  
  
  
  
  
  
Lesion measurement (post-
biopsy) 
X 
  
  
  
  
  
  
  
  
  
Lesion photography  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Tumor margins and local 
landmarks map 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Lesion punch 
biopsy/biopsies 
X 
  
  
  
X 
  
  
  
  
  
Urine Pregnancy Test 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP/CBC Tests 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Patient reported outcome 
questionnaires 
  
X 
  
X 
  
X 
  
X 
 X 
 X 
Review subject diary 
  
  
X 
X 
X 
X 
X 
X 
X 
  
Study drug instructions 
  
X 
X 
X 
X 
X 
X 
  
  
  
Reminder to use effective 
measures to avoid 
pregnancy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer study drug 
  
X 
X 
X 
X 
X 
X 
  
  
  
Pathological Evaluation 
(H&E) 
X 
  
  
  
X 
  
  
  
X 
  
Immunohistochemical 
Evaluation 
X 
  
  
  
X 
  
  
  
X 
  
Pathologic Slide 
Photography 
X 
  
  
  
X 
  
  
  
X 
  
Breslow depth ("invasion 
index") 
X 
  
  
  
X 
  
  
  
X 
  
Perform Mohs Surgery on 
target lesion(s) 
  
  
  
  
  
  
  
  
X 
  
Assess/treat post-surgical 
tumor area 
  
  
  
  
  
  
  
  
  
X 
Assess Adverse Events 
(AEs)  
  
 X 
X  
X  
X  
X  
X  
X  
X  
X 


60 
v.3.1 January 27, 2017  
Subjects with complete clinical response and complete histologic response at Week 24 
 
 
Pre-study 
Screening 
Visit 
Treatment 
Initiation 
Visit 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Observation 
Visit 1 
Observation 
Visit 2 
Observation 
Visit 3 
Observation 
Visit 4 
  
Day 0 
Baseline / 
Day 1 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 36 
Week 48 
Week 60 
Week 72 
Description 
  
  
  
  
  
  
  
  
  
  
  
  
Informed Consent 
X 
Medical History 
X 
Inclusion/Exclusion 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Target lesion 
identification 
X 
Lesion measurement 
(pre-biopsy) 
X 
Lesion measurement 
(post-biopsy) 
X 
Lesion photography  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor margins and 
local landmarks map 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lesion punch 
biopsy/biopsies 
X 
X 
Urine Pregnancy Test 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMP?CBC Tests 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Patient reported 
outcome 
questionnaires 
X 
X 
X 
X 
X 
Review subject diary 
X 
X 
X 
X 
X 
X 
Study drug instructions 
X 
X 
X 
X 
X 
X 
Reminder to use effective 
measures to avoid 
pregnancy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer study drug 
X 
X 
X 
X 
X 
X 
X 
Adverse Events (AE) 
monitoring - PI and 
Oncologist 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 


61 
v.3.1 January 27, 2017  
 
Subjects with complete clinical response and complete histologic response at Week 12 visit 
 
 
Pre-study 
Screening 
Visit 
Treatment 
Initiation 
Visit 
Visit 2 
Visit 3 
Visit 4 
Observation 
Visit 1 
Observation 
Visit 2 
Observation 
Visit 3 
Observation 
Visit 4 
  
Day 0 
Baseline / 
Day 1 
Week 4 
Week 8 
Week 
12 
Week 24 
Week 36 
Week 48 
Week 60 
Description 
Informed Consent 
X 
Medical History 
X 
Inclusion/Exclusion 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Target lesion identification 
X 
Lesion measurement (pre-
biopsy) 
X 
Lesion measurement (post-
biopsy) 
X 
Lesion photography  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor margins and local 
landmarks map 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lesion punch biopsy/biopsies 
X 
X 
Urine Pregnancy Test 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
CMP?CBC Tests 
X 
X2 
X2 
X2 
X2 
Patient reported outcome 
questionnaires 
X 
X 
X 
Review subject diary 
X 
X 
X 
Study drug instructions 
X 
X 
X 
X 
Reminder to use effective 
measures to avoid pregnancy 
X 
X 
X 
X 
X 
X 
X 
Administer study drug 
X 
X 
X 
X 
Adverse Events (AE) monitoring 
- PI and Oncologist 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
1. Two negative pregnancy tests with a sensitivity of at least 25 mIU/mL prior to starting medication. These 
tests must be at least 19 days apart.  For patients with regular menstrual cycles, the second pregnancy test 
should be done during the first 5 days of the menstrual period immediately preceding the beginning of 
therapy and after the patient has used 2 forms of contraception for 1 month.  For patients with amenorrhea, 
irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy 
test must be done immediately preceding the beginning of therapy and after the patient has used 2 forms of 
contraception for 1 month. 
2. Repeat testing after screening test is at the discretion of the investigator as clinically determined  
3. 
Post surgical subjects will be offered observational follow up as office visits or telephone visits 


62 
v.3.1 January 27, 2017  
 
14.7 
APPENDIX 7:  SKINDEX-16 
 
http://www.proqolid.org/instruments/skindex_skindex_skindex_29_skindex_16 
 
 


63 
v.3.1 January 27, 2017  
14.8 
APPENDIX 8:  INSTRUCTIONS FOR STUDY PARTICIPANTS 
 
Thank you for participating in this study.  We appreciate it.  Please see below for instructions 
during your study participation. 
 
USE OF STUDY MEDICATION 
 
1. Do not share your study medication with any other person; it was prescribed only for you. 
2. If you take any other drugs during this study, you should tell the study nurse or doctor.  They 
will need to know the name of the drug, how much you took, how often you took it, why you 
took it, and when you started and stopped taking it. 
3. Some drugs are not allowed at all during the study.  The study nurse or doctor will discuss 
these drugs with you.  If you have any questions about whether or not you can take a certain 
drug, please contact the study staff. 
 
4. Take your study medication at approximately the same time each day, with or without food.  
Capsules must be swallowed whole and must not be opened under any circumstances.  If you 
miss a dose inform your study doctor and do not to take or make up that dose. Resume your 
study medication at the next scheduled dose.   
 
5. Please record the days and time that you take the medication in the dosing diary that we have 
given you.  It is important for this to be accurate, so if you miss some doses, please record 
this truthfully. 
 
6. As part of your participation in the trial, you have agreed to adhere to the measures 
below to avoid pregnancy below and to avoid blood or blood product donation until 
________________ . 
 
(13 months after Today’s date _________________, 9 months after expected last dose of 
vismodegib) 
 
- 
Females of reproductive potential must use 2 effective methods to avoid pregnancy 1 
month prior to starting the medication, during therapy, and for 9 months after 
completing therapy.  
 
- 
Male patients must use effective measures to avoid pregnancy in their partner, even 
after vasectomy, during treatment and for 9 months after the last dose.  
 
7. If you suspect that you (or your partner) are pregnant, please call the study site immediately. 
 
8. If you have any new health problems, new medications, surgeries or procedures, please 
contact the study staff.  Please sign a medical records release form and have your treating 
physician send us a copy of your medical records.  We will need to record this information in 
our files. 
 
Please call us if you have any questions.  Thank you again! 
 
 


64 
v.3.1 January 27, 2017  
14.9 
APPENDIX 9:  FACT-G (VERSION 4) 
 
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy ........................................................
0 
1 
2 
3 
4 
GP2 
I have nausea ......................................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family .........................................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ..........................................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .........................
0 
1 
2 
3 
4 
GP6 
I feel ill ...............................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ........................................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends ....................................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ............................
0 
1 
2 
3 
4 
GS3 
I get support from my friends .............................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ....................................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support) ...............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, Please answer 
the following question. If you prefer not to answer it, please mark 
this box and go to the nextection. 
 
 
 
 
 
GS7 
I am satisfied with my sex life .............................................
0 
1 
2 
3 
4 


65 
v.3.1 January 27, 2017  
Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GE1 
I feel sad .............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness .........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness .................
0 
1 
2 
3 
4 
GE4 
I feel nervous ......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ...........................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A 
little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) .........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ..................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun .....................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now .............
0 
1 
2 
3 
4 
 
 
 


66 
v.3.1 January 27, 2017  
14.10 
APPENDIX 10:  TARGET LESION ASSIGNMENT EXAMPLES 
 
 
If a patient has multiple BCC tumors, target 
lesion assignment will be based on histology 
using algorithm in Figure 2. 
 
Histology is the primary consideration for “target 
lesion assignment.”  Histology trumps size.  Size 
is only considered if there are two lesions that 
may be eligible for target lesion assignment based 
on histologic subtype.  In this case, the lesion 
with larger clinical dimensions will be designated 
the “target lesion”.   
 
See Example 1 and Example 2 for more details. 
 
 
 
 
 
 
 
 
 
 
 
 


67 
v.3.1 January 27, 2017  
 
14.11 
APPENDIX 11.  NCI COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS (CTCAE) V.4 
 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html