A Phase II Study of Radiation Therapy and Vismodegib, for the Treatment of Locally Advanced Basal Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Locally Advanced Basal Cell Carcinoma, Skin Cancer, Cutaneous Malignancy
Sponsor: Sue Yom

Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
A PHASE II STUDY OF RADIATION THERAPY AND 
VISMODEGIB, FOR THE TREATMENT OF LOCALLY 
ADVANCED BASAL CELL CARCINOMA OF THE HEAD AND 
NECK 
Protocol Number:  CC #122011 
Study Drug:  Vismodegib 
Version Number:  8.0  
Version Date:  11-07-2016 
IND Number:  118,067 (Exempt) 
Principal Investigator /Study Chair (Sponsor-Investigator) 
Sue S. Yom, MD, PhD 
University of California San Francisco 
 
 
 
 
Co-Principal Investigators
Roy Grekin, MD 
Co-Investigators 
Sarah Arron, MD, PhD  
Alain Algazi, MD 
Adam Garsa, MD    
Statistician 
David Glidden, PhD  
Clinical Research Coordinator 
 
Revision History 
Version 8.0 
11-07-16
Version 7.0 
08-01-16
Version 5.0 
10-20-14
Version 6.3 
02-16-16
Version 4.0 
11-27-13
Version 6.2 
09-16-15
Version 3.0 
02-06-13
Version 6.1 
06-01-15
Version 2.0 
12-17-12
Version 6.0 
01-27-15
Version 1.0 
11-16-12
NCT# 01835626

 
Version date: 11-07-2016 
 
Protocol CC#: 122011 
Phase 2 – vismodegib & radiation therapy 
 
Page 2 of 74 
Protocol Signature Page 
Protocol No.: 122011 
Version Date: 11-07-2016 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC).  
2. I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations. 
UCSF Principal Investigator / Study Chair 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
Participating Site(s) 
San Francisco General Hospital   
 
  
Memorial Sloan-Kettering Center 
 
 
 
 
Principal Investigator 
 
Site 
Printed Name 
 
 
Signature 
 
Date 

 
Version date: 11-07-2016 
 
Protocol CC#: 122011 
Phase 2 – vismodegib & radiation therapy 
 
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Abstract 
Title 
A Phase II Study of Radiation Therapy and Vismodegib, for the Treatment of Locally 
Advanced Basal Cell Carcinoma of the Head and Neck 
Patient 
population 
Patients with locally advanced basal cell carcinoma in the head and neck, who are 
ineligible for surgical resection and are planned for definitive intent radiation therapy. 
Rationale for 
Study 
Vismodegib is a proven effective means for treating locally advanced and metastatic 
BCC. Radiotherapy for advanced, unresectable BCC can be effective as well, but 
ultimate success rates can remain limited for complex, unresectable tumors, either 
due to anatomic or technical factors. Vismodegib alone produces high response rates 
in BCC but is unlikely to sustain permanent eradication of very advanced tumors. This 
study is designed to assess the safety and demonstrate the efficacy of a combined 
approach using radiation therapy after induction and concurrent systemic 
administration of vismodegib, which may increase the rates of complete response and 
sustained local control in patients with locally advanced BCC. This population was 
chosen for study based on unmet medical need and evidence of efficacy observed in 
earlier studies of vismodegib in advanced BCC. At this point in time, despite the clear 
success of vismodegib in treating BCC, there is no guidance about how to integrate 
this treatment with other curative-intent therapies. 
Primary 
Objective 
To determine local-regional control rate at 12 months from protocol therapy 
completion, defined as complete or partial response, with absence of progressive 
disease within the irradiated planning tumor volumes (PTV) for patients with locally 
advanced basal cell carcinoma in the head and neck. 
Secondary 
Objectives 
• To estimate of the probability of PFS, with failure defined as any disease 
recurrence or death due to any cause, and OS with the duration for each measured 
from the time of first treatment with vismodegib to 12 months after completion of 
study treatment.  
• To evaluate toxicity during the drug-alone and combined-modality components of 
the protocol regimen during treatment. This will be assessed by:  
1) The number and attribution of all adverse events, (including vital signs, 
physical findings, and clinical laboratory results, CTCAE, v 4.0) in patients 
who receive any amount of study drug and radiation therapy. 
2) The proportion of any adverse events (CTCAE, v. 4.0) assessed to be 
definitely, probably, or possibly related to vismodegib or its combination with 
radiation therapy. 
3) The proportion of patients experiencing Grade 4-5 adverse events assessed 
to be definitely, probably, or possibly related to the induction or concurrent 
treatment components of the protocol regimen (that is not definitely related to 
disease progression).  
• To evaluate initial toxicity during the 3 months immediately after completion of 
protocol therapy. 
• To estimate the feasibility of administering concurrent vismodegib with radiation 
therapy determined by the proportion of patients discontinuing treatment due to 
toxicity during the concurrent administration of vismodegib and radiation therapy 
(<75% of planned radiation therapy delivered). 
• To evaluate the response rate (as per RECIST version 1.1) of the primary site and 
regionally involved areas following all treatment components at 3 months after the 
completion of protocol therapy.  
• To estimate the clinical response to vismodegib and radiation therapy determined 
by the proportion of patients with a decrease of BCC within the irradiated planning 
tumor volumes (PTVs, see Section 5.0 for definition) in patients who complete 
combined therapy.  

 
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Study Design 
This is a single arm, multi-centered Phase II clinical trial to assess the safety and 
demonstrate the efficacy of a combined modality approach using radiation therapy 
after induction and concurrently with systemic administration of vismodegib, which 
may increase the rates of complete response and sustained local control in patients 
with locally advanced BCC. 
Number of 
patients 
24 evaluable patients who complete at least 75% of protocol-mandated radiotherapy.  
Duration of 
Therapy 
Patients will receive treatment for approximately 21 weeks.  
Duration of 
Follow up 
Follow-up visits will occur at 3, 6, & 12 months (+/- 2 weeks) post End of Treatment 
visit.  Survival follow-up information may be collected via telephone calls and/or at 
clinic visits every 3 months for 12 months.  
Duration of 
study 
The study will reach completion 3-4 years from the time the study opens to accrual. 
Study Drugs 
Vismodegib capsules (150 mg QD PO) will be taken orally (whole). Patients will be 
instructed to swallow one capsule once a day (preferably at the same time each day) 
7 days/week, with or without food, with about 1 cup (240 mL) of water. Capsules must 
be swallowed whole; they must not be opened, chewed, broken, or crushed under any 
circumstances. 
Safety 
Assessments 
The study will use the CTCAE v 4.0 for reporting of non-hematologic adverse events 
and modified criteria for hematologic adverse events.  Safety assessments will consist 
of monitoring and reporting adverse events (AEs) and serious adverse events (SAEs) 
that are considered related to vismodegib, all events of death, and any study specific 
issue of concern. 
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 12 months 
following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. 
Efficacy 
Assessments 
Measurable lesions are those that can be accurately measured in at least one 
dimension as ≥20mm with CT or MRI scan or on color photographs.  Patients will 
undergo tumor assessments per RECIST version 1.1 tumor response criteria outlined 
below.  No central review of imaging data will be required due to the visual clarity in 
identifying the lesions and the consistent method of assessment to be used by all 
participating sites. 
Prior radiation therapy is acceptable but there cannot be major overlap of the 
previously irradiated tissues with the new radiation treatment volumes anticipated to 
be delivered for the purposes of this protocol, in such a way that curative intent with 
radiation cannot be met. Furthermore, the total dose from all radiation delivered and 
expected to be delivered should not exceed the suggested dose constraints given for 
normal structures. 
To ensure a valid comparison of tumor data and uniformity in the assessment of 
tumor response and disease progression, the following procedures should be 
implemented: 
- The same local physician should perform all physical tumor assessment evaluations 
for an individual patient. Radiologic interpretation should be performed by designated 
faculty members with experience in describing skin lesions. 
- All lesions (target and non-target) identified at baseline will be reassessed according 
to the imaging schedule provided in Table 6-1. The same method of evaluation (either 
CT scan or MRI), and/or color photography in the case of skin lesions, if feasible, 
must be used from baseline until the end of the study. 

 
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List of Abbreviations 
AE 
ADR 
adverse event 
adverse drug reaction 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
BCC 
CBC 
Basal Cell Carcinoma 
complete blood cell (count) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
CTV 
Clinical Target Volume 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCT 
hematocrit 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
laBCC 
LDH 
Locally advanced Basal Cell Carcinoma 
lactate dehydrogenase 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 

 
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List of Abbreviations 
PFS 
Progression-free survival 
PD 
disease progression 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PRC 
Protocol Review Committee (UCSF) 
PRV 
planning risk volumes  
PTV 
planning tumor volume 
QD 
RBC 
once daily 
red blood cell (count) 
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 

 
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Table of Contents 
Protocol Signature Page ................................................................................................. 2 
Abstract 
……………………………………………………………………………………3 
List of Abbreviations ........................................................................................................ 5 
Table of Contents ............................................................................................................ 7 
1 
Introduction ............................................................................................................. 10 
1.1 
Background on Indication ....................................................................... 10 
1.1.1 Advanced Basal Cell Carcinoma ......................................................... 10 
1.1.2 Basal Cell Carcinoma and Surgery ..................................................... 10 
1.1.3 Basal Cell Carcinoma and Radiation Therapy .................................... 11 
1.1.4 Basal Cell Carcinoma and Chemotherapy .......................................... 11 
1.1.5 Hedgehog signaling pathway .............................................................. 12 
1.2 
Background on Vismodegib .................................................................... 12 
1.2.1 Pharmacokinetics and Drug Metabolism (Safety) ............................... 12 
1.2.2 Clinical Experience of Vismodegib ...................................................... 13 
1.3 
Rationale for the Proposed Study ........................................................... 14 
2 
Objectives of the Study ........................................................................................... 14 
2.1 
Primary ................................................................................................... 14 
2.2 
Secondary .............................................................................................. 14 
2.3 
Endpoints ............................................................................................... 15 
2.3.1 Primary Endpoints ............................................................................... 15 
2.3.2 Secondary Endpoints .......................................................................... 15 
3 
Study Design .......................................................................................................... 16 
3.1 
Characteristics ........................................................................................ 16 
3.2 
Number of Subjects ................................................................................ 16 
3.3 
Eligibility Criteria ..................................................................................... 16 
3.3.1 Inclusion Criteria ................................................................................. 16 
3.3.2 Exclusion Criteria ................................................................................ 18 
3.4 
Duration of Therapy ................................................................................ 19 
3.5 
Duration of Follow Up ............................................................................. 19 
3.6 
Study Timeline ........................................................................................ 20 
3.6.1 Primary Completion ............................................................................. 20 
4 
Study Drugs ............................................................................................................ 20 
4.1 
Description, Supply and Storage of Investigational Drugs ...................... 20 
4.1.1 Vismodegib ......................................................................................... 20 
4.2 
Radiation Therapy .................................................................................. 22 
4.3 
Drug Accountability................................................................................. 23 
4.4 
Drug Ordering ......................................................................................... 23 
4.5 
Packaging and Labeling of Study Drugs ................................................. 23 
4.6 
Reconciliation ......................................................................................... 23 
5 
Treatment Plan ....................................................................................................... 23 
5.1 
Dosage and Administration:  Vismodegib ............................................... 23 
5.2 
Dosage and Administration:  Radiation Therapy .................................... 24 

 
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Table of Contents 
5.2.1 Three-dimensional conformal radiation therapy .................................. 24 
5.2.2 Intensity modulated radiation therapy ................................................. 24 
5.2.3 Technical Factors ................................................................................ 25 
5.2.4 Treatment Planning, Imaging and Localization Requirements ............ 25 
5.2.5 Treatment Planning/Target Volumes ................................................... 25 
5.2.6 Critical Structures ................................................................................ 27 
5.2.7 Planning Goals: Normal Structures ..................................................... 27 
5.2.8 Planning Priorities ............................................................................... 28 
5.3 
Dose Modifications and Dosing Delays .................................................. 28 
5.3.1 Intolerable Toxicity Requiring Discontinuation of Vismodegib ............. 28 
5.4 
Monitoring and Toxicity Management ..................................................... 29 
5.5 
Other Therapy ........................................................................................ 29 
5.5.1 Permitted Supportive Therapy ............................................................ 29 
5.5.2 Non-permitted Supportive Therapy ..................................................... 29 
5.6 
Compliance Criteria ................................................................................ 30 
6 
Study Procedures and Observations ...................................................................... 30 
6.1 
Schedule of Procedures and Observations ............................................ 30 
6.1.1 Pretreatment Period ............................................................................ 30 
6.1.2 Treatment Period ................................................................................ 31 
6.1.3 End-of-Treatment Study Procedures ................................................... 33 
6.1.4 Post-treatment/Follow Up Visits .......................................................... 33 
6.1.5 Long Term/Survival Follow-up Procedures ......................................... 34 
6.2 
Usage of Concurrent/Concomitant Medications ..................................... 37 
7 
Reporting and Documentation of Results ............................................................... 37 
7.1 
Evaluation of Efficacy (or Activity) .......................................................... 38 
7.2 
Antitumor Effect – Solid Tumors ............................................................. 38 
7.3 
Assessment of Failure Patterns .............................................................. 41 
7.4 
Evaluation of Safety................................................................................ 41 
7.5 
Definitions of Adverse Events ................................................................. 42 
7.5.1 Adverse Event ..................................................................................... 42 
7.5.2 Adverse reaction ................................................................................. 42 
7.6 
Recording of an Adverse Event .............................................................. 43 
7.7 
Follow-up of Adverse Events .................................................................. 44 
7.8 
Adverse Events Monitoring ..................................................................... 44 
7.9 
Expedited Reporting ............................................................................... 45 
8 
Statistical Considerations and Evaluation of Results .............................................. 47 
8.1 
Study Design .......................................................................................... 47 
8.2 
Study Endpoints ..................................................................................... 47 
8.3 
Determination of Sample Size and Accrual Rate .................................... 47 
8.3.1 Sample Size and Power Estimate ....................................................... 47 
8.3.2 Replacement Policy ............................................................................ 48 
8.3.3 Accrual estimates ................................................................................ 48 
8.4 
Interim Analysis for Safety and Stopping Rules ...................................... 48 
8.5 
Analyses Plans ....................................................................................... 48 
8.5.1 Analysis Population ............................................................................. 49 

 
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Table of Contents 
8.6 
Evaluation of Safety................................................................................ 49 
9 
Study Management ................................................................................................. 49 
9.1 
Pre-study Documentation ....................................................................... 49 
9.2 
Institutional Review Board Approval ....................................................... 50 
9.3 
Informed Consent ................................................................................... 50 
9.4 
Changes in the Protocol ......................................................................... 50 
9.5 
Handling and Documentation of Clinical Supplies .................................. 50 
9.6 
Case Report Forms (CRFs) .................................................................... 51 
9.7 
Modality Review ..................................................................................... 51 
9.8 
Oversight and Monitoring Plan ............................................................... 52 
9.9 
Multicenter communication ..................................................................... 52 
9.10 
Record Keeping and Record Retention .................................................. 52 
9.11 
Coordinating Center Documentation of Distribution ............................... 53 
9.12 
Regulatory Documentation ..................................................................... 53 
10 Protection of Human Subjects ................................................................................ 53 
10.1 
Protection from Unnecessary Harm........................................................ 53 
10.2 
Protection of Privacy ............................................................................... 54 
References 
55 
Appendices 
57 
Appendix 1 
Performance Status Criteria ................................................................... 57 
Appendix 2 
AJCC Staging System for Cutaneous Carcinoma .................................. 58 
Appendix 3 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme ..................... 59 
Appendix 4 
Management of Dental Problems in Irradiated Patients ......................... 62 
Appendix 5 
Medications with Potential to Interact with Vismodegib .......................... 65 
Appendix 6 
Skindex-16 Survey ................................................................................. 66 
Appendix 7 
Digital Photographic Procedures For Serial Photographic Documentation 
Of Basal Cell Carcinoma ........................................................................ 67 
Appendix 8 
Data Submission .................................................................................... 68 
Appendix 9 
Data and Safety Monitoring Plan* for a Multicenter Institutional Study ... 69 
Appendix 10 UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Multicenter Investigator-Initiated Oncology Clinical Trials with an 
Investigator held Investigational New Drug (IND) ................................... 71 
Appendix 11 Genentech Safety Reporting Fax Cover Sheet ...................................... 74 
List of Tables 
Table 5.1 
Regimen Description .............................................................................. 24 
Table 6.1 
Schedule of Study Procedures and Assessments .................................. 35 
Table 7.1 
Response Criteria ................................................................................... 40 
 
 
 

 
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1 Introduction 
1.1 
Background on Indication 
1.1.1 Advanced Basal Cell Carcinoma 
Basal Cell Carcinoma (BCC) is the most common malignancy in people; of the more than 1 
million cases of non-melanoma skin cancers reported in the United States in 2007, 
approximately 80% are BCC (American Cancer Society 2007). Almost all of these cases are 
small BCCs that can be effectively treated by dermatologists using several surgical modalities. 
However, in a subset of patients, invasion of the BCC into subcutaneous structures can occur. 
In some cases, this results from neglect of indolent BCCs, whereas in other cases, patients may 
develop particularly aggressive BCCs that recur and progress despite standard surgical 
treatment. If further surgical resection is not possible, there are many types of non-surgical 
treatment, although no one clear standard of care exists. 
Although radiation therapy may be used for either palliative or curative intent, its use may be 
limited by the proximity of the tumor to nearby radiation-sensitive structures, as well as prior 
interventions and/or cumulative radiation dosage. Locally advanced BCC (laBCC) can be 
associated with significant morbidity as the result of chronic pain, risk of bacterial infection and 
sepsis, bleeding/oozing, and compromise of function, resulting from invasion of structures such 
as the ear, nose, and eye. In some cases, invasion can progress to involve critical organs such 
as the meninges, brain, and spinal cord, resulting in death (Cohen et al. 2000; Korvarik et al. 
2005). In such cases, comprehensive radiation may become very technically challenging or 
pose risks to the patient’s function. 
Metastatic BCC (mBCC) is extremely rare. BCC has an overall reported metastasis rate ranging 
from .0028% to 0.55%, but most believe the true metastasis rate to be significantly less than 
0.1% (Wadhera et al. 2006). A total of approximately 300 cases of mBCC have been reported in 
the literature. The most common sites of metastasis are the lymph nodes, lung, bone, liver, 
other viscera, and soft tissue (Snow et al. 1994). Once metastasis is detected, survival can be 
short for some patients, but a range of 8 to 14 months has been reported by some investigators, 
and individual patients have been reported to live for as many as 25 years (von Domarus and 
Stevens 1984; Lo et al. 1991; Spates et al.2003). For treatment of distant metastasis, there is 
anecdotal use of chemotherapeutic agents such as platinum compounds (Pfeiffer et al. 1990). 
There is also vismodegib, an orally administered, systemically targeted agent recently approved 
for use in treatment-refractory BCC (Sekulic 2012). 
1.1.2 Basal Cell Carcinoma and Surgery  
Standard surgical excision is the preferred method for removal of most small and well defined 
BCCs. When a standard surgical margin is applied (usually 4 mm or more), a high cure rate can 
be achieved. A weakness of standard surgical excision is the high recurrence rate of BCC of the 
face, especially around eyelids, nose, and facial structures. On the face, or for recurrent BCC, 
surgical margins must be assured with controlled processing via complete circumferential 
peripheral and deep margin assessment. 
Most standard excisions are evaluated by a standard bread loafing method of processing. This 
method has a high "false negative" rate due to the random sampling of the tumor. It is likely that 
less than 5% of the surgical margin is examined, as each slice of tissue is only 6 micrometers 
thick, about 3 to 4 serial slices are obtained per section, and only about 3 to 4 sections are 
obtained per specimen. Usually, if a 4 mm free surgical margin is obtained around a small tumor 
(less than 6mm), or a wider 6 mm free surgical margin is obtained around a larger tumor 
(greater than 6mm), the cure rate is very high, at 95% or better. For cosmetic reasons, many 
doctors take only very small surgical margins 1–2 mm especially when facial tumor is being 
removed. A pathology report from such a case indicating "margins free of residual tumor,” often 
is inaccurate, and there are recurrence rates of up to 38%.  

 
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Mohs micrographic surgery (Mohs) is an outpatient procedure in which the tumor is surgically 
excised and then immediately examined under a microscope. It has the highest cure rate of 
97% to 99.8% in some reports. The base and edges of the tumor are microscopically examined 
to verify sufficient margins before the surgical repair of the site. If the margins are insufficient, 
more tissue is removed from the patient until the margins are sufficient.  
Extensive BCC that involves central facial structures, the base of skull, or specialized sensory 
organs requires oncologically oriented head and neck surgical resection with advance planning 
for reconstruction. If complete surgical removal of the tumor is not possible, there is no clear 
standard of care to treat these lesions. In these unresectable cases, radiotherapy, either for 
palliative or definitive intent, can play a major role in this setting. If treatment with radiotherapy is 
not possible due to surrounding radiation-sensitive organs or contraindicating medical 
conditions, treatment with vismodegib has recently been FDA-approved for use. 
1.1.3 Basal Cell Carcinoma and Radiation Therapy  
Radiation therapy is appropriate for all forms of BCC, and adequate doses will frequently 
eradicate the disease. Although radiotherapy is often used in older patients who are not 
candidates for surgery, it is also used in cases where surgical excision will be extremely 
disfiguring or difficult to reconstruct (such as the anterior portions of the nose, nostril rims, lips, 
or eyelids). Longer and more extended fractionation schedules are associated with fewer long-
term complications to the normal tissue supporting the tumor.  
Radiotherapy is also delivered with curative intent if a surgical excision has been done 
incompletely or if the pathology report following surgery suggests a high risk of recurrence, such 
as if significant nerve involvement by tumor has been demonstrated. Some tumors are deemed 
unresectable at the outset and definitive radiotherapy is the only remaining standard option. 
Cure rates resulting from radiotherapy in this setting are difficult to determine due to the 
historical heterogeneity of treatment approaches and the lengthy natural history of the disease.  
However, certain prognostic factors are known to predispose for worse outcome, either due to 
bone invasion, gross perineural invasion, or adjacency or invasion of a critical anatomic 
structure, which limits the amount of radiotherapy dose that can be delivered to the tumor. The 
presence of bone or soft tissue invasion or gross perineural spread is associated with lower 
rates of success resulting from radiation therapy treatment. Cure rates can be low for extremely 
invasive tumors that are difficult to encompass properly with radiotherapy. Usually, invasive 
tumors that have recurred or remain persistent after radiation therapy are treated with surgery 
and/or vismodegib, and not with reirradiation.  
1.1.4 Basal Cell Carcinoma and Chemotherapy 
Some superficial BCC respond to local therapy with 5-fluorouracil, a chemotherapy agent. 
Topical treatment with 5% Imiquimod cream, with five applications per week for six weeks, has 
a reported 70-90% success rate at reducing, or even removing, the BCC. Both Imiquimod and 
5-fluorouracil have received FDA approval for the treatment of superficial BCC. Off-label use of 
imiquimod on invasive BCC has been reported. Neither of these therapies is penetrating enough 
for deeply invasive BCC. 
Topical chemotherapy may be used following Mohs surgery to eliminate residual superficial 
BCC after the invasive portion is removed. Some advocate the use of imiquimod prior to Mohs 
surgery to remove the superficial component of the cancer and reduce the size of the ultimate 
surgical defect required for removal of the cancer. These experimental procedures likely will 
result in better cure rate than one modality alone, but are not the standard of care.  
Locally advanced or deeply invasive BCC are not treated with chemotherapy and no real 
standard exists for the use of systemically administered agents in this setting, although 
vismodegib can be considered if other standard therapies do not apply. 

 
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1.1.5 Hedgehog signaling pathway 
The Hedgehog (Hh) signaling pathway presents a novel and potentially beneficial target for 
cancer therapy. Hh signaling regulates epithelial and mesenchymal interactions in a variety of 
tissues during mammalian embryogenesis (Ingham and McMahon 2001). The Hh ligand in the 
extracellular space binds to Patched (PTCH1), a 12-pass transmembrane receptor on the 
surface of cells. Hh binding relieves the inhibitory effect of PTCH1 on Smoothened (SMO), a 7-
pass transmembrane domain protein and a member of the G-protein coupled receptor 
superfamily. Signal transduction by SMO then leads to the activation and nuclear localization of 
GLI1 transcription factors and induction of Hh target genes, many of which are involved in 
proliferation and survival, as well as angiogenesis.  
A role for aberrant Hh signaling in cancer was initially discovered in patients with Gorlin 
syndrome, a rare genetic disorder associated with predisposition to BCC, medulloblastoma, and 
rhabdomyosarcoma. In these patients, mutations in the PTCH1 gene lead to ligand-independent 
activation of SMO and constitutive activity of the Hh pathway (Johnson et al. 1996). Recent 
molecular and genetic studies have demonstrated that the majority of sporadic human BCCs 
also have mutations in the Hh signaling pathway, resulting in aberrant activation of the pathway 
and uncontrolled proliferation of basal cells (Galilani et al. 1966; Aszterbaum et al. 1998). Two 
mutations commonly found in BCC result from either the inactivation of the PTCH1 receptor or 
the activation of SMO protein (Xie et al. 1998). Both have the same functional consequence, 
i.e., the uncontrolled activation of the Hh signaling pathway in the absence of the Hh protein. 
High levels of Hh target genes, such as GLI1 and PTCH1, are found in nearly all cases of 
human BCC examined (Dahmane et al. 1997; Unden et al. 1997), suggesting that activation of 
this pathway is a causal even in the initiation of tumor formation. These data suggest that 
blocking the Hh signaling pathway at the level or downstream of SMO may provide a 
therapeutic benefit in the treatment of BCC (Williams et al. 2003).  
The feasibility of blocking Hh signaling in vivo was first demonstrated as a result of teratogenic 
phenomena occurring in lambs with mothers that had ingested a particular forage plant, 
Veratrum californicum (Binns et al 1963). Cyclopamine, a steroid alkaloid isolated from this 
plant, was shown to induce midline deformities, including cyclopia, by blocking SMO signaling in 
the developing lamb fetuses (Chen et al. 2002). Cyclopamine has proven to be valuable as a 
tool compound to confirm the importance of Hh signaling in a subset of malignancies, such as 
slowing the growth of pancreatic cancer xenografts and blocking the metastatic potential of 
prostate cancer cells in mice (Thayer et al. 2003; Karhadkar et al. 2004).  
1.2 
Background on Vismodegib 
Vismodegib is a small-molecule antagonist of the Hh signal pathway with a molecular weight of 
421.30 g/mol. The International Union of Pure and Applied Chemistry name for vismodegib is 2-
chloro-N-(4-chloro-3-pyridin-2-yl-phenyl)-4-methanesulfonyl-benzamide. 
Vismodegib, the molecule to be evaluated in this Phase II study, has oral bioavailability and 
potent anti-tumor activity in a variety of primary human tumor xenografts and tumor cell line 
xenograft models (see the vismodegib Investigator Brochure and the U.S. package insert for 
further details).  
1.2.1 Pharmacokinetics and Drug Metabolism (Safety) 
As part of a phase I trial for patients with any advanced or metastatic solid malignancy, 33 
patients with metastatic or locally advanced BCC were randomized to receive oral vismodegib 
150mg/day (17 patients), 270mg/day (15 patients), and 540mg/day (one patient). 
Pharmacokinetic data were obtained by a unique schedule of administration of the first dose at 
day 1, followed by a second dose at day 8 with daily dosing thereafter. Subsequent expansion 
cohorts included additional patients who received daily oral vismodegib at either 150mg/day or 
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The half life of the drug on a daily dosing schedule was 10-14 days and maximal drug 
concentration after a single dose was the same in the 270 and 540 mg cohorts. Steady state 
serum levels were the same in all three dose cohorts, indicating pharmacodynamic futility at 
doses higher than 150 mg/day on this schedule (Molckovsky J Hem Oncol 2008). 
Of the 33 patients with BCC, 19 had an objective response to vismodegib for an overall 
response rate of 58%. Two of these patients had a complete response, and 17 had a partial 
response. Of the remaining patients, only four had progression of disease, and 10 patients 
remained stable.  
Dose-limiting toxicities (DLTs) were not seen with vismodegib; prevalent adverse events 
included grade 1-2 dysgeusia and grade 1-2 alopecia. Reversible Grade 3 fatigue and 
asymptomatic hyponatremia were reported beyond the DLT window. Although disease 
stabilization has been previously seen in some patients with malignancies other than BCC, all 
major responses seen to date in the clinical trial setting have been in patients with advanced 
BCC (Lorusso, Clinical Cancer Research 2011). 
1.2.2 Clinical Experience of Vismodegib  
The oral small-molecule hedgehog inhibitor vismodegib has provided promising results in 
treatment of advanced BCC. Abnormal signaling in the Hh pathway is implicated in more than 
90 percent of sporadic BCC cases due to loss-of-function mutations in at least one allele of 
PTCH1, and an additional 10% have activating mutations in the downstream SMO protein. 
Results of a larger phase II trial offer additional positive evidence for the hedgehog inhibitor. The 
Erivance trial was an international, single-arm, multi-center, two-cohort, open-label study that 
enrolled 104 patients with advanced BCC, including locally advanced BCC (laBCC, n=71) and 
metastatic BCC (mBCC, n=33) (Sekulic 2012a). laBCC patients had lesions that were 
inappropriate for surgery and for which radiotherapy was unsuccessful or contraindicated. 
These patients were either deemed inoperable, or it was judged that surgery would result in 
substantial deformity. mBCC was defined as BCC that had spread to other parts of the body, 
including the lymph nodes, lung, bones and/or internal organs. Subjects received 150 mg 
vismodegib orally, once daily, until disease progression or intolerable toxicity.  
The primary endpoint of overall response rate was 43 percent in the laBCC cohort, and 30 
percent in mBCC, as assessed by strict independent review. Based on the secondary endpoint 
of clinical study investigators’ assessments, the overall response rate for laBCC was 60 percent 
and for mBCC, it was 46 percent. The median duration of progression-free survival by 
independent review was 9.5 months for both metastatic and locally advanced BCC patients and 
11.3 months by investigators’ assessments. 
In 73 percent of patients, vismodegib was shown to shrink tumors, heal visible lesions, or 
prevent tumor growth. The most common adverse events included muscle spasms, hair loss, 
altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. Serious 
adverse events were reported in 26 patients (25 percent), but these were considered after 
review to be related to vismodegib in only four subjects (four percent). Although fatal events 
were reported over the course of the study in seven patients (seven per 
cent), none were considered by investigators to be related to treatment with vismodegib. These 
events included death from an unknown cause (in 3 patients) and hypovolemic shock, 
myocardial infarction, meningeal disease, and ischemic stroke (in 1 patient each). A review of 
these events suggested no definite pattern, and these 7 patients had clinically significant risk 
factors or coexisting conditions at baseline. Pre-existing diseases or symptoms, primarily 
cardiac conditions, were most likely related to the presumed causes of death (Sekulic 2012b). 

 
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1.3 
Rationale for the Proposed Study 
Vismodegib is a proven effective means for treating locally advanced and metastatic BCC. 
Radiotherapy for advanced, unresectable BCC can be effective as well, but ultimate success 
rates can remain limited for complex, unresectable tumors, either due to anatomic or technical 
factors. Vismodegib alone produces high response rates in BCC but is unlikely to sustain 
permanent eradication of very advanced tumors. This study is designed to assess the safety 
and demonstrate the efficacy of a combined approach using radiation therapy after induction 
and concurrent systemic administration of vismodegib, which may increase the rates of 
complete response and sustained local control in patients with locally advanced BCC.  
Preclinical evidence indicates a role for vismodegib in combination with radiation therapy. In a 
number of solid tumor types, the Hh signaling pathway has been implicated in therapeutic 
resistance to both chemotherapy and radiation therapy. A leading hypothesis is that the Hh 
signaling pathway may mediate therapeutic resistance via a paracrine effect on stromal and 
endothelial components of tumor. This resistance mechanism, which has been observed in 
parallel to upregulation of PTCH1 and GLI1, has been implicated in adenocarcinoma models of 
pancreas and colon cancer (Yauch 2008), as well as in radiation resistance of hepatocellular 
carcinoma cells (Chen 2011). GLI1 has been implicated independently in impairment of 
radiation-induced checkpoint activation (Leonard 2008). In non-small cell lung cancer, a recent 
study demonstrated a lack of radiation sensitization for in vitro cultures but did show radiation 
sensitization by Hh antagonists in vivo, indicating the influence of a paracrine effect; this effect 
was confirmed by genetic analysis showing downregulation of PTCH1 in mouse stromal cells by 
Hh antagonist (Zeng 2012). Hh signaling has also been implicated in human tumor survival 
following chemoradiation therapy for esophageal cancers. One study found upregulated PTCH1 
expression in xenografts and residual tumors after chemoradiation, and additional clonogenic 
assays demonstrated increased radiosensitization with Hh inhibition (Sims-Mourtada 2006). A 
second esophageal cancer study found that expression of PTCH1 and GLI1 predicted for a lack 
of complete pathologic response (Ajani 2011). Thus, there is growing interest in the possibility of 
a synergistic effect that might be achieved from the combination of radiation therapy with 
paracrine-mediated stromal effects of Hh antagonist. 
The advanced BCC population was chosen for study based on unmet medical need and 
evidence of efficacy observed in earlier studies of vismodegib in advanced BCC. At this point in 
time, despite the clear success of vismodegib in treating BCC, there is no guidance about how 
to integrate this treatment with other curative-intent therapies. 
2 Objectives of the Study 
2.1 
Primary 
• 
To determine local-regional control rate at 12 months from protocol therapy completion, 
defined as complete or partial response, with absence of progressive disease (PD)  
within the irradiated planning tumor volumes (PTV) for patients with locally advanced basal 
cell carcinoma in the head and neck. 
2.2 
Secondary 
• 
To estimate of the probability of progression free survival (PFS), with failure defined as 
any disease recurrence or death due to any cause, and overall survival (OS) with the 
duration for each measured from the time of first treatment with vismodegib to 12 
months after completion of study treatment. 
• 
To evaluate toxicity during the drug-alone and combined-modality components of the 
protocol regimen during treatment. This will be assessed by 

 
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o The number and attribution of all adverse events, (including vital signs, physical 
findings, and clinical laboratory results, CTCAE, v 4.0) in patients who receive 
any amount of study drug and radiation therapy. 
o The proportion of any adverse events (CTCAE, v. 4.0) assessed to be definitely, 
probably, or possibly related to vismodegib or its combination with radiation 
therapy. 
o The proportion of patients experiencing Grade 4-5 adverse events assessed to 
be definitely, probably, or possibly related to the induction or concurrent 
treatment components of the protocol regimen (that is not definitely related to 
disease progression).  
• 
To evaluate initial toxicity during the 3 months immediately after completion of protocol 
therapy. 
• 
To estimate the feasibility of administering concurrent vismodegib with radiation therapy 
determined by the proportion of patients discontinuing treatment due to toxicity during 
the concurrent administration of vismodegib and radiation therapy (<75% of planned 
radiation therapy delivered) 
• 
To evaluate the response rate (as per RECIST) at completion of protocol therapy of the 
primary site and regionally involved areas in subjects with measurable disease prior to 
initiation of therapy at 3 months after the completion of protocol therapy. 
• 
To evaluate the clinical response to vismodegib and radiation therapy determined by the 
proportion of patients with a decrease of BCC within the irradiated planning tumor 
volumes (PTVs) in patients who complete the combined therapy. 
2.3 
Endpoints 
2.3.1 Primary Endpoints 
• 
The proportion of patients with local-regional control rate at 12 months from protocol 
therapy completion, defined as complete or partial response, with absence of PD within 
the irradiated PTV.  
2.3.2 Secondary Endpoints 
• 
Estimate of the probability of PFS, with failure defined as any disease recurrence or 
death due to any cause, and OS with each duration measured from the time of first 
treatment with vismodegib to 12 months after completion of study treatment.  
• 
The number and attribution of all adverse events, (including vital signs, physical findings, 
and clinical laboratory results, CTCAE, v 4.0) in patients who receive any amount of 
study drug and radiation therapy at any point during protocol therapy or during the 
followup period. 
• 
The proportion of any adverse events (CTCAE, v. 4.0) assessed to be definitely, 
probably, or possibly related to vismodegib or its combination with radiation therapy at 
any point during protocol therapy or during the followup period. 
• 
The proportion of patients experiencing Grade 4-5 adverse events assessed to be 
definitely, probably, or possibly related to the induction or concurrent treatment 
components of the protocol regimen (that is not definitely related to disease progression) 
at any point during protocol therapy or during the followup period. 
• 
The proportion of patients discontinuing treatment due to toxicity during the concurrent 
administration of vismodegib and radiation therapy (<75% of planned radiation therapy 
delivered). 
• 
Response rate (as per RECIST) of the primary site and regionally involved areas 
following all treatment components at 3 months after the completion of protocol therapy. 

 
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• 
Proportion of patients with a decrease of BCC within the irradiated planning tumor 
volumes (PTV) in patients who complete initial combined therapy, indicating a clinical 
response to vismodegib and radiation therapy. 
3 Study Design 
3.1 
Characteristics 
This is a single arm, multi-centered Phase II clinical trial to assess the safety and demonstrate 
the efficacy of a combined approach using radiation therapy after induction and concurrently 
with systemic administration of vismodegib, which may increase the rates of complete response 
and sustained local control in patients with locally advanced BCC. 
3.2 
Number of Subjects 
Required Sample Size: 24 evaluable patients who complete at least 75% of protocol-mandated 
radiotherapy. Patients who withdraw consent, drop out of the study before starting radiation 
therapy or before completing 75% of protocol treatment without grade ≥3 toxicity will be 
replaced. Any patient receiving any study drug will be included in the analysis of toxicity.  
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent.  The written informed consent must be obtained 
from the patient prior to enrollment.  The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
3.3.1 Inclusion Criteria 
1. Patients with locally advanced BCC of the head and neck, consisting of at least one 
histologically or cytologically confirmed lesion ≥ 20 mm in longest diameter that is 
considered to be inoperable or to have a medical contraindication to surgery, in the 
opinion of a Mohs dermatologic surgeon, head and neck surgeon, or plastic surgeon. 
Locally advanced disease is considered to include involved lymph nodes of the neck.  A 
patient with regionally involved lymph nodes in the neck is considered eligible. The 
patient should be considered a candidate for radiotherapy and should not have medical 
contraindications to receipt of radiation therapy. 
If a patient has distant metastatic spread of BCC (e.g., spread to distant areas outside 
the regional lymph nodes, clearly non contiguous areas of bone involvement, or distant 
metastasis to lung, brain, or other visceral organs), the patient should be considered as 
having distant metastasis and is not eligible. 
Note: All lesions that the investigator proposes to follow as target lesions during the 
course of the study must have previously been histologically confirmed as BCC.  
Acceptable contraindications to surgery include:  
o BCC that has recurred in the same location after two or more surgical procedures 
and successful curative resection is deemed unlikely 
o Complete surgical resection is not possible or is deemed excessively morbid 
(e.g. invasion into cranial nerves or skull base, proximity to brain, spinal canal, or 
orbit) 

 
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o Anticipated substantial morbidity and/or major deformity from surgery (e.g. 
removal of a major facial structure, such as nose, ear, eyelid, eye, or jaw; or 
requirement for upper limb amputation) 
o Medical contraindication to surgery 
o Patient refusal of surgery due to anticipated morbidity 
o Other conditions considered to be contraindicating must be discussed with Data 
Coordinator before enrolling the patient. 
2. Prior radiation therapy is acceptable but there cannot be major overlap of the previously 
irradiated tissues with the new radiation treatment volumes anticipated to be delivered 
for the purposes of this protocol, in such a way that curative intent with radiation cannot 
be met. Furthermore, the total dose from all radiation delivered and expected to be 
delivered should not exceed the suggested dose constraints given for normal structures 
(see Section 5.2.7). 
3. Zubrod Performance Status 0-2  
4. Age ≥18 years of age 
5. Adequate bone marrow and organ function defined as follows:  
Adequate bone marrow function: 
 
leukocytes 
> 3,000/mcL 
absolute neutrophil count 
≥1000 cells/mm3 
platelets 
≥75,000 cells/mm3 
hemoglobin 
≥ 8.5 g/dl (recommended cutoff subject to judgment of medical 
oncologist), but cannot be transfusion dependent 
Adequate hepatic function: 
 
total bilirubin 
≤ 1.5x institutional ULN or within 3x the ULN for patients with Gilbert 
disease 
AST(SGOT) 
< 3 X institutional upper limit of normal 
ALT(SGPT) 
< 3 X institutional upper limit of normal 
Adequate renal function: 
 
creatinine 
within normal institutional limits 
OR 
creatinine clearance  
 
> 60 mL/min/1.73 m2 for patients with creatinine levels above 
institutional normal 
 
6. Agreement not to donate blood or blood products during the study and for 24 months 
after discontinuation of vismodegib.  
7. For male patients, agreement not to donate sperm during the study and for 3 months 
after the final dose of vismodegib. Male patients must use condoms at all times, even 
after a vasectomy, during sexual intercourse with pregnant partners or female partners 
of reproductive potential during treatment with vismodegib.  Vismodegib is present in 
semen. It is not known if the amount of vismodegib in semen can cause embryo-fetal 
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8. Verify the pregnancy status of females of reproductive potential within 7 days prior to 
initiating vismodegib.  For women of childbearing potential, a negative pregnancy test 
within 7 days prior to commencement of dosing is required. Women of reproductive 
potential are required to use two forms of acceptable contraception (including one 
acceptable barrier method with spermicide) during therapy and for 24 months after 
completing therapy.  Acceptable forms of primary contraception include the following:  
Combination hormonal contraceptives, subcutaneous hormonal implant, hormonal patch, 
hormonal contraceptives (levonorgestre-releasing intrauterine system, 
medroxyprogesterone acetate depot), tubal sterilization, vasectomy, and intrauterine 
device (IUD).  Acceptable forms of barrier contraception include the following:  any male 
condom (with spermicide) or diaphragm (with spermicide).  
3.3.2 Exclusion Criteria 
1. Patients with distant metastasis (e.g. spread to distant areas outside the regional lymph 
nodes, clearly non contiguous areas of bone involvement, or distant metastasis to lung, 
brain, liver or other visceral organs) are ineligible. 
2. Patients with nevoid BCC syndrome (Gorlin syndrome) should not enroll in this study.  
3. A patient with a known other malignancy is eligible if there is a negligible risk for disease 
progression or death within one year, there is no active ongoing treatment for this 
malignancy, and the malignancy and/or any anticipated future treatments would not 
interfere with protocol-mandated evaluations at 1 year.  
4. Prior vismodegib or other antagonists of the Hh pathway;  
5. Concurrent non-protocol-specified anti-tumor therapy (e.g., chemotherapy, other 
targeted therapy, topical therapy such as 5-Fluorouracil or imiquimod, radiation therapy, 
surgery, or photodynamic therapy.  
• 
For patients with multiple cutaneous BCCs at baseline that are not designated by 
the investigator as target lesions, treatment of these non-target BCCs with 
surgery may be permitted but must be discussed with Data Coordinator prior to 
any surgical procedure. 
6. Recent (within 4 weeks of Registration), current, or planned participation in another 
experimental drug study.  
7. Prior radiotherapy to the region of the study cancer that would result in overlap of 
radiation therapy fields in such a way that curative intent with radiation cannot be met  
8. Inability or unwillingness to swallow capsules; Patients with any condition that may 
impair the ability to swallow or absorb oral medications/investigational product including:  
o any lesion, whether induced by tumor, radiation or other conditions, which makes 
it difficult to swallow capsules or pills;  
o prior surgical procedures affecting absorption including, but not limited to major 
resection of stomach or small bowel;  
o active peptic ulcer disease;  
o malabsorption syndrome 
9. Pregnant or lactating women.  Patients who are unable or are unwilling to adhere to the 
required contraceptive methods are excluded from the study.  
o Women of reproductive potential are required to use two forms of acceptable 
contraception (including one acceptable barrier method with spermicide) during 

 
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therapy and for 24 months after completing therapy.  Acceptable forms of primary 
contraception include the following:  Combination hormonal contraceptives, 
subcutaneous hormonal implant, hormonal patch, hormonal contraceptives 
(levonorgestre-releasing intrauterine system, medroxyprogesterone acetate 
depot), tubal sterilisation, vasectomy and intrauterine device (IUD).  Acceptable 
forms of barrier contraception include the following: Any male condom (with 
spermicide) or diaphragm (with spermicide). 
o Women should not breastfeed a baby while on this study, or for 24 months after 
completing therapy. 
o Male patients must use condoms at all times, even after a vasectomy, during 
sexual intercourse with female partners of reproductive potential during treatment 
with vismodegib and for 2 months after the last dose to avoid exposing a 
pregnant partner and unborn fetus to vismodegib. 
10. Life expectancy of <1 year  
11. Patients with widespread superficial multifocal BCC who are considered unresectable 
due to breadth of involvement and do not have a single definable area of disease 
amenable to radiation therapy targeting.  
Note: If an area including one or more lesions is definable for radiation therapy targeting, 
the patient may be eligible for treatment on study using the designated target lesion(s) 
identified by the investigator. 
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection 
or psychiatric illness/social situations that would limit compliance with study 
requirements; 
13. History of other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates use of an investigational drug or that might affect interpretation of the 
results of the study or renders the patient at high risk form treatment complications 
14. HIV-positive patients on combination antiretroviral therapy, because of the potential for 
pharmacokinetic interactions with vismodegib; 
3.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 
approximately 21 weeks or until: 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patients decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
• 
General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
3.5 
Duration of Follow Up 
Patients will be followed for 12 months after completion of all protocol therapy, or until death, 
whichever occurs first.  Patients removed from study for unacceptable treatment related adverse 
event(s) will be followed until resolution or stabilization of all treatment related adverse events to 
Grade 2 or lower. 

 
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3.6 
Study Timeline 
3.6.1 Primary Completion 
It is estimated that study accrual will be completed within 12-18 months of the time at which the 
study is opened for enrollment.  It is estimated that primary outcome measure will be 
determined approximately 3 years after the study is opened for enrollment.   
Study Completion 
It is estimated that study completion will occur within 3-4 years of the time from when the study 
is open for enrollment. 
4 Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Vismodegib 
Vismodegib capsules will be taken orally (whole). Patients receive vismodegib on an outpatient 
basis. Patients are instructed to swallow one capsule once a day (preferably at the same time 
each day) 7 days/week, with or without food, with about 1 cup (240 mL) of water. Capsules must 
be swallowed whole; they must not be opened, chewed, broken, or crushed under any 
circumstances. It is preferable that vismodegib be taken prior to radiation therapy throughout the 
treatment course.  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 asked to document daily vismodegib on a pill diary during pre-radiation 
treatment and concurrent treatment, which will be collected by the institution as source 
documentation. Institutions will submit a (DP) form at the end of both induction treatment and 
concurrent treatment. 
Classification 
Inhibitor of the hedgehog (Hh) signaling pathway 
Mechanism of Action 
Vismodegib is a more potent novel and specific synthetic oral hedgehog pathway inhibitor with 
an IC50 of 3 nM. Vismodegib targets the Hedgehog signaling pathway, blocking the activities of 
the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog 
signaling. The Hedgehog signaling pathway plays an important role in tissue growth and repair; 
aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular 
proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors 
PTCH and SMO. Vismodegib also inhibits ABCG2, Pgp, and MRP1-important ABC transporters 
associated with multidrug resistance.  
Metabolism 
Greater than 98% of the total circulating drug-related components are the parent drug. 
Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine 
ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in 
vitro by recombinant CYP2C9 and CYP3A4/5. 
Contraindications 
None per product insert.   
Availability 

 
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Each vismodegib capsule has a pink opaque body and a grey opaque cap with “150 mg” printed 
on the capsule body and “VISMO” printed on the capsule cap in black ink. Vismodegib capsules 
are available in bottles of 28 capsules (NDC 50242-140-01). 
Storage and handling 
Drug storage will be in the site pharmacy, according to institutional guidelines. Store at room 
temperature 15°C to 30°C (59°F to 86°F). 
 
Side Effects 
Though no specific concomitant medications are prohibited during this study (other than 
concomitant anti-tumor therapies), vismodegib may potentially affect the pharmacokinetics of 
other drugs by altering their metabolism. In addition, metabolic inducers could possibly modify 
the pharmacokinetics of vismodegib. Therefore, concomitant medications should be used with 
care, and the risk benefit profile of each agent should be taken in to consideration. 
Identified Risks (excerpted from IB, version 6.0, dated 01-25-2012) 
The safety of vismodegib has been evaluated in 138 laBCC patients from four open-label, 
single-arm Phase I and II clinical studies. One hundred thirty-eight laBCC patients received at 
least one 150 mg dose of vismodegib monotherapy. Doses > 150 mg did not result in higher 
plasma concentrations in patients administered doses > 150 mg and have been included in 
analyses. In general, the observed safety profile was consistent between mBCC and locally 
advanced BCC patients as described below.  
Adverse reactions are presented by MedDRA System Organ Class and absolute frequency in 
Table 16. Frequencies are defined as:  
• 
Very common: ≥ 1/10  
• 
Common: <1/10 to ≥ 1/100  
• 
Uncommon: <1/100 to ≥1/1000  

 
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Within each frequency grouping, adverse reactions are presented in the order of decreasing 
seriousness. Frequency categories do not account for other factors such as varying study 
duration, pre-existing conditions or baseline patient characteristics. ADR frequency categories 
are assigned based on clinical trial experience and may not reflect the frequency of adverse 
events occurring during normal clinical practice.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Vismodegib in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent.  
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product package insert.  
4.2 
Radiation Therapy 
The administration of radiation therapy is outlined in section 5.2. 
There will be expected radiation related toxicities; very likely toxicities are mucositis, mouth 
dryness or changes in taste and/or smell that may be permanent, thick saliva, hoarseness, 
tanning or redness and/or irritation of the skin in the head and neck area being treated with 
radiation, ear pain and/or pressure, fatigue, weight loss, permanent hair loss in the area treated 
with radiation (face, chin, neck), and hypersensitivity of teeth and/or loss of teeth or cavities in 
the teeth, if strict dental care is not followed. 
Serious but less likely toxicities are decreases in function of the thyroid gland that may require 
thyroid replacement therapy; serious damage to the spinal cord, nerves in the neck, jawbone, 
larynx, skin, or other parts of the head and neck that may require surgical intervention and may 

 
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be life threatening; temporary pain or scarring around nerves in the shoulder that could cause 
numbness and/or weakness; breathing problems; difficulty with swallowing and eating, 
possibility of inhaling food and/or liquids into the lungs which could result in pneumonia; serious 
ear infections and/or hearing loss; damage to the spinal cord leading to permanent weakness 
and/or symptoms like a stroke; loss of hearing; and decreased vision. 
In general, the anticipated toxicities from the combination of vismodegib and radiation therapy 
should not be overlapping in a synergistic fashion with the possible exception of wound healing. 
It is possible that the side effects of radiation therapy which are related to wound healing may 
be intensified in the presence of vismodegib. In the absence of any further surgical procedures 
given after the combined therapy, it is not expected that there should be serious additional 
toxicity related to wound healing over that expected from a typical standard-of-care radiation 
therapy course, although these types of effects will be tracked carefully as part of this study 
protocol. 
4.3 
Drug Accountability 
The Investigational Pharmacist will manage drug accountability records.  Drug will be shipped  
for assigned study patients only.  Drug from one patient cannot be transferred to another patient 
even if that patient is on protocol.  
4.4 
Drug Ordering 
Study investigators will obtain vismodegib directly from pharmaceutical company as study 
supply.  Participating sites will receive drug shipments directly from Genentech. 
4.5 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per institutional standards, adhering to applicable local and 
federal laws. 
4.6 
Reconciliation 
The Sponsor-Investigator agrees to conduct reconciliation for the product. Genentech and the 
Sponsor-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-Investigator 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. 
5 Treatment Plan 
5.1 
Dosage and Administration:  Vismodegib 
Treatment will be administered on an outpatient basis. Patients will take vismodegib 150 mg 
orally (QD PO).  Prior to Radiation Treatment, patients will take vismodegib (150 mg/day) for 
approximately 12 weeks, then for 1-14. days as required until the start of radiation therapy.  If 
there is an unforeseen delay in starting the radiation therapy after the induction phase, an 
additional 1-2 weeks of treatment with vismodegib may be given after contacting and getting the 
consent of the Principal Investigator.  During radiation treatment, vismodegib (150mg/day) 
concurrent treatment will be given on the same day as the first fraction of radiation therapy and 
will continue daily through the completion of radiation treatment. The patient will be requested to 
maintain a medication diary of each dose of medication.  The medication diary will be returned 
to clinic staff approximately every four weeks (Week 5, 9, 13-15, 18, and at the end of drug 
treatment) . 

 
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Table 5.1 
Regimen Description 
Study Drug 
Dose 
Route 
Schedule 
Vismodegib 
150 mg 
Oral 
Induction Phase (12 weeks) 
End of Induction / Re-Evaluation (2 weeks) 
Radiation Treatment (7 weeks) 
 
5.2 
Dosage and Administration:  Radiation Therapy  
5.2.1 Three-dimensional conformal radiation therapy 
For three-dimensional conformal radiation therapy, the PTV1 (CTV1 + margin) will receive 
6600-7000 cGy in 33-35 fractions, with the final prescribed dose decided per discretion of the 
prescribing investigator, and the PTV2 (CTV2 + margin) will receive 5000 cGy in 25 fractions.  
The PTV1 should encompass any area of disease visible or palpable at post-induction restaging 
and any areas involved on the initial imaging prior to induction, even if the area has responded 
to the drug. The PTV2 should encompass any areas of elective coverage deemed necessary, 
such as the regional lymph node drainage basins. 
Treatment will be delivered once daily, 5 fractions per week, over 7 weeks. After the initial 25 
fractions for treatment of the PTV2, a reduced field will be given encompassing only PTV1. If 
PTV2 is not required, then PTV1 will be treated for the entire course of radiation. 
The reported doses for PTV1 and PTV2 shall include the prescription dose as well as the 
maximum point dose (maximum dose encompassing 0.1 cc volume) for that PTV, % PTV 
receiving > 110% and 115% for that PTV and the PTV receiving < 93% of the prescribed dose 
for that PTV, and the mean dose for that PTV.  
All plans shall be normalized such that 95% of the volume of each PTV is covered by the 
prescription isodose surface. To avoid a minor variation:   
• 
No more than 20% of PTV1 will receive 110% of the prescription dose and no more than 
5% of PTV1 will receive 115% of the prescription dose.  
• 
No more than 1% of any distinct PTV should receive <93% of its prescribed dose.  
5.2.2 Intensity modulated radiation therapy 
IMRT is particularly encouraged for tumors involving the skull base or which lie in close 
approximation to critical structures such as the eye, brain, or spinal cord. 
For intensity modulated radiation therapy, the PTV2 (CTV2 + margin), if deemed necessary by 
the investigator, will receive 5000 cGy in 25 fractions and the PTV1 (CTV1 + margin) will 
receive 6600-7000 cGy in 33-35 fractions (maximum total dose to be at discretion of the 
investigator). The PTV1 should encompass any anatomic areas involved by disease that remain 
visible or palpable at post-induction restaging and any anatomic areas involved on the initial 
imaging prior to induction, even if the area has exhibited response to the drug. The PTV2 should 
encompass any areas of elective coverage deemed necessary, such as the regional lymph 
node drainage basins. 
Treatment will be delivered once daily, at a rate of 5 fractions per week, over 7 weeks. There 
are two options for radiation treatment planning, either employing a field reduction and boost at 

 
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the end of treatment, or a simultaneous integrated boost with all PTVs being treated 
simultaneously.  
For the sequential boost approach: After the initial 25 fractions for treatment of the PTV2, a 
reduced field will be given encompassing only PTV1. For this approach, two separate plans are 
required, the first encompassing the entirety of the 5000 cGy volume, with a boost plan to 
encompass the smaller volume which will be treated for an additional 1600-2000 cGy. 
For the simultaneous integrated boost approach: Alternatively, a simultaneous integrated boost 
plan can be used in which the PTV1 receives 6600-7000 cGy in 33-35 fractions, but the PTV2 is 
to be treated in the same plan for all 33-35 fractions. For this approach, the PTV2 dose should 
be increased to 5400-5600 cGy given in 33-35 fractions, to account for the more extended 
fractionation schema. 
The reported doses for PTV1 and PTV2 shall include the prescription dose as well as the 
maximum point dose (maximum dose encompassing 0.1 cc volume) for that PTV, % PTV 
receiving > 110% and 115% for that PTV and the PTV receiving < 93% of the prescribed dose 
for that PTV, and the mean dose for that PTV.  
All plans shall be normalized such that 95% of the volume of each PTV is covered by the 
prescription isodose surface. To avoid a minor variation:   
• 
No more than 20% of PTV1 will receive 110% of the prescription dose and no more than 
5% of PTV1 will receive 115% of the prescription dose.  
• 
No more than 1% of any distinct PTV should receive <93% of its prescribed dose.  
5.2.3 Technical Factors  
5.2.3.1 External Beam Equipment and Beam Delivery Methods  
Megavoltage equipment capable of delivering static modulation with a multileaf collimator or 
dynamic intensity modulation (using a multileaf collimator or tomotherapy) is required. 
Volumetric arc delivery techniques can be used. 
5.2.4 Treatment Planning, Imaging and Localization Requirements  
The immobilization device should include the body area of the primary tumor volume and any 
grossly involved, regional nodal volumes to be treated with radiation therapy. It is strongly 
encouraged that the participating centers include the entire head, neck, and shoulders in the 
immobilization. Accuracy of patient set-up should be ensured with verification using on-board 
imaging, either portal films or conebeam CT, at least twice per week of treatment. 
Treatment planning CT scans will be required to define gross target volume(s) and clinical target 
volume(s). The treatment planning CT scan should be acquired with the patient in the same 
position and using the same immobilization device as for treatment.  
All tissues to be irradiated must be included in the CT scan. CT scan slice thickness should be 
no more than 0.3 cm through the entirety of the region that contains the primary target volumes. 
The regions above and below the target volume may be scanned with 0.5 cm slice thickness, 
although 0.3 cm slice thickness is preferred.  
The GTV and CTV and normal tissues must be outlined on all CT slices in which the structures 
exist.   
5.2.5 Treatment Planning/Target Volumes  
The definition of volumes will be in accordance with the 1993 ICRU Report #50, but the dose 
reporting and prescription are specified in Sections 5.2.   

 
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The Gross Tumor Volume (GTV) is defined as all known gross disease determined from 
imaging studies at presentation, clinical information, and physical examination findings. The 
GTV should encompass any area of disease visible or palpable at post-induction restaging and 
any areas involved on the initial imaging prior to induction, even if the area has responded to the 
drug. Grossly positive lymph nodes are defined as any lymph nodes > 1 cm in shortest 
dimension or nodes with a necrotic center. It is strongly encouraged that the radiation oncologist 
outline the radiologic extent of the primary tumor and any involved nodes along with a 
radiologist. Whenever possible, it is recommended that the diagnostic-quality images be fused 
to the planning CT scan image dataset to more accurately define the GTV as it existed prior to 
induction with vismodegib. To further subdivide the GTV, gross disease at the primary site may 
be designated as GTV-P and clinically involved gross lymph nodes may be designated GTV-N. 
In situations where the patient underwent surgical biopsy or surgery prior to radiation therapy, 
the GTV is defined as the residual gross disease thought to remain following the surgery.  
The Clinical Target Volume (CTV): See Sections 5.2 for delineation details.  
For patients without complete surgical resection: In terms of the GTV (GTV-P and GTV-N), a 
margin of 5 mm should be given circumferentially around the GTV (GTV-P and GTV-N) and this 
volume will be called the CTV1 (CTV1-P and CTV1-N). This margin can be reduced to as low as 
1 mm for tumors in close proximity to critical structures, e.g., tumors next to the spinal cord or 
brain.  
For regions deemed to be at high risk for microscopic disease, the treating radiation oncologist 
should delineate all potential routes of spread for primary and nodal GTVs. This is known as 
CTV for subclinical disease or CTV2. Delineation and treatment of CTV2 is optional and based 
on the judgment of the study investigators. 
For patients who have undergone a prior surgical resection: CTV2 should include all of the 
original sites of gross disease at the primary disease site and any grossly involved but resected 
lymph nodes (e.g the post-operative bed). A CTV1 should be delineated if a region has had 
surgery but still contains residual gross disease. 
To further define the subclinical region at risk for microscopic spread at the primary disease site, 
CTV2-P includes CTV1-P + at least 3 mm margin. This margin can be reduced to as low as 1 
mm for tumors in close proximity to critical structures, e.g., tumors next to the spinal cord or 
brain. At the discretion of the treating physician, elective nodal regions considered to be at high 
risk can be covered in CTV2 when indicated.  
Note: Thus, if CTV-2 is delineated and treated, the outermost boundary of CTV2-P should 
usually be 8 mm from the GTV-P. In regions near the spinal cord or other sensitive or critical 
structures, the total margin between GTV-P and CTV2-P can be as low as 2 mm.   
A separate Planning Target Volume (PTV) will provide a margin around the CTV’s to 
compensate for the variabilities of treatment set up and internal organ motion. A minimum of 3 
mm around the CTV’s is required in all directions to define each respective PTV (PTV1, PTV2). 
Careful consideration should be made when defining the superior and inferior margins in three 
dimensions. Note that at any given point, the margin from the GTV to the PTV1 should usually 
be at least 8 mm and to the PTV2 should usually be at least 11 mm. The exception is when the 
tumor is close to the spinal cord or other sensitive structures where CTV margins may be 
reduced as described; for these cases, the PTV may be set as equal to the CTV to ensure 
avoidance of critical neural structures. In these exceptionally difficult cases, the total expansion 
from the GTV to the PTV1 could be as low as 1 mm and to the PTV2 could be as low as 2 mm. 
Margins may be reduced to these absolute minima just around the anatomic areas of greatest 
risk; expansion to the larger standard margins is encouraged wherever possible. 
The treatment plan used for each patient will be based on an analysis of the volumetric dose, 
including dose-volume histogram (DVH) analyses of the PTVs and critical normal structures. An 

 
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“inverse” planning process using computerized optimization should be used. The treatment aim 
will be the delivery of radiation to the PTVs and the exclusion of non-involved tissue.  
5.2.6 Critical Structures  
Critical Normal Structures  
Surrounding critical normal structures, including spinal cord, brain, brainstem, orbits, chiasm 
and optic nerves, cochlea, parotid glands, submandibular glands, skin, oral cavity, mandible, 
brachial plexus, esophagus and glottic larynx should be outlined.  
Physicians should assist the planner in identifying the critical normal structures. If planning risk 
volumes (PRVs) are used, the spinal cord PRV will be defined as a three-dimensional margin at 
least 4 mm larger than the spinal cord to ensure that the PRV margin is at least 4 mm from any 
portion of the spinal cord. The normal tissues will be contoured and considered as solid organs. 
The tissue within the skin surface and outside all other critical normal structures and PTVs is 
designated as unspecified tissue.  
DVH’s must be generated for all critical normal structures, any corresponding PRVs, and the 
unspecified tissues. Institutions that use PRVs must clearly define them as such.  
Unspecified tissue outside the targets: No more than 8cc of unspecified tissue can receive 
greater than 6600 cGy or more and no more than 1cc of unspecified tissue can receive 7000 
cGy or more. Participants are strongly encouraged to remain within these limits. The treating 
physician is encouraged to call the Principal Investigator should questions arise.  
The method used for tissue heterogeneity calculations shall be recorded. The dose prescription 
is to be based on a dose distribution corrected for heterogeneities.  
5.2.7 Planning Goals: Normal Structures  
 These dose objectives are recommendations. An effort should be made to stay within the 
normal tissue dose guidelines stipulated in this protocol.  
• 
Spinal Cord: The PRV should not exceed 48 Gy to any volume in excess of 0.03 cc 
(approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV should not exceed 50 Gy to 
any volume in excess of 0.01 cc. This PRV should be given the highest priority. 
• 
Brainstem: The PRVbrainstem should not exceed 56 Gy to any volume in excess of 0.03 
cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, the PRVbrainstem 
should be given less priority than the PRVcord but more priority than other critical 
structures. 
• 
Optic chiasm, optic nerves, and globe: The PRV should not exceed 54 Gy to any volume 
in excess of 0.01 cc. Every effort should be made to keep the dose as low as possible in 
these areas. 
• 
Parotid glands: Mean dose < 2600 cGy should be achieved in at least one gland, or at 
least 20 cc of the combined volume of both parotid glands will receive < 2000 cGy, or at 
least 50% of one gland will receive < 3000 cGy. Every effort should be made to achieve 
the lowest mean doses as possible without compromising tumor coverage.  
• 
Submandibular glands and oral cavity: Reduce the dose as much as possible, preferably 
with a mean dose < 3900 cGy. If, at the discretion of the treating physician, level I region 
of the neck must be covered, there is no need to constrain the submandibular glands.  
• 
Mandible: Reduce the dose as much as possible. It is recognized that portions of the 
mandible will overlap the CTVs and/or PTVs but hot spots within the mandible should be 
avoided. It is recommended that maximum dose within the mandible be < 6600 cGy. 

 
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5.2.8 Planning Priorities  
Critical normal structure constraints followed by the prescription goals are the most important 
planning priorities. The priorities in addressing the protocol aims and constraints will be in the 
following order: 1) Critical Normal Structure Constraints (Section 5.2.6); 2) Dose Specifications 
(Section 5.2); 3) Planning Goals: Salivary glands (Section 5.2.7); 4) Planning Goals: Other 
normal structures (Section 5.2.7).  
5.3 
Dose Modifications and Dosing Delays 
There are no planned dose reductions of vismodegib.  
Treatment with vismodegib may be interrupted for up to 4 weeks for evaluation of an intolerable 
toxicity finding. In addition, treatment with vismodegib may be interrupted for up to 4 weeks if a 
patient becomes temporarily unable to swallow capsules or is in need of an unrelated surgical 
procedure which does not require disenrollment from the study. Any other proposed reasons for 
interruption of treatment should be discussed in advance with the Principal Investigator. If the 
patient resumes drug, administration will start at the point in the protocol at which was 
interrupted and the total durations of days of drug given to the patient should equal those 
specified in the protocol. 
Radiation therapy should not be halted if at all possible and any radiation delays are to be 
stringently avoided, even if drug administration is interrupted. If radiation therapy treatments are 
interrupted for any reason, including holidays or mechanical breakdown, the missed treatments 
are to be addended to the end of the treatment course, such that the total radiation dosage and 
days of radiation therapy given to the patient should equal those specified in the protocol. 
If either vismodegib or radiation treatment has been held for more than 28 days to allow for 
resolution of an adverse event, the treating physician should contact the Study Chair to review 
the subject’s condition prior to resuming the patient’s treatment, except for delays due to 
hypertension. As a patient progresses from one treatment to another (i.e., pre-radiation therapy, 
radiation therapy, post radiation therapy), the patient should remain at the SAME DOSE LEVEL.   
5.3.1 Intolerable Toxicity Requiring Discontinuation of Vismodegib 
Intolerable toxicities are defined as new (not present at baseline) Grade 3 or 4 adverse events 
considered related to vismodegib that are likely to be life-threatening or irreversible, and when in 
the opinion of the investigator, the risk outweighs the benefit of continued treatment. 
The following adverse events are not considered intolerable: 
• 
Grade 3 or 4 events that in the opinion of the investigator are more likely related to 
ongoing or recent procedures or concomitant medications other than vismodegib 
• 
Hematologic or metabolic/chemistry laboratory abnormalities that are found on routine 
testing and are not considered clinically significant  
• 
Musculoskeletal abnormalities, skin ulceration, fracture, debridement or wound care, and 
dental or periodontal disease related to underlying medical conditions  
• 
Nausea, vomiting, or diarrhea that is adequately controlled after optimization of medical 
management. 
• 
Grade 3 infection that is transient and treatable or manageable 
• 
Grade 3 sterility 
• 
Asymptomatic thromboembolism found incidentally on imaging and managed with anti-
coagulation therapy 

 
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Patients with an asymptomatic or tolerable severe adverse event may continue to receive study 
drug, provided that the adverse event is manageable and the patient and the investigator agree 
that continued study participation is acceptable.  
5.4 
Monitoring and Toxicity Management 
Each patient receiving vismodegib will be evaluable for safety.  The safety parameters include 
all laboratory tests and hematological abnormalities, physical findings, performance status 
evaluations, Skindex-16 survey responses and spontaneous reports of adverse events reported 
to the investigator by patients. 
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI 
CTCAE v4.0.  Dose adjustments will be made according to the system showing the greatest 
degree of toxicity.  
5.5 
Other Therapy  
5.5.1 Permitted Supportive Therapy  
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented 
on each site’s source documents as concomitant medication.  
After the 12 month follow-up period has ended following completion of combination therapy, 
patients may receive standard-of-care treatment for recurrence or for other skin cancers. These 
therapies may include vismodegib. 
5.5.2 Non-permitted Supportive Therapy  
The patient’s medications will be evaluated within 4 weeks prior to treatment (see Section 
6.1.1.1) to assess any medication that affects CYP3A4.  
Certain medications act through the CYP450 system. Strong inhibitors of CYP3A4 such as 
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin, voriconazole may increase vismodegib concentrations and 
are generally prohibited although, if absolutely necessary, they may be administered with 
caution. Grapefruit juice is also an inhibitor of CYP450. CYP3A4 inducers such as rifampin may 
decrease vismodegib concentrations and therefore are strictly prohibited. Caution should be 
used when strong inhibitors and/or inducers of CYP2D6 are co-administered with vismodegib. 
Concomitant use of vismodegib with agent with narrow therapeutic windows that are 
metabolized by CYP3A4, CYP2D6 or CYP2C8 should be avoided. In addition, the use of St. 
John’s Wart is not recommended.  
Vismodegib, 150 mg once daily, has no effect on CYP2C9, CYP1A2 or CYP2C19 in vivo 
although it does in vitro. Therefore, therapeutic doses of warfarin, a substrate of CYP2C9, and 
omeprazole, a substrate of CYP2C19 are permitted. Caffeine, a substrate of CYP1A2, is also 
permitted. A list of medications that should be used with caution during this trial of vismodegib 
can be found in Appendix 5. Comprehensive lists of agents that could affect vismodegib through 
the cytochrome P450 system can be found in Appendix 5. No drugs are specifically prohibited 
but caution is recommended for these agents. 
Amifostine or other intravenously administered supportive systemic therapies are not allowed 
due to the unknown interaction of these compounds with vismodegib. 

 
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5.6 
Compliance Criteria 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Treatment breaks, if necessary, should ideally not exceed five treatment 
days at a time and ten treatment days total. Treatment breaks should be allowed only for 
resolution of severe acute toxicity and/or for intercurrent illness and not for social or logistical 
reasons. Treatment or visit delays for public holidays or weather conditions do not constitute a 
protocol violation. 
Institutions are encouraged to generate treatment that fall within the dose limits defining the per 
protocol category. For those target to critical structures geometries that are more challenging, 
some variation from the specified protocol dose limits is acceptable.   
6 Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Section 6 Schedule 
of Study Procedures and Assessments.  Screening assessments must be performed within 28 
days prior to the first dose of investigational product unless otherwise noted.  Any results falling 
outside of the reference ranges may be repeated at the discretion of the investigator. All on-
study visit procedures are allowed a window of ± 3 days unless otherwise noted.  Treatment or 
visit delays for public holidays or weather conditions do not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements. 
6.1.1 Pretreatment Period 
6.1.1.1 Screening Assessments  
The Screening procedures and assessments must be completed within 14 days of the Day 1 
Visit unless otherwise noted.  
• 
Physical examination - The initial complete physical examination should include 
evaluation of the head, eyes, ears, nose and throat (HEENT); cardiovascular, 
dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological systems. 
Height and weight will also be recorded. 
• 
Vital signs 
• 
Complete medical history – can be done within 28 days of Day 1  
• 
Baseline conditions assessment 
• 
Documentation of disease assessment - Assessments should include an evaluation of 
all sites of disease. Patients will undergo tumor assessments per RECIST version 1.1 
tumor response criteria.  Can be done within 28 days of Day 1 
• 
Performance status  
• 
Skindex-16 questionnaire 
• 
History of prior treatments and any residual toxicity relating to prior treatment 
• 
Baseline medications taken within 28 days of Day 1 

 
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• 
Laboratory assessments 
o Hematology (hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
percent and absolute differential count [neutrophils, bands, eosinophils, 
lymphocytes, monocytes, basophils, other cells])  
o Serum chemistries (sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, calcium, alkaline phosphatase, magnesium, total bilirubin, albumin, 
total protein, ALT, AST, and as clinically indicated; LDH, and phosphorus)  
o Pregnancy test: All women of childbearing potential (including those who have 
had a tubal ligation) will have a serum pregnancy test at screening, within 7 days 
of Day 1.  
 
Urine or serum pregnancy tests will be performed every 4 weeks at 
specified subsequent visits. If a urine pregnancy test is positive, it must 
be confirmed by a serum pregnancy test.  
o Urinalysis 
• 
Imaging (CT or MRI) of primary tumor region and any involved regional lymph nodes for 
tumor assessment.   Can be done within 28 days of Day 1 
o Note: The CT scan with contrast or an MRI with gadolinium must be done unless 
medically contraindicated.  The MRI or CT scan must encompass the skull base 
and/or upper mediastinum if those areas are involved. If locally advanced BCC 
lesions with a RECIST-measurable component are identified, the same imaging 
modality used at baseline must be used throughout the study. 
• 
Chest x-ray or chest CT scan, or CT of chest and abdomen – can be done within 28 
days of Day 1 
• 
For externally visible tumors 
o Bidimensional measurements of externally visible tumor dimension 
o Description of the lesion at baseline 
o Digital photography of target lesion(s) 
o Tumor biopsy for pathologic diagnosis - can be done within 360 days prior to  
Day 1 
The following pre-treatment evaluations/interventions are not required but are highly 
recommended:  
• 
PET/CT scan for patients with suspected metastatic disease 
• 
Brain MRI for patients with disease located at or near the skull base 
• 
Biopsy confirmation of suspected involved regional nodes (fine needle aspiration is 
acceptable); 
• 
For patients with head and neck cancers who will have treatment-related risk to salivary 
function, pre-radiotherapy dental evaluation is strongly recommended 
6.1.2 Treatment Period 
6.1.2.1 Study Procedures, Week 5 and 9 (Induction Phase) 
• 
Physical examination including weight 
• 
Vital signs 
• 
Performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 

 
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• 
Skindex-16 survey  
• 
Laboratory assessments 
o Hematology  
o Serum chemistries  
• 
Urine or serum pregnancy tests at weeks 5 and 9 - if a woman of childbearing age  
6.1.2.2 Study Procedures, Week 13-14 (End of Induction) 
Within 14 days after completion of induction vismodegib therapy, patients must have a re-
evaluation to determine if there has been disease progression prior to starting concurrent 
treatment. Patients whose disease has progressed will no longer continue on study. 
• 
Physical examination including weight 
• 
Vital signs 
• 
Performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
Skindex-16 survey 
• 
Laboratory assessments 
o Hematology  
o Serum chemistries  
• 
Urine or serum pregnancy tests  - if a woman of childbearing age  
• 
Disease assessment 
• 
Imaging (CT or MRI) of head and neck for tumor assessment 
• 
CT chest or chest x-ray – if clinically indicated 
• 
For externally visible tumors 
o Bidimensional measurements of externally visible tumor dimension 
o Standardized digital photography of target lesion(s) 
6.1.2.3 Study Procedures, Week 15-21 (Radiation Therapy)  
Three-dimensional conformal therapy is required for this study. IMRT is allowed as deemed 
appropriate and is highly encouraged for very advanced disease presentations.  
Following conclusion of induction drug therapy and completion of re-evaluation procedures, 
radiation should start within 1 to 14 days after completion of induction vismodegib, unless there 
is an unforeseen delay. During the re-evaluation interval, vismodegib will continue to be given 
daily until radiation therapy starts.  Radiation therapy is anticipated to last approximately 7 
weeks depending on the prescription dose chosen by the study investigator. 
Note: If there is an unforeseen delay in starting the radiation therapy, an additional 1-2 weeks of 
treatment with vismodegib may be given after contacting and getting the consent of the Principal 
Investigator.  If there is a delay over 4 weeks in initiation of radiation therapy, investigators 
should consider removal of the patient from the protocol.  
While receiving radiation therapy, patients will have limited physical exams, evaluation of 
adverse events, and assessment of concomitant medications weekly. At week 18 only, 
patients will have urinalysis, pregnancy test, and laboratory assessments (hematology 
and serum chemistries).  The drug diary will be collected at week 18.   

 
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Radiation therapy will be 66-70 Gy in 33-35 fractions over 7 weeks as prescribed in Section 5.2. 
See section 5 for Radiation Therapy treatment planning, imaging, and localization requirements. 
6.1.3 End-of-Treatment Study Procedures 
To be completed within 8 – 12 weeks of the last dose of study drug. 
• 
Physical examination including weight 
• 
Vital signs 
• 
Performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
Skindex-16 survey 
• 
Laboratory assessments 
o Hematology  
o Serum chemistries  
• 
Urine or serum pregnancy tests within 4 weeks after completion of radiation therapy - if a 
woman of childbearing age  
• 
Disease assessment 
• 
Imaging (CT or MRI) of head and neck for tumor assessment 
• 
CT chest or chest x-ray – if clinically indicated 
• 
For externally visible tumors 
o Bidimensional measurements of externally visible tumor dimension 
o Digital photography of target lesion(s) 
o Description of the lesion 
o Tumor biopsy – as needed to confirm progression 
If biopsy results are confirmatory of persistent cancer, the patient may be offered 
salvage surgery as indicated. This would result in discontinuation from the study. 
Post-salvage follow-up may be conducted by UCSF investigators with separate 
consent by the patient. 
6.1.4 Post-treatment/Follow Up Visits 
Patients will be followed at 3, 6, and 12 months (+/- 2 weeks) after the End of Treatment visit or 
until disease progression.  The following procedures will be performed at the Follow-Up Visit(s): 
• 
Evaluation of clinical response or deterioration 
• 
Physical examination including weight 
• 
Vital signs 
• 
Performance Status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
Skindex-16 survey 
• 
Laboratory assessments 
o Hematology  

 
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o Serum chemistries  
• 
Urine or serum pregnancy tests  - if a woman of childbearing age – at 3 and 6 month 
visits only 
• 
Disease assessment 
• 
Imaging (CT or MRI) of head and neck for tumor assessment 
• 
CT chest or chest x-ray – if clinically indicated 
• 
For externally visible tumors 
o Bidimensional measurements of externally visible tumor dimension 
o Digital photography of target lesion(s) 
o Description of the lesion 
o Tumor biopsy  - to confirm progression 
6.1.5 Long Term/Survival Follow-up Procedures 
The study team will follow patients for survival outcome via telephone calls or medical record 
requests approximately every 3 months for 12 months, until death or loss to follow-up, 
whichever occurs first.  Additional, survival follow-up information may be collected via telephone 
calls and/or at clinic visits every 3 months for 12 months.  Follow-up may consist of at least a 
telephone contact with the patient, a family member, or physician to inquire about the patient’s 
survival status. 
If/when a subject begins a new type of non-protocol treatment for laBCC or mBCC, long-term 
follow up may cease.  Subjects will continue to be followed if they have not recurred local-
regionally within the original treated PTV. If they have a BCC in a non-treated separate location, 
or if metastatic disease occurs, subjects will continue to be followed for the local-regional 
disease control outcomes. Subjects would be taken off protocol if they have any form of non-
protocol treatment affecting the primary local or nodal site that was originally treated or if they 
receive vismodegib or other Hedgehog inhibitor or chemotherapy outside of original protocol 
parameters.  Patients off study protocol who need to have vismodegib will not have drug 
provided by the study.  
6.1.6 Discontinuation of Therapy 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, 
disease progression inside the PTV or at distant sites at any point, the occurrence of an adverse 
event or a concurrent illness, excessive delay in protocol treatment (greater than 4 weeks), a 
patient’s request to end participation, a patient’s non-compliance or simply significant 
uncertainty on the part of the Investigator that continued participation is prudent.  There may 
also be administrative reasons to terminate participation, such as concern about a patient’s 
compliance with the prescribed treatment regimen. 

 
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Table 6.1 
Schedule of Study Procedures and Assessments 
All evaluations have a window of +/- 3 days unless noted otherwise below. 
Period/ 
Procedure 
Screening 
Induction 
End of Induction 
(Re-Evaluation) 
Concurrent Therapy 
End of 
Treatment  
Follow-up visits 1 
Study Week/Visit Week 
-28 
to -1 
-14 
to -1 
5 
9 
13-14 
15 
16 
17 
18 
19 
20 
21 
29-33 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment of patient ID 
number 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline conditions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessment 2 
 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment/Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
 
Vismodegib 
 
 
Daily (150 mg/day) 
 
 
Radiation Therapy 
 
 
 
 
 
Daily (5 fractions/week) 
 
 
Clinical procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 4 
 
X 
 X 
X 
X 
 
 
 
 
 
 
 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease assessment 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Performance status 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
Biopsy  
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skindex-16 Survey 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
Digital photographs 5 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Tumor measurements 5 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Fine Needle Biopsy 6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dental evaluation 6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology  7 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
Blood chemistry 8 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 

 
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Table 6.1 
Schedule of Study Procedures and Assessments 
All evaluations have a window of +/- 3 days unless noted otherwise below. 
Period/ 
Procedure 
Screening 
Induction 
End of Induction 
(Re-Evaluation) 
Concurrent Therapy 
End of 
Treatment  
Follow-up visits 1 
Study Week/Visit Week 
-28 
to -1 
-14 
to -1 
5 
9 
13-14 
15 
16 
17 
18 
19 
20 
21 
29-33 
 
Pregnancy test (HCG) 
 
X11 
X 
X 
X 
 
 
 
X 
 
 
 
X 
X11 
Urinalysis 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
Imaging procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging (CT or MRI) 6,9 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Chest x-ray, CT Chest, or 
PET/CT 6,10 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
1. 
Follow-up visits will occur at 3, 6, & 12 months (+/- 2 weeks)post EOT.  Patients with documented disease progression within the irradiated PTV will be removed from study treatment. Survival 
follow-up information may be collected via telephone calls and/or at clinic visits every 3 months for 12 months.  
2. 
The reporting period for adverse events (AEs) and serious adverse events (SAEs) will begin at the time of enrollment and continues until 90 days after the last dose of vismodegib. During 
screening, only SAEs related to protocol-mandated procedures should be reported. At the end of the study period, any patient with an ongoing AE or SAE will be followed until the event 
resolves, the investigator assesses the event as stable, or the patient is lost to follow-up. 
3. 
A complete physical exam includes evaluation of the head, eyes, ears, nose and throat; cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, and neurological 
systems.  Exam includes height (at screening only) and weight. 
4. 
Vital signs include pulse, systolic and diastolic blood pressure while the patient is in a seated position, respiratory rate, and temperature. 
5. 
For externally visible tumors.  Can be done up to 180 days prior to day 1.  Additional biopsy after screening will only be to confirm progression.   
6. 
Dental evaluation, fine needle biopsy, Brain MRI, and PET/CT are highly recommended but not required at screening.   
7. 
Hematology consists of hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, white blood cell (WBC) count, and percent or absolute differential count (neutrophils, eosinophils, 
lymphocytes, monocytes, basophils, and other cells). 
8. 
Serum chemistry includes glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, magnesium, chloride, bicarbonate (if routinely performed on venous blood samples), calcium, 
total protein, albumin, total bilirubin, alkaline phosphatase, AST, and ALT, and as clinically indicated; LDH, and phosphorus 
9. 
The CT scan with contrast or an MRI with gadolinium must be done unless medically contraindicated.  The MRI or CT scan must encompass the skull base and/or upper mediastinum if those 
areas are involved.  If locally advanced BCC lesions with a RECIST-measurable component are identified, the same imaging modality used at baseline must be used throughout the study. 
10. Locally advanced BCC patients should have a CT of the chest and abdomen at baseline to assess for possible metastatic disease or other significant abnormalities. Abdominal imaging must 
cover the liver and adrenal glands; therefore, separate abdominal imaging is not required if these areas are covered by a chest CT scan.  If this scan shows no significant findings at baseline, it 
does not need to be repeated for tumor assessment.  
11. No need to repeat Week 1 if screening test is within 1 week prior.  Pregnancy testing at 3 months and 6 months Follow-Up visits only. 

 
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6.2 
Usage of Concurrent/Concomitant Medications 
Though no specific concomitant medications are prohibited during this study (other than 
concomitant anti-tumor therapies), vismodegib may potentially affect the pharmacokinetics of 
other drugs by altering their metabolism. In addition, metabolic inducers could possibly modify 
the pharmacokinetics of vismodegib. Therefore, concomitant medications should be used with 
care, and the risk benefit profile of each agent should be taken in to consideration. 
Vismodegib inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro at 
clinically relevant concentrations. Caution should be exercised and dose reduction of the 
concomitant substrate drug should be considered when dosing vismodegib concurrently with 
medications with narrow therapeutic windows that are substrates of CYP2C8, CYP2C9, and 
CYP2C19, because their concentrations may become elevated and their effects increased or 
prolonged.  
Vismodegib did not significantly inhibit CYP3A4 at clinically relevant concentrations in vitro; 
however, the clinical impact of vismodegib on substrates of CYP3A4 is unknown. Vismodegib is 
a substrate of CYP3A4; however, the in vitro metabolic conversion of vismodegib is low. Effects 
of CYP inducers (i.e, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St John’s 
wort, and troglitazone) on clinical concentrations of vismodegib are unknown; it is possible that 
these drugs could reduce concentrations of vismodegib. Likewise, the effects of strong inhibitors 
of CYP3A4 (i.e., clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, 
telithromycin) on vismodegib clinical concentrations are unknown; it is possible that these drugs 
could increase the concentrations of vismodegib. Use of these drugs should be documented. 
The table in Appendix 5 lists substrate drugs in columns under the designation of specific 
cytochrome P450 isoforms. A drug appears in a column if there is published evidence that it is 
metabolized, to a clinically relevant degree by that isoform or in the FDA table of in vivo 
substrates for study. This is not necessarily a complete list; other medications may also interact 
with vismodegib. 
7 Reporting and Documentation of Results 
Measurable lesions are those that can be accurately measured in at least one dimension as 
≥20mm with CT or MRI scan or on color photographs.  Patients will undergo tumor assessments 
per RECIST tumor response criteria outlined below.  No central review of imaging data will be 
required due to the visual clarity in identifying the lesions and the consistent method of 
assessment to be used by all participating sites. 
Prior radiation therapy is acceptable but there cannot be major overlap of the previously 
irradiated tissues with the new radiation treatment volumes anticipated to be delivered for the 
purposes of this protocol, in such a way that curative intent with radiation cannot be met. 
Furthermore, the total dose from all radiation delivered and expected to be delivered should not 
exceed the suggested dose constraints given for normal structures. 
To ensure a valid comparison of tumor data and uniformity in the assessment of tumor response 
and disease progression, the following procedures should be implemented.  
The same local physician should perform all physical tumor assessment evaluations for an 
individual patient. Radiologic interpretation should be performed by designated faculty members 
with experience in describing skin lesions. 
All lesions (target and non-target) identified at baseline will be reassessed according to the 
imaging schedule provided in Table 6-1. The same method of evaluation (either CT scan or 

 
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MRI), and/or color photography in the case of skin lesions, if feasible, must be used from 
baseline until the end of the study. 
7.1 
Evaluation of Efficacy (or Activity) 
A new cutaneous BCC will be considered as progressive local-regional disease (locally or 
regionally relapsed) if the lesion is > 5 mm, within the PTVs, and can be clearly documented as 
not being previously present. The new lesion should be biopsied but will be considered as PD 
unless confirmed on biopsy not to be consistent with BCC. If the new cutaneous lesion is not 
biopsied or the histology is inconclusive, it should be considered to be BCC and indicative of 
PD. Significant enlargement of a cutaneous BCC that was present at baseline should also be 
considered as PD. 
If imaging shows a high likelihood of distant metastases (investigators are highly encouraged to 
contact one of the Principal Investigators with any questions in this matter), ongoing protocol-
prescribed therapy may be terminated based on evaluation of potential clinical benefits versus 
risks to the patient, as assessed by the study investigator. The patient may still be eligible for 
follow-up, per stipulations in section 6.1.5. New distant metastatic lesions should be biopsied if 
possible and will be considered as PD unless confirmed on biopsy not to be consistent with 
BCC. If the new metastatic lesion is not biopsied or the histology is inconclusive, it should be 
considered to be indicative of PD. 
Note: Information about patients who have progressed on study and been removed from study 
may be voluntarily submitted at the discretion of the treating investigator (see Section 6.1.5). 
7.2 
Antitumor Effect – Solid Tumors 
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Assessments should include an evaluation of all sites of disease. 
Patients will undergo tumor assessments per RECIST tumor response criteria. Screening digital 
photographs of visible portions of the lesions may be taken any time from the start of screening 
until just prior to dosing on Day 1. Tumor measurements will be performed measuring the 
maximal diameter as the maximal extent of tumor plus any adjacent or underlying ulceration. 
Any tumors which were included in the original assessment as either a primary involved site or 
involved regional lymph node must be measured.  
7.2.1.1 Definitions 
Evaluable for toxicity 
All patients receiving any study drug will be evaluable for toxicity from the time of their first 
treatment with the study drug. 
Evaluable for objective response 
Only those patients who have measurable disease present at baseline, have completed at least 
75% of protocol-mandated radiotherapy, and have had their disease re-evaluated will be 
considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior 
to the end of induction therapy will also be considered evaluable.) 
 

 
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7.2.1.2 Disease Parameters 
Measurable disease 
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Tumor measurements will be performed measuring the maximal diameter as the maximal extent 
of tumor plus any adjacent or underlying ulceration.  All tumor measurements will be recorded in 
millimeters or decimal fractions of centimeters.  Previously irradiated lesions are considered 
non-measurable except in cases of documented progression of the lesion since the completion 
of radiation therapy. 
Target lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
Non-measurable disease  
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques are all non-
measurable. 
7.2.1.3 Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 
Conventional CT and MRI 
CT or MRI scans will be performed of the primary tumor site and any regionally involved nodal 
regions.  These imaging studies will be performed with contrast (iodinated or gadolinium) unless 
medically contraindicated.  These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis. 
 

 
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7.2.1.4 Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions in the irradiated PTV, determined by two separate 
observations conducted not less than 4 weeks apart.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm (the sum may not be “0” if 
there are target nodes).  There can be no appearance of new lesions in irradiated PTV. 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions in the 
irradiated PTV, taking as reference the baseline sum LD.  There can be no appearance of new 
lesions in irradiated PTV. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or 
the appearance of one or more new lesions in the irradiated PTV. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
Table 7.1 
Response Criteria 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this Category 
Also Requires 
CR 
CR 
No 
CR 
> 4 weeks confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
> 4 weeks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once > 4 weeks 
from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. These circumstances should be discussed with the Principal Investigators. 
 
Duration of Response 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 

 
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documented (taking as reference for PD the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death due to any cause. 
7.3 
Assessment of Failure Patterns  
Local or Regional Relapse  
Relapse is defined as reappearance of tumor after complete response. If possible, relapse 
should be confirmed by biopsy.  
 
Local or Regional Progression  
Progression is defined as an estimated increase in the size of the tumor (product of the 
perpendicular diameters of the two largest dimensions) of greater than 20%, taking as reference 
the smallest value of all previous measurements or appearance of new areas of malignant 
disease. This should be compared to radiology reassessment done after the completion of 
radiation therapy.  
 
Distant Metastasis Progression  
Progression of a distant metastasis (e.g. lung, bone, brain, liver) is defined as an estimated 
increase in the size of the tumor (product of the perpendicular diameters of the two largest 
dimensions) of greater than 20%, taking as reference the smallest value of all previous 
measurements or appearance of new areas of malignant disease. This should be compared to 
radiology reassessment done after the completion of radiation therapy.  
7.4 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE v4.0 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events.  Safety assessments will consist of monitoring and 
reporting adverse events (AEs) and serious adverse events (SAEs) that are considered related 
to vismodegib, all events of death, and any study specific issue of concern. 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.  The Study Chair 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).  
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 1 year 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. 

 
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7.5 
Definitions of Adverse Events 
7.5.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose.  
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with locally advanced BCC of 
the head and neck 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. 
7.5.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.5.2.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction. 
7.5.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 

 
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Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure.  For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
7.5.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
7.5.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death.  
7.6 
Recording of an Adverse Event 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v4.0.   
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below:  

 
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Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention  
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE v 4.0.  When specific adverse events are not listed in the CTCAE v 4.0 
they will be graded by the Investigator as none, mild, moderate or severe according to the 
following grades and definitions: 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
Grade 4: Life-threatening consequences; urgent intervention indicated 
Grade 5: Death related to AE 
7.7 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
7.8 
Adverse Events Monitoring  
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board 
(IRB); and, when the study is conducted under an Investigational New Drug Application (IND), 
to the Food and Drug Administration (FDA) if it meets the FDA reporting criteria.. 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s). 

 
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In addition, all adverse events and suspected adverse reactions considered “serious,” entered 
into OnCore® will be reviewed and monitored by the Data and Safety Monitoring Committee on 
an ongoing basis and discussed at DSMC meetings which take place every six (6) weeks.  For 
a detailed description of the Data and Safety Monitoring Plan for a Multicenter Study refer to 
Appendix 9. 
7.9 
Expedited Reporting  
Participating sites reporting to Study Chair 
In addition to complying with all applicable regulatory reporting laws and regulations, each site 
will report the following information in writing to the Sponsor-Investigator within one business 
day of the Investigator’s awareness of occurrence: 
• 
All SAEs 
• 
Reports of pregnancy exposure (pregnancy encompasses the entire course of 
pregnancy and delivery, perinatal and neonatal outcomes, even if there were no 
abnormal findings; both maternal and paternal exposure is collected); 
• 
Reports of lactation exposure; 
• 
Overdose (with or without an SAE); 
• 
Abuse (use for non-clinical reasons with or without an SAE); 
• 
Inadvertent or accidental exposure; and 
• 
Follow-up information regarding any of the above.  
• 
The participating investigator should include his or her assessment of the causal 
relationship between each SAE and the study treatment. 
Death from any cause while a patient is receiving protocol treatment and up to 30 days after the 
end of protocol must be telephoned and reported within ten days of discovery. Death related to 
surgery, regardless of the interval from surgery, must be reported by telephone within 10 days 
of discovery. 
Reports will include the cover page provided, and reference the Protocol Number.   
A copy of the report should be sent to the coordinating center CRC at UCSF.  Information will be 
provided. 
 
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event.  
Reporting to Genentech or Roche 
Study investigators must report all SAEs to Genentech or Roche within the timelines described 
below. The completed IND Safety Reports submitted to the FDA/Medwatch/case report should 

 
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be faxed immediately upon completion to Genentech Drug Safety at: 
 
 
 
• 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon 
as it becomes available. 
• 
If a female subject becomes pregnant while receiving the study drug or within 24months 
after the last dose of study drug, a report should be completed and expeditiously 
submitted to the Genentech. If a male subject receiving study drug (or within 3 month 
after the last dose of study drug) impregnates a female partner, then the female partner 
will be requested to provide informed consented to permit a report of the pregnancy to 
be completed and expeditiously submitted to Genentech.  
Follow-up to obtain the outcome of the pregnancy should also occur. Abortion, whether 
accidental, therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a 
child born to a female subject exposed to the vismodegib should be reported as an SAE. 
Additional information on any vismodegib-exposed pregnancy and infant will be 
requested by Roche Drug Safety at specific timepoints (i.e., after having received the 
initial report, at the end of the second trimester, 2 weeks after the expected date of 
delivery, and at 3, 6, and 12 months of the infant’s life). 
• 
Serious AE reports that are related to the vismodegib and AEs of Special Interest (AESI) 
(regardless of causality) will be transmitted to Genentech within fifteen (15) calendar 
days of the Awareness Date. 
• 
Serious AE reports that are unrelated to the vismodegib will be transmitted to Genentech 
within thirty (30) calendar days of the Awareness Date. 
• 
Additional Reporting Requirements to Genentech include the following: 
o Any reports of pregnancy following the start of administration with the vismodegib 
will be transmitted to Genentech within thirty (30) calendar days of the 
Awareness Date.  
o All Non-serious Adverse Events originating from the Study will be forwarded in a 
quarterly report Genentech. 
o All IND annual reports submitted to the FDA by the Sponsor-Investigator should 
be copied to Genentech. 
Refer to Appendix 11 for Genentech safety reporting fax cover sheet. 
Study Close-Out 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be 
sent to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 

 
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8 Statistical Considerations and Evaluation of Results 
8.1 
Study Design 
This is a single arm, multi-center, phase II study evaluating the safety and efficacy of treating 
locally advanced and metastatic BCC patients with vismodegib alone followed by concurrent 
vismodegib with radiation therapy for a total of 21 weeks.  After completing protocol therapy 
patients will be followed for 12 months.  The primary efficacy study outcome measure is the 
proportion of patients with local-regional control at 12 months after completing protocol therapy.   
8.2 
Study Endpoints 
Primary Endpoint: 
• 
The proportion of patients with local-regional control at 12 months from protocol therapy 
completion, defined as complete or partial response, with absence of PD (see section 
7.2) within the irradiated PTV.  
Secondary Endpoints:  
• 
Estimate of the probability of PFS and OS 12 months after protocol therapy completion. 
PFS is measured until disease recurrence or death due to any cause, whichever occurs 
first.   
• 
Number and attribution of all adverse events (including vital signs, physical findings, and 
clinical laboratory results, CTCAE, v 4.0) in patients who receive any amount of study 
drug and radiation therapy. 
• 
For each toxicity, the maximum occurring grade will be tabulated for each patient.  The 
results will be summarized by toxicities observed during vismodegib treatment alone, 
during concurrent vismodegib with radiation therapy, for 3 months immediately following 
the completion of protocol therapy and for up to 12 months after completion of protocol 
therapy. The focus will be on the proportion of patients experiencing >grade 3 toxicity 
during each of these intervals. 
• 
Proportion of patients experiencing Grade 4-5 adverse events assessed to be definitely, 
probably, or possibly related to the induction or concurrent treatment components of the 
protocol regimen (that is not definitely related to disease progression).  
• 
Proportion of patients discontinuing treatment due to toxicity during the concurrent 
administration of vismodegib and radiation therapy. For this endpoint, discontinuation is 
defined as < 75% of planned radiation therapy delivered. 
• 
Response rate per RECIST criteria in patients who complete initial combined therapy of 
the primary site and regionally involved areas in subjects with measurable disease prior 
to initiation of therapy at 3 months after completion of protocol therapy. 
• 
Proportion of patients with a decrease of BCC within the irradiated PTV after completing 
all protocol therapy to estimate clinical response to vismodegib and radiation therapy. 
8.3 
Determination of Sample Size and Accrual Rate 
8.3.1 Sample Size and Power Estimate 
The sample size for this single-arm phase II study is based upon the anticipated degree of 
improvement in the primary clinical hypothesis (i.e. local-regional control rate) at 12 months 
after completing all protocol treatment. The null hypothesis is that 60% of patients treated may 
achieve local-regional control after treatment on the study. Patients treated for advanced-stage 

 
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nonmelanomatous skin cancers typically achieve 50-60% local-regional control with radiation 
therapy alone. The alternative hypothesis is that 80% of the patients will obtain local-regional 
control at 12 months from the end of protocol therapy. This goal for local-regional control is 
justifiable as the current study includes radiation therapy, which is known to be effective against 
advanced BCC, in combination with vismodegib, also known to have high efficacy against BCC 
when administered alone. 
Sample Size Justification: With accrual of 24 evaluable patients, this test will have 81% power 
to detect an increase in the overall proportion of patients achieving local-regional control 
assuming a directional level of significance of 0.10 based upon a one sample exact binomial 
test.  It is anticipated that accrual will be completed in 12-18 months, with each patient treated 
for approximately 5.5 months and then followed for 12 months after completing protocol therapy. 
The total study duration is expected to be about 3 years. 
8.3.2 Replacement Policy 
Patients who drop-out before starting radiation therapy will be replaced.  In addition, patients 
who come off study before completing at least 75% of radiation therapy given concurrently with 
vismodegib without grade ≥3 toxicity will be replaced.  The frequency of each of these events 
will be reported and reasons for replacement reviewed. 
8.3.3 Accrual estimates 
The multi-center study expects to accrue 1-2 patients per month over a 2 year period.  The 
UCSF radiation oncology program sees approximately 15 patients with locally advanced BCC of 
the head and neck per year.  Approximately 8 patients have inoperable carcinomas or have a 
medical contraindication to surgery.  UCSF will accrue 5-6 patients per year for a total of 
approximately 10 patients.   
8.4 
Interim Analysis for Safety and Stopping Rules 
An interim analysis for safety will be performed once 5 patients have been treated on study and 
completed all drug and radiation-based protocol therapy. This will occur approximately 7-8 
months after the start of accrual assuming 2 patients are enrolled per month and protocol 
therapy is completed in about 5.5 months. After the fifth patient completes radiation therapy, 
accrual will be temporarily stopped in order to perform this interim analysis.  Thus no additional 
patients will start radiation therapy during the evaluation interval that overlaps with the treatment 
period for patients included in the interim analysis. During the conduct of this study, toxicity will 
also be evaluated weekly so that any unacceptable toxicity can be identified early. If there is no 
reason to stop accrual (as defined below), the remainder of the 19 patients will be recruited.  
Stopping rules: Acceptable occurrence of toxicity is defined as the discontinuation of treatment 
in ≤40% of patients (2 of 5 patients who discontinue protocol treatment, having completed <75% 
of planned radiation therapy) and the proportion of patients with grade 4-5 toxicity is ≤20%.  
Accrual of the final 19 patients will be determined by the results of the interim analysis.  
8.5 
Analyses Plans 
Data will be summarized with respect to demographic and baseline characteristics and safety 
observations and measurements. The assessment of safety will include calculation of all 
specified study endpoints (see section 8.2) and will be based mainly on the frequency and 
attribution of adverse events, the frequency of discontinuation of treatment due to toxicity during 
concurrent vismodegib plus radiation therapy, and the proportion of patients experiencing Grade 

 
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3 or higher AEs related to the treatment components.   Adverse events will be summarized by 
presenting the number and percentage of patients having any adverse event.  Any other 
information collected (e.g. severity or relatedness to study medication) will be listed as 
appropriate. Toxicities will be tabulated by maximum grade occurring and organ system using 
the NCI Common Toxicity Criteria version 4.1 during each of 4 protocol stages (vismodegib 
alone, in combination with radiation therapy, during the immediate 3 months following 
completion of protocol therapy and then up to 12 months of follow-up after completing 
treatment).  
To evaluate the primary protocol aim the proportion of patients with local-regional control (LRC),  
those with a CR or PR as defined by RECIST criteria, at 12 months after completing protocol 
therapy will be calculated and presented with 95% confidence intervals.  As a most conservative 
estimate of disease control any patient beginning concurrent vismodegib and radiation therapy 
who is removed from study prior to completion of at least 75% of radiation therapy without a 
documented complete or partial response will be considered as a local-regional failure. To test 
the primary study hypothesis the observed proportion with LRC will be compared with the null 
hypothesis of 60% using a one sample test of a binomial proportion.   
The secondary clinical aims of the duration of progression free survival (PFS) and overall 
survival (OS) will be measured from the start of protocol therapy until death due to any cause or 
until the first evidence of any disease progression, or death, respectively.  Point estimates (e.g. 
median, percent PFS at 12 months) with 95% confidence intervals will be calculated using the 
Kaplan-Meier product limit method to summarize results. Based upon RECIST criteria, the 
proportion of patients responding in the primary site and regionally involved areas at 3 months 
after completing protocol therapy will be determined and presented with 95% confidence 
intervals.  The proportion of patients achieving any decrease in BCC within the boundaries of 
the treated radiation PTV area will be determined and presented with a 95% confidence interval.  
In addition, the proportion of patients who start concurrent vismodegib and radition therapy and 
receive at least 75% of the planned radiation therapy will be determined and presented with a 
95% confidence interval to  summarize the feasibility of administering concomitant therapy.  
8.5.1 Analysis Population 
The statistical analysis of efficacy will include all patients completing the initial treatment with 
vismodegib alone and start the concurrent vismodegib with radiation therapy. Anyone who 
receives any vismodegib with radiation therapy will be included in the assessment of efficacy. 
As the most conservative approach, any patient removed from study prior to completion of at 
least 75% of radiation therapy without a documented complete or partial response will be 
considered as a case of local-regional failure. 
Failure is defined as a lack of local-regional control within the boundaries of the treated radiation 
PTV area within the 12 month follow-up period.  
8.6 
Evaluation of Safety 
The analyses of safety will be performed for all patients having received at least one dose of 
study drug.  The study will use the NCI CTCAE v4.0. 
9 Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 

 
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applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB (UCSF Institutional Review Board).  Prior to obtaining IRB  
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation.   
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file.  
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after implementation.  
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites. 
9.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug. 

 
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The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
9.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs  after that time can 
only be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
Each participating site will complete study specific CRFs for safety monitoring and data 
analysis.  Each site will enter the study data into OnCore® via standardized CRFs in accordance 
with the CTMS study calendar, using single data entry with a secure access account. The 
participating site’s Clinical Research Coordinator (CRC) will complete the CRFs; the Investigator 
will review and approve the completed CRFs – this process must be completed within 3 
business days of the visit. Study data from the participating site will be reported and reviewed in 
aggregate with data from patients enrolled at the coordinating center, UCSF.  All source 
documentation and CTMS data will be available for review/monitoring as needed. 
9.7 
Modality Review 
The Principal Investigator will perform a Quality Assurance Review of all patients in this trial. 
The goal of the review is to evaluate protocol compliance. The review process is contingent on 
timely submission of chemotherapy treatment data as specified in Appendix 8. The scoring 
mechanism is: Per Protocol/Acceptable Variation, Not Per Protocol, and Not Evaluable. A report 
is sent to each institution once per year to notify the institution about compliance for each case 
reviewed in that year.  
The Principal Investigator will perform a Quality Assurance Review after complete data for the 
first 4 cases enrolled has been received. The Principal Investigator will perform the next review 
after complete data for the next 4 cases enrolled. The final cases will be reviewed within 3 

 
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months after this study has reached the target accrual or as soon as complete data for all cases 
enrolled has been received, whichever occurs first.  
9.8 
Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”.  The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 9 Data and Safety Monitoring Plan for additional information. 
9.9 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, quarterly conference calls with the 
participating sites or more frequently as needed to discuss risk assessment.  The following 
issues will be discussed as appropriate:  
• 
Enrollment information  
• 
Adverse events (i.e. new adverse events and updates on unresolved adverse events 
and new safety information) 
• 
Protocol violations 
• 
Other issues affecting the conduct of the study 
9.10 Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends.   
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 

 
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is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 
9.11 Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 
9.12 Regulatory Documentation  
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Institutional Review Board (IRB). Prior to implementing this protocol at the 
participating sites, approval for the UCSF IRB approved protocol must be obtained from the 
participating site’s IRB.  
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants:  
• 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization  
• 
Participating Site IRB approved consent form  
• 
Participating Site IRB membership list  
• 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number  
• 
Curriculum vitae and medical license for each investigator and consenting professional  
• 
Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site  
• 
Participating site laboratory certifications and normals  
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment.  See Appendix 10 for submission information. 
10 Protection of Human Subjects  
10.1 Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The 
IRB reviews all proposed studies involving human experimentation and ensures that the 

 
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subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits.  
10.2 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document. 

 
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carcinoma. N Engl J Med. 2012 Jun 7;366(23):2171-9. 
Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell 
carcinoma. N Engl J Med 2012;366:2171-9. Supplementary Appendix. 
Sims-Mourtada J, Izzo JG, Apisarnthanarax S, et al. Hedgehog: An attribute to tumor regrowth 
after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res 
2006;12:6565-72. 
Snow SN, Sahl W, Lo JS, et al. Metastatic basal cell carcinoma. Report of five cases. Cancer 
1994;73:328−35. 
Spates ST, Mellette JR Jr, Fitzpatrick J. Metastatic basal cell carcinoma. Dermatol Surg 
2003;29:650−2. 
Thayer SP, Pasca di Magliano M, Heiser PW, et al. Hedgehog is an early and late mediator of 
pancreatic cancer tumorigenesis. Nature 2003;425:851–6. 
Unden AB, Zaphiropoulos PG, Bruce K, et al. Human patched (PTCH) mRNA is overexpressed 
consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res 
1997;57:2336–40. 
von Domarus H, Stevens PJ. Metastatic basal cell carcinoma: report of five cases and review of 
170 cases in the literature. J Am Acad Dermatol 1984; 10:1043−60. 
Wadhera A, Fazio M, Bricca G, et al. Metastatic basal cell carcinoma: a case report and 
literature review. How accurate is our incidence data? Dermatol Online J 2006;12:7. 
Williams JA, Guicherit OM, Zaharian BI, et al. Identification of a small molecule inhibitor of the 
Hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci 
USA 2003;100:4616−21. 
Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in 
cancer. Nature 2008;455(7211):406-10. 
 
Zeng J, Aziz K, Chettiar ST, et al. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell 
Lung Cancers. Int J Radiat Oncol Biol Phys. 2012 Nov 20. doi:pii: S0360-3016(12)03664-4. 
 

 
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Appendices 
Appendix 1 Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on all 
pre-disease performance without 
restriction 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active work 
2 
In bed < 50% of the time 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities 
Up and about more than 50% of 
waking hours 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs 
50 
Requires considerable assistance 
and frequent medical care 
3 
In bed > 50% of the time 
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization 
indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
20 
Very sick, hospitalization indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 
 
 
 

 
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Appendix 2 AJCC Staging System for Cutaneous Carcinoma 
PRIMARY TUMOR (T) 
TX Primary tumor cannot be assessed 
T0 No evidence of primary tumor 
Tis Carcinoma in situ 
T1 Tumor 2 cm or less in greatest dimension with less than two high risk features** 
T2 Tumor greater than 2 cm in greatest dimension or Tumor any size with two or more high risk features** 
T3 Tumor with invasion of maxilla, orbit, or temporal bone 
T4 Tumor with invasion of skeleton (axial or appendicular) or perineural invasion of 
skull base 
* Excludes cutaneous carcinoma of the eyelid. 
**High Risk Features for the Primary Tumor (T) Staging : 
Depth/Invasion: >2 mm thickness, Clark level Ñ IV, Perineural invasion 
Anatomic Location: Primary site ear, Primary site hair-bearing lip 
Differentiation: Poorly differentiated or undifferentiated 
 
REGIONAL LYMPH NODES (N) 
NX Regional lymph nodes cannot be assessed 
N0 No regional lymph node metastasis 
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension 
N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 
6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none 
more than 6 cm in greatest dimension; or in bilateral or contralateral lymph 
nodes, none more than 6 cm in greatest dimension 
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 
6 cm in greatest dimension 
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest 
dimension 
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in 
greatest dimension 
N3 Metastasis in a lymph node, more than 6 cm in greatest dimension 
 
DISTANT METASTASIS (M) 
M0 No distant metastasis (no pathologic M0; use clinical M to complete stage group) 
M1 Distant metastasis 
 
ANATOMIC STAGE/PROGNOSTIC GROUPS 
Group T N M 
0 Tis N0 M0 
I T1 N0 M0 
II T2 N0 M0 
III T3 N0 M0 
T1 N1 M0 
T2 N1 M0 
T3 N1 M0 
IV T1 N2 M0 
T2 N2 M0 
T3 N2 M0 

 
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T Any N3 M0 
T4 N Any M0 
T Any N Any M1 
Appendix 3 RTOG/EORTC Late Radiation Morbidity Scoring Scheme 
RTOG/EORTC Late Radiation Morbidity Scoring Scheme  
 
ORGAN TISSUE 
0 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
5 
SKIN 
None 
Slight atrophy; 
Pigmentation 
change; Some hair 
loss 
Patch atrophy; Moderate 
telangiectasia; Total hair 
loss 
Marked atrophy; 
Gross telangiectasia 
Ulceration 
  
  
D 
E 
A 
T 
H 
 
D 
I 
R 
E 
C 
E 
T 
L 
Y 
  
R 
E 
SUBCUTANEOUS 
TISSUE 
None 
Slight induration 
(fibrosis) and loss 
of subcutaneous fat 
Moderate fibrosis but 
asymptomatic; Slight field 
contracture; <10% linear 
reduction 
Severe induration and 
loss of subcutaneous 
tissue; Field 
contracture > 10% 
linear measurement 
Necrosis 
  
MUCOUS 
MEMBRANE 
None 
Slight atrophy and 
dryness 
Moderate atrophy and 
telangiectasia; Little 
mucous 
Marked atrophy with 
complete dryness; 
Severe telangiectasia 
Ulceration 
SALIVARY 
GLANDS 
None 
Slight dryness of 
mouth; Good 
response on 
stimulation 
Moderate dryness of 
mouth; Poor response on 
stimulation 
Complete dryness of 
mouth; No response 
on stimulation 
Fibrosis 
SPINAL 
CORD 
None 
Mild L’Hermitte’s 
syndrome 
Severe L’Hermitte’s 
syndrome 
Objective 
neurological findings 
at or below cord level 
treated 
Mono, para 
quadriplegia 
BRAIN 
None 
Mild headache; 
Slight lethargy 
Moderate headache; Great 
lethargy 
Severe headaches; 
Severe CNS 
dysfunction (partial 
loss of power or 
dyskinesia) 
Seizures or 
paralysis; Coma 
EYE 
None 
Asymptomatic 
cataract; Minor 
corneal ulceration 
or keratitis 
Symptomatic cataract; 
Moderate corneal 
ulceration; Minor 
retinopathy or glaucoma 
Severe keratitis; 
Severe retinopathy or 
detachment Severe 
glaucoma 
Panopthalmitis/
Blindness 
LARYNX 
None 
Hoarseness; Slight 
arytenoid edema 
Moderate arytenoid 
edema; Chondritis 
Severe edema; Severe 
chondritis 
Necrosis 
LUNG 
None 
Asymptomatic or 
mild symptoms 
(dry cough); Slight 
radiographic 
appearances 
Moderate symptomatic 
fibrosis or pneumonitis 
(severe cough); Low grade 
fever; Patchy radiographic 
appearances 
Severe symptomatic 
fibrosis or 
pneumonitis; Dense 
radiographic changes 
Severe 
respiratory 
insufficiency/co
ntinuous 
O2/Assisted 
ventilation 
HEART 
None 
Asymptomatic or 
mild symptoms; 
Transient T wave 
inversion & ST 
Moderate angina on effort; 
Mild pericarditis; Normal 
heart size; Persistent 
abnormal T wave and ST 
Severe angina; 
Pericardial effusion; 
Constrictive 
pericarditis; Moderate 
Tamponade/Sev
ere heart 
failure/Severe 
constrictive 

 
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Changes; Sinus 
tachycardia >110  
(at rest) 
changes ; Low ORS 
heart failure; Cardiac 
enlargement; EKG 
abnormalities 
pericarditis 
L 
A 
T 
E 
D 
  
T 
O 
 
R 
A 
D 
I 
A 
T 
I 
O 
N 
  
E 
F 
F 
E 
C 
T 
S 
ESOPHAGUS 
None 
Mild fibrosis; 
Slight difficulty in 
swallowing solids; 
No pain on 
swallowing 
Unable to take solid food 
normally; Swallowing 
semi-solid food; Dilation 
may be indicated 
Severe fibrosis; Able 
to swallow only 
liquids; May have 
pain on swallowing 
Dilation required 
Necrosis/Perfor
ation Fistula 
SMALL/LARGE 
INTESTINE 
None 
Mild diarrhea; 
Mild cramping; 
Bowel movement 5 
times daily Slight 
rectal discharge or 
bleeding 
Moderate diarrhea and 
colic; Bowel movement >5 
times daily; Excessive 
rectal mucus or 
intermittent bleeding 
Obstruction or 
bleeding, requiring 
surgery 
Necrosis/Perfor
ation Fistula 
LIVER 
None 
Mild lassitude; 
Nausea, dyspepsia; 
Slightly abnormal 
liver function 
Moderate symptoms; 
Some abnormal liver; 
function tests; Serum 
albumin normal 
Disabling hepatitic 
insufficiency; Liver 
function tests grossly 
abnormal; Low 
albumin; Edema or 
ascites 
Necrosis/Hepati
c coma or 
encephalopathy 
KIDNEY 
None 
Transient 
albuminuria; No 
hypertension; Mild 
impairment of 
renal function; 
Urea 25-35 
mg%;Creatinine 
1.5-2.0 mg%; 
Creatinine 
clearance > 75% 
Persistent moderate 
albuminuria (2+); Mild 
hypertension; No related 
anemia; Moderate 
impairment of renal 
function; Urea > 36-
60mg% Creatinine 
clearance (50-74%) 
Severe albuminuria; 
Severe hypertension 
Persistent anemia (< 
10%); Severe renal 
failure; Urea >60 
mg% Creatinine >4.0 
mg% Creatinine 
clearance < 50% 
Malignant 
hypotension; 
Uremic 
coma/Urea > 
100% 
BLADDER 
None 
Slight epithelial 
atrophy; Minor 
telangiectasia 
(microscopic 
hematuria) 
Moderate frequency; 
Generalized telangiectasia; 
Intermittent macroscopic 
hematuria 
Severe frequency & 
dysuria Severe 
generalized 
Telangiectasia (often 
with petechiae); 
Frequent hematuria; 
Reduction in bladder 
capacity  
(< 150 cc) 
Necrosis/Contra
cted bladder 
(capacity < 100 
cc); Severe 
hemorrhagic 
cystitis 
BONE 
None 
Asymptomatic; No 
growth retardation; 
Reduced bone 
Density 
Moderate pain or 
tenderness; Growth 
retardation; Irregular bone 
sclerosis 
Severe pain or 
tenderness; Complete 
arrest of bone growth; 
Dense bone sclerosis 
Necrosis/Sponta
neous fracture 
JOINT 
None 
Mild joint stiffness; 
Slight limitation of 
movement 
Moderate stiffness; 
Intermittent or moderate 
joint pain; Moderate 
limitation of movement 
Severe joint stiffness; 
Pain with severe 
limitation of 
movement 
Necrosis/Compl
ete fixation 

 
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Appendix 4 Management of Dental Problems in Irradiated Patients 
Dental Care for Irradiated Patients Goals for a dental care program include:  
1. To reduce incidence of bone necrosis.  
2. To reduce incidence of irradiation caries.  
3. To allow proper fitting of dentures following treatment.  
Pre-irradiation Care and Procedures The patients may be grouped into four groups in 
accordance with the problems they present prior to irradiation.  
Group 1  
Includes edentulous patients. They may require surgical removal of any symptomatic cysts, 
infected retained root tips, or alveolar hyperplasia. These patients require hygiene instruction 
and precautionary instruction about trauma with premature use of a prosthesis.  
Group 2  
Includes those with poor dental hygiene, including those patients whose teeth are beyond repair 
by ordinary dental procedure, those with generalized oral sepsis, those with generalized 
periodontal disease, and those with chronic periapical abscesses or granulomas.  
Procedures performed on this group include removal of all remaining teeth prior to irradiation 
with primary closure and surgical preparation of the alveolar ridges to laterally support a 
prosthesis. There should be antibiotic coverage during the healing stage and adequate time 
prior to the start of radiation therapy. These patients need complete hygiene instruction and 
precautionary instruction about premature use of a prosthesis.  
Group 3  
Includes those in whom dental condition is fair, including those patients whose teeth are 
restored, ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious 
lesions are not in proximity to the pulp, and no more than 20 restorable carious lesions are 
present. X-ray examinations show at least 1/2 of the bone still present around root surfaces. 
These patients require removal of any teeth that are non-salvageable in accordance with the 
above and restorations of the remaining teeth as required. The patients are instructed for dental 
prophylaxis and the patients utilize custom-made fluoride carriers.  
Group 4  
Includes those in whom dental hygiene is good. This includes patients who do not have severe 
malocclusion in whom few carious lesions are present. Carious lesions are not in close 
proximity to the pulp and are correctable by conventional methods. These patients require 
periodontal evaluation and dental prophylaxis training, restorations as needed, no extractions 
prior to radiation therapy, and fitting for custom carriers.  
Extraction of Teeth: If extraction of teeth is necessary prior to radiation therapy, the bone must 
be contoured so that closure at the extraction site is possible. All loose spicules and sharp 
projections must be removed. The approximation of the gingival tissue must be such that the 

 
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closure is neither too loose nor too tight. At least 10 days are required for adequate healing prior 
to initiation of therapy.  
Causative Factors: The major causative factors appear to be the reduction of the amount of 
saliva and secondarily, reduced pH in the mouth. This occurs following high dose radiation to 
the major salivary glands using parallel opposed fields. The decay process usually occurs in the 
first year following radiation therapy. It tends to occur more quickly in teeth which have a large 
amount of root cementum exposed to those teeth with large amounts of plaque formation 
present. Doses of radiation in excess of 20 Gy to salivary tissue place the teeth at risk.  
Preventive Program: The rationale behind the use of fluoride treatments is to make the tooth 
surfaces less susceptible to the decay process. This is accomplished by a combination of 
increasing fluoride concentration on the tooth surface and by the effect of fluoride on the plaque 
and flora that are present in the oral cavity. Adequate results are obtained by: 1) cleansing the 
teeth thoroughly, followed by a good home care dental prophylaxis program, 2) construction of 
fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution 
to the gingiva and tooth surfaces. Fluoride carriers are made individually with the use of casts. 
Material used for making a mouth guard is "Sta-Guard" plastic used in conjunction with 
vacutrole unit produced by Jelrus Technical Products, Corp., both of which are available through 
local dental supply. This material is molded to the cast impression and allowed to harden. The 
patients are instructed to cleanse their teeth prior to placement of the carrier. It is then worn in 
place for 5 minutes each day. The patients are instructed to rinse their mouths thoroughly 
following the use of the carrier. This will be continued for an indefinite period of time. Close 
follow-up is necessary.  
Results: In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 
304 patients shows that the incidence of necrosis of the jaw was reduced to approximately 21% 
compared to 37% prior to initiation of the study. Groups 3 and 4 patients randomized with and 
without fluoride treatment showed reduction in radiation carries from 67% to 34% among Group 
3 patients, and from 65% to 22% among Group 4 patients.  
Failure to Control Decay: Management of failure to control radiation decay includes silver fillings 
with continued use of fluoride treatments. If the decay process is sufficiently advanced that a 
filling will no longer stay in place, these teeth are merely smoothed so that there will be no 
sharp, irritating edges. The mere existence of such a decayed tooth is not necessarily reason 
for extraction, for it must be remembered that extraction could lead to complications such as 
bone necrosis.  
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics 
and/or root-canal therapy.  
Hypersensitivity of Teeth: Occasionally, a patient will exhibit extreme sensitivity of the teeth 
secondary to diminished amounts of saliva. This has been shown to be reduced in incidence 
with the fluoride treatments. Should this problem become manifest, increasing the fluoride 
treatment to 10 to 15 minutes 3 times a day is recommended.  
Infections: Infections occurring in patients under or after radiation therapy are best managed 
conservatively with good oral hygiene, irrigation and flushing procedures, and systemic 
antibiotics.  
Bone Necrosis: The patients receiving radiation therapy to a high dose to the head and neck 
region have increased susceptibility to bone necrosis for several reasons including: impairment 
of normal metabolism, increased susceptibility to infection and severely limited repair process. 

 
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Bone necrosis occurs most often after dental or oral surgery in patients who have been 
previously radiated. Conservative management should be tried first, though in more aggressive 
lesions a more radical approach may ultimately be necessary.  

 
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Appendix 5 Medications with Potential to Interact with Vismodegib 
Vismodegib inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro at 
clinically relevant concentrations. Caution should be exercised and dose reduction of the 
concomitant substrate drug should be considered when dosing vismodegib concurrently with 
medications with narrow therapeutic windows that are substrates of CYP2C8, CYP2C9, and 
CYP2C19, because their concentrations may become elevated and their effects increased or 
prolonged. 
Vismodegib did not significantly inhibit CYP3A4 at clinically relevant concentrations in vitro; 
however, the clinical impact of vismodegib on substrates of CYP3A4 is unknown. Vismodegib is 
a substrate of CYP3A4; however, the in vitro metabolic conversion of vismodegib is low. Effects 
of CYP inducers (i.e., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St John’s 
wort, and troglitazone) on clinical concentrations of vismodegib are unknown; it is possible that 
these drugs could reduce concentrations of vismodegib. Likewise, the effects of strong inhibitors 
of CYP3A4 (i.e., clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, 
telithromycin) on vismodegib clinical concentrations are unknown; it is possible that these drugs 
could increase the concentrations of vismodegib. 
Use of these drugs with vismodegib should be documented. The table below lists substrate 
drugs in columns under the designation of specific cytochrome P450 isoforms. A drug appears 
in a column if there is published evidence that it is metabolized, to a clinically relevant degree by 
that isoform (Flockhart) or in the FDA table of in vivo substrates for study. This is not necessarily 
a complete list; other medications may also interact with vismodegib. 
2C8 
Miscellaneous: 
2C9 
NSAIDs: 
2C19 
Proton Pump Inhibitors: 
repaglinide  
rosiglitazone 
Diclofenac 
Ibuprofen 
piroxicam 
naproxen 
celecoxib 
 
Oral Hypoglycemic Agents: 
 
glipizide 
tolbutamide 
 
Angiotensin II Blockers: 
 
irbesartan 
losartan 
NOT candesartan 
 
NOT valsartan 
 
Miscellaneous:  
fluvastatin  
phenytoin 
sulfamethoxazole 
tamoxifen torsemide 
warfarin 
omeprazole 
lansoprazole 
pantoprazole 
rabeprazole 
esoprazole 
Anti-epileptics: 
diazepam  
phenytoin 
phenobarbitone 
Miscellaneous: 
amitriptyline 
clomipramine 
clopidogrel 
cyclophosphamide 
progesterone 
Reference: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction; Table. Indiana University School of Medicine 
(2007); http://medicine.iupui.edu/flockhart/clinlist.htm 
FDA Drug Development and Drug Interactions: Table of Substrates; Inhibitors and Inducers (May 2006). 
http://www.fda.gov/cder/drug/drugInteractions/tableSubstrates.htm#classSub 

 
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Appendix 6 Skindex-16 Survey  

 
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Appendix 7 Digital Photographic Procedures For Serial Photographic 
Documentation Of Basal Cell Carcinoma  
Views 
• 
Close-up view with millimeter scale of the target area of the basal cell carcinoma(BCC): 
two each 
• 
Global view of the target BCC area: two each 
 
Procedures 
In these clinical photographs for the duration of the study, the only variable allowed to change is 
the skin condition itself. Therefore, anything extraneous to the condition (furniture, etc.) is to be 
eliminated from the photographic field, starting at the entry visit through the final visit. The 
necessity of good end-of-study photographs should be stressed to patients to ensure their 
cooperation. Lighting, framing, exposure, and reproduction ratios must be held constant. In the 
end, the images should read like a time-lapse movie. Any doubt as to the correctness of the 
photographic technique should result in an immediate re-shoot. 
 
Each photographic session includes an exposure series of: 
a. Patient ID, which will include the following legible information in black indelible ink (two 
exposures): 
Date 
Center name 
Patient’s study ID number 
Photographer’s initials 
b. Close-up view of patient’s target BCC area(s), consisting of one individual BCC lesion 
(two exposures) 
c. Global view of patient’s target BCC area(s), consisting of up to two individual BCC 
lesions (two exposures) 

 
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Appendix 8 Data Submission  
Participating sites must submit the following data components. 
• 
Within 2 weeks of study entry, the following documents must be submitted to the 
coordinating center 
o Demographic Form (A5)  
o Initial Evaluation Form (I1)  
o Pathology Report (P1)  
• 
At the completion of preradiotherapy component and at the completion of concurrent 
therapy component: Treatment Form (TF) and Pill Diary (DP) 3 months from the start of 
treatment, after restaging imaging and before starting post-radiation therapy: Initial 
Follow-up Form (F0)    
• 
After the F0, q 12 weeks for 1 year, all subsequent follow up with patient will be done by 
UCSF per section 6.1.5 
 
Dosimetry Data Submission  
Hard copy isodose distributions for total dose plan  
DVH printouts showing doses to critical structures 
Summary printout of entire plan, including summary table of contour names, with contour 
(region) volume, and the Min, Mean and Max dose to the regions of interest. 
 
Data should be submitted to:  
 
 
 

 
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Appendix 9 Data and Safety Monitoring Plan* for a Multicenter Institutional Study 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes:  
• 
Review of subject data 
• 
Review of suspected adverse reactions considered “serious” 
• 
Monthly monitoring (depending on study accrual) 
• 
Minimum of a yearly regulatory audit 
Monitoring and Reporting Guidelines 
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three). 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters. 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject’s treatment at monthly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes. 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate: 
• 
Enrollment information  
• 
Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information) 
• 
Protocol violations 
• Other issues affecting the conduct of the study 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites.  The data (i.e. 
copies of source documents) from the participating sites will be sent electronically or faxed over 
to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor 
the participating site’s compliance with the protocol, patient safety, and to verify data entry. 
 

 
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Adverse Event Review and Monitoring 
Adverse Event Monitoring 
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered to be 
associated with the use of study drug, will be entered into OnCore®, UCSF’s Clinical Trial 
Management System. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All clinically significant adverse events must be reported to the 
UCSF Coordinating Center by the participating sites within 10 business days of becoming aware 
of the event or during the next scheduled quarterly conference call, whichever is sooner. The 
UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites. 
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® 
and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse 
reactions considered “serious” will be reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take 
place every six (6) weeks. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or 
the assigned designee must be notified within 1 business day from the participating site(s) and 
the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of 
this notification. The contact may be by phone or e-mail. 
Increase in Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified.  The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in 
the Investigator Brochure or package insert. 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail.  The DSMC 
must receive a formal letter within 10 business days and the IRB must be notified. 
Data and Safety Monitoring Committee Contacts: 
DSMC Chair:  
 
DSMC Monitors  
Phone:  
Email: 
Address:  
 
 
 
 
 
 
 
 
 
 
*  DSMP approved by NCI 09/February2012 

 
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Appendix 10 UCSF Policy/Procedure for Required Regulatory Documents for a 
UCSF Multicenter Investigator-Initiated Oncology Clinical Trials with an 
Investigator held Investigational New Drug (IND) 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND. 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
reconscilimanagement of a clinical trial. 
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well 
as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
Procedures 
1.   HDFCCC Essential Regulatory Documents 
Documents Filed in iMedRIS: 
• 
IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals 
• 
Current and prior approved protocol versions with signed protocol signature page(s) 
• 
Institutional Review Board (IRB) approval letters and Informed Consent Form(s) (ICF) 
• 
Current and prior versions of the Investigator Brochure (IB). 
• 
Serious Adverse Event Reporting 
• 
Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting 
fax documentation 
Documents Filed in OnCore®: 
• 
Package Insert (if the study drug is commercial) or Investigator Brochure 
• 
Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) 
• 
Patient handouts 
• 
Screening/enrollment log 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports 
• 
DSMC dose escalation approvals with study status summary forms 
• 
OnCore® Case Report Form (CRF) completion manual 
 
 
Documents Filed in Regulatory Binder: 

 
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• 
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature 
• 
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.) 
• 
Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center 
• 
Serious Adverse Event (SAE) reports to IRB and sponsor. 
• 
MedWatch reporting to FDA and sponsor 
• 
Delegation of Authority Form 
• 
Drug Destruction Standard Operating Procedure (SOP) 
• 
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
2.  Additional Essential Documents for Multicenter Trials for the Coordinating 
Center (filed in Regulatory Binder or OnCore) 
• 
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form for 
the Participating Site(s) 
• 
For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s) – Financial Disclosure Forms, CVs, MD Licenses, and Staff Training 
documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational 
New Drug Application 
• 
Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s).  
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s) 
• 
Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting 
fax documentation for Participating Site(s) 
• 
Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s) 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s) 
• 
For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, 
lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating 
Site(s) 
• 
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating 
site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan 
(if an outside CRO is used for the study) 
• 
Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the 
Participating Site(s) 
 
3 
Required Regulatory Documents for Sub-sites Participating in a UCSF 
Investigator Initiated Multicenter Trial (Checklist) 
Directions:  

 
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1)  Fax the documents listed below to the UCSF Coordinating center 
 or  
2)  Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found 
1572 
  PI and Sub investigators: 
CV and Medical license  
Financial disclosure form 
NIH or CITI human subject protection training certification 
  Laboratories   
CLIA and CAP 
CV of Lab Director and Lab Licenses 
Laboratory reference ranges 
Local Institutional Review Board  
  IRB Approval letter 
  Reviewed/Approved documents 
• 
Protocol version date:   
___________ 
• 
Informed consent version date:  ___________ 
• 
Investigator Brochure version date:  ___________ 
• 
HIPAA  
  Current IRB Roster 
Other  
  Delegation of Authority Log  
• 
Include NIH or CITI human subject protection training certificates or GCP training 
certification 
  Pharmacy 
• 
Drug destruction SOP and Policy 
  Protocol signature page  
  Executed sub contract 
 
27.apr.2012 

 
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Appendix 11 Genentech Safety Reporting Fax Cover Sheet