Conditions: Basal Cell Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 1232
Healthy volunteers: no

Brief summary:
This single-arm, open-label, multi-center study will evaluate the safety and efficacy of vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma. Patients will receive oral doses of vismodegib 150 mg once daily until disease progression or unacceptable toxicity.

Detailed description:

Arms:
arm 1: Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity arm 2: Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity

Interventions: intervention 1: vismodegib
Intervention descriptions: intervention 1: 150 mg once daily until disease progression or unacceptable toxicity

Protocol document:
Prot_000.pdf: 
Official Title: 
STEVIE—A SINGLE-ARM, OPEN-LABEL, PHASE II, 
MULTICENTER STUDY TO ASSESS THE SAFETY OF 
VISMODEGIB (GDC-0449) IN PATIENTS WITH LOCALLY 
ADVANCED OR METASTATIC BASAL CELL CARCINOMA 
NCT Number: 
NCT01367665 
Document Date(s): 
Protocol Version 7: 04-Apr-16 


Title
04-Apr-2016 16:12:47
Date and Time (UTC)
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
Vismodegib—F. Hoffmann-La Roche Ltd 
Protocol MO25616, Version 7 
PROTOCOL 
TITLE: 
STEVIE—A SINGLE-ARM, OPEN-LABEL, PHASE II, 
MULTICENTER STUDY TO ASSESS THE SAFETY OF 
VISMODEGIB (GDC-0449) IN PATIENTS WITH LOCALLY 
ADVANCED OR METASTATIC BASAL CELL 
CARCINOMA 
PROTOCOL NUMBER: MO25616/ NCT01367665 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
2011-000195-34 
IND NUMBER:
Not Applicable
TEST PRODUCT: 
Vismodegib 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
Version 1:  11 February 2011
DATES AMENDED: 
Version 2:  27 January 2012 
Version 3:  08 November 2012 
Version 4: 08 May 2013 
Version 5:  03 October 2013 
Version 6:  20 November 2013 
Version 7:  See electronic date stamp below 


PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
In accordance with the revised Investigator’s Brochure Version 10 (dated 
29 January 2016), Protocol MO25616 has been amended to reflect new information on 
the elimination of vismodegib from the body after treatment discontinuation.  Changes to 
the protocol, along with a rationale for each change, are summarized below. 
1. 
Revised the pregnancy prevention duration and the waiting time for blood 
donations after vismodegib discontinuation. 
The population pharmacokinetic (popPK) model has been updated and finalized 
with additional pharmacokinetic data up to 12 months post-treatment obtained in this 
study.  As a result of this popPK analysis, the recommended time period for females 
to avoid pregnancy and for males and females to avoid blood donations has been 
increased from 7 to 9 months after the last dose of vismodegib.  
2. 
Introduced additional wording to be in accordance with approved local labels. 
Since vismodegib has been approved in many of the countries in which this study is 
being conducted, wording has been introduced in the protocol to emphasize that the 
contraception duration for male and female patients, accepted forms of 
contraception, blood and sperm donation waiting time, and timeframe to report 
pregnancies have to be in accordance with the approved local prescribing 
information (where applicable). 
 
An addendum to the model Informed Consent Forms has been prepared (Model ICF 
Addendum 1 to ICF Version 7, dated 12 February 2016) reflecting the changes to the 
protocol. 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
Vismodegib—F. Hoffmann-La Roche Ltd 
2/Protocol MO25616, Version 7 


 
PROTOCOL AMENDMENT, VERSION 7: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.3:  BENEFIT-RISK 
Potential Risks of the Study 
Finally, small-molecule inhibitors of the Hedgehog pathway are known teratogens that 
result in midline malformations and other severe developmental defects in mammalian 
model systems (see the Vismodegib Investigator Brochure).  Consequently, to be 
eligible for this trial, female patients of childbearing potential must use two methods of 
acceptable contraception, including one highly effective means of contraception and one 
barrier method during treatment and for at least 79 months or as per approved local 
prescribing information for vismodegib (where available), whichever is longer,  after 
completion of treatment.  Fertile male patients must utilize a condom with spermicide, 
(where available), even if he has had a vasectomy, during treatment.  Additionally, 
female patients must exhibit negative serum pregnancy tests within 7 days prior to 
dosing and throughout the trial.  After discontinuing treatment, female patients of 
childbearing potential must continue to use an effective method of contraception for at 
least 79 months or as per approved local prescribing information for vismodegib (where 
available), whichever is longer.  Acceptable contraception and duration of contraceptive 
use should comply with locally approved vismodegib (Erivedge®, the trade name for 
vismodegib) Pregnancy Prevention Program or prescribing information where 
vismodegib is commercially available. 
SECTION 3.1.5:  Rationale for Pharmacokinetic Assessments at Designated 
Investigative Sites 
Vismodegib is a teratogen and a threshold for plasma concentrations of vismodegib in 
patients has been established.  Currently available post-treatment discontinuation PK 
data for vismodegib is limited to 56 days.  Based on the elimination kinetics of 
vismodegib in plasma after treatment discontinuation, it is predicted that the vast 
majority of patients will have plasma concentrations below the threshold for 
teratogenicity after 7 months.  Notably, there is some uncertainty in this extrapolation, 
and until additional post-treatment discontinuation PK data are available, the duration for 
pregnancy prevention measures in female patients taking vismodegib has been 
prolonged to 24 months in the EU.  The PK data obtained from this study will be utilized 
to inform and possibly revise the current recommended duration for pregnancy 
prevention measures after discontinuation of vismodegib treatment. 
Acceptable contraception and duration of contraceptive use and waiting time for blood 
donations should comply with locally approved vismodegib Pregnancy Prevention 
Program or prescribing information where vismodegib is commercially available. 
Vismodegib—F. Hoffmann-La Roche Ltd 
3/Protocol MO25616, Version 7  


 
SECTION 4.2:  INCLUSION CRITERIA 
10. Women of childbearing potential must use two methods of acceptable contraception 
including one highly effective method and a barrier method (see also Appendix 2), 
as directed by their physician during treatment and for at least 79 months or as per 
approved local prescribing information for vismodegib (where available), whichever 
is longer, after completion of study treatment.  Highly-effective methods of 
contraception are defined as those which result in a low failure rate (i.e., less than 
1% per year) when used consistently and correctly (e.g., implants, injectables, or 
intra-uterine devices.  At the discretion of the Investigator, acceptable methods of 
contraception may include total abstinence.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, and postovulation methods) and withdrawal are not 
acceptable methods of contraception (see Appendix 2) 
NOTE:  The pregnancy prevention duration for female patients was changed from 
7 to 9 months or as per approved local prescribing information, whichever is longer, 
after all patients were enrolled in the study. 
11. For male patients with female partners of childbearing potential, agreement to use a 
condom with spermicide (where available), even after vasectomy, during sexual 
intercourse with female partners while being treated with vismodegib and for 
2 months or as per approved local prescribing information for vismodegib (where 
available), whichever is longer,  after completion of study treatment 
NOTE:  The contraception duration for male patients was changed from 2 months 
to 2 months or as per approved local prescribing information, whichever is longer, 
after all patients were enrolled in the study. 
12. Agreement not to donate blood or blood products during the study and for at least 
79 months or as per approved local prescribing information for vismodegib (where 
available), whichever is longer after discontinuation of vismodegib.  Because 
vismodegib has been detected in seminal fluid, in addition for men, agreement not 
donate sperm during the study or for at least 2 months or as per approved local 
prescribing information for vismodegib (where available), whichever is longer after 
discontinuation of therapy 
NOTE:  The waiting time for blood donations was changed from 7 to 9 months or 
as per approved local prescribing information, whichever is longer, after all 
patients were enrolled in the study. 
 
SECTION 5.3.5:  Post-Study Pregnancy Assessments 
Female patients of childbearing potential must continue to use an effective method of 
contraception for 79 months after the last dose of vismodegib.  Acceptable contraception 
and duration of contraceptive use should comply with locally approved vismodegib 
(Erivedge®, the trade name for vismodegib) Pregnancy Prevention Program or 
prescribing information where vismodegib is commercially available.  If a pregnancy 
occurs within 79 months or within the designated window per approved local 
prescribing information for vismodegib (where available), whichever is longer, of the 
last dose of vismodegib, the Investigator should report to the Sponsor (refer to 
Sections 7.1.1.4 and 7.1.2).  The Investigator should counsel the patient, discussing the 
Vismodegib—F. Hoffmann-La Roche Ltd 
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risks of continuing with the pregnancy and the possible effects on the fetus.  Monitoring 
of the patient should continue until conclusion of the pregnancy. 
SECTION 7.1.2:  Pregnancy and Lactation 
Small-molecule inhibitors of the Hedgehog pathway are known teratogens that result in 
midline malformations, such as holoprosencephaly, cyclopia, and other severe 
developmental defects.  The teratogenic potential of vismodegib has been confirmed in 
an embryo-fetal development study in rats (please see the updated Vismodegib 
Investigator Brochure).  Women who plan to become pregnant (during a study or for 
79 months after the last dose or within the designated window per approved local 
prescribing information for vismodegib [where available], whichever is longer) are 
excluded from all vismodegib clinical studies.  Please refer to the Vismodegib 
Investigator Brochure for further information regarding the teratogenic potential of 
vismodegib. 
• 
Pregnant women: Vismodegib is contraindicated in pregnant women or women 
planning to become pregnant during treatment and for 79 months or within the 
designated window per approved local prescribing information for vismodegib 
(where available), whichever is longer, after the last dose. 
 
SECTION 7.1.2.1:  Use in Women of Childbearing Potential 
To prevent pregnancy and the risk of fetal exposure to vismodegib, female patients 
should not become pregnant or plan to become pregnant during treatment with 
vismodegib and for 79 months or within the designated window per approved local 
prescribing information for vismodegib (where available), whichever is longer, after the 
last dose. 
Specific actions are required when treating female patients of childbearing potential.  
Patients should be thoroughly counseled and informed of the teratogenic potential of 
vismodegib.  All pregnancy prevention measures for women of childbearing potential 
must be followed for the duration of the study and for 79 months or within the 
designated window per approved local prescribing information for vismodegib (where  
available), whichever is longer,  after the last dose.  Patients should be counseled on 
the use of contraception before beginning treatment with vismodegib.  As appropriate, 
the treating physician should refer the subject to her gynecologist or other healthcare 
provider to ensure proper understanding of the use of her chosen contraceptive method.  
Acceptable contraception and duration of contraceptive use should comply with locally 
approved vismodegib (Erivedge®, the trade name for vismodegib) Pregnancy Prevention 
Program or prescribing information where vismodegib is commercially available. 
SECTION 7.1.2.2:  Male Patients 
It is not known if vismodegib that may be present in seminal fluid would cause 
teratogenic effects in a fetus born to the female partner of a male subject.  Therefore, 
sexually active male patients must utilize a barrier form of contraception, even if he has 
had a vasectomy, during vismodegib treatment and for 2 months or as per approved 
Vismodegib—F. Hoffmann-La Roche Ltd 
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local prescribing information for vismodegib (where available), whichever is longer, 
after the last dose.   
SECTION 7.1.2.3:  Pregnancy Reporting 
If a female patient becomes pregnant while receiving investigational therapy with 
vismodegib or within 79 months or within the designated window per approved local 
prescribing information for vismodegib (where available), whichever is longer, after the 
last dose, the Investigator must report all pregnancies immediately i.e., no more than 24 
hours after learning of the event to the Sponsor. 
A female patient must be instructed to stop taking the test “drug” and immediately inform 
the Investigator if she becomes pregnant during the study.  The Investigator should 
report all pregnancies immediately i.e., no more than 24 hours after learning of the event 
to the Sponsor, using the Clinical Trial Pregnancy Reporting Form.  The Investigator 
should counsel the patient, discussing the risks of continuing with the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Pregnancies occurring up to 79 months or within the designated 
window per approved local prescribing information for vismodegib (where available), 
whichever is longer, after the completion of the study medication must also be reported 
to the Investigator. 
If a female partner of a male patient becomes pregnant during vismodegib treatment or 
within 2 months or within the designated window per approved local prescribing 
information for vismodegib (where available), whichever is longer, after the last dose of 
vismodegib, the pregnancy must be reported to the Investigator and the Sponsor and 
alert the female partner to consult with her physician.  The partner should be counseled 
and the risks of continuing the pregnancy discussed, as well as the possible effects on 
the fetus.  Monitoring of the female partner should continue until conclusion of the 
pregnancy.  
SECTION 7.1.4:  Blood Donation
Patients must not donate blood or blood products while on study and for 79 months or as 
per approved local prescribing information for vismodegib (where available), whichever 
is longer, after discontinuation of vismodegib.  Where vismodegib is commercially 
available, avoidance of blood donation should comply with locally approved prescribing 
information. 
SECTION 7.2.1:  Recording and Collection of Adverse Events
If a female patient becomes pregnant while receiving investigational therapy or within 
79 months or within the designated window per approved local prescribing information 
for vismodegib (where available), whichever is longer,  after the last dose of 
investigational product, the Investigator should report to the Sponsor immediately within 
one working day (24 hours) of learning of the pregnancy. 
Vismodegib—F. Hoffmann-La Roche Ltd 
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APPENDIX 2:  Definition of Women of Childbearing Potential and 
Acceptable and Unacceptable Forms of Contraception 
Appendix 2 has been revised to reflect the changes to the protocol. 
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TABLE OF CONTENTS 
SYNOPSIS OF PROTOCOL MO25616 ............................................................. 13 
GLOSSARY OF ABBREVIATIONS.................................................................... 32 
1. 
BACKGROUND, RATIONALE, AND BENEFIT-RISK................................. 34 
1.1 
Background ........................................................................... 34 
1.1.1 
Advanced Basal Cell Carcinoma ........................................... 34 
1.1.2 
Vismodegib............................................................................ 35 
1.1.2.1 
Vismodegib Pharmacokinetics............................................... 35 
1.1.2.2 
Clinical Development Program in BCC.................................. 38 
1.2 
Rationale for the Study .......................................................... 40 
1.3 
Benefit-Risk ........................................................................... 41 
2. 
OBJECTIVES.............................................................................................. 42 
2.1 
Primary Objective .................................................................. 42 
2.2 
Secondary Objectives............................................................ 42 
2.3 
Exploratory Objectives........................................................... 42 
3. 
STUDY DESIGN ......................................................................................... 43 
3.1 
Overview of Study Design ..................................................... 43 
3.1.1 
Rationale for Study Design.................................................... 46 
3.1.2 
Rationale for Dose Selection ................................................. 46 
3.1.3 
Rationale for Disease Symptom Assessment........................ 46 
3.1.4 
Rationale for Biomarker Assessments................................... 47 
3.1.5 
Rationale for Pharmacokinetic Assessments at 
Designated Investigative Sites............................................... 47 
3.1.6 
End of Study.......................................................................... 48 
3.2 
Number of Patients................................................................ 48 
3.3 
Centers.................................................................................. 49 
4. 
STUDY POPULATION................................................................................ 49 
4.1 
Overview................................................................................ 49 
4.2 
Inclusion Criteria.................................................................... 49 
4.3 
Exclusion Criteria................................................................... 51 
4.4 
Concomitant Medication and Treatment................................ 51 
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4.4.1 
Concomitant Therapy ............................................................ 51 
4.4.2 
Excluded Therapy and Potential Interactions 
With Concomitant Drugs........................................................ 52 
4.5 
Criteria for Premature Study Withdrawal ............................... 53 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES............................ 54 
5.1 
Screening Examination and Eligibility Screening 
Form ...................................................................................... 54 
5.2 
Procedures for Enrollment of Eligible Patients....................... 55 
5.3 
Clinical Assessments and Procedures .................................. 55 
5.3.1 
Screening/Baseline Period Assessments .............................. 55 
5.3.2 
Treatment Phase Assessments............................................. 57 
5.3.3 
End of Treatment Visit Assessments..................................... 58 
5.3.4 
Safety Follow-Up Phase Assessments.................................. 59 
5.3.5 
Post-Study Pregnancy Assessments..................................... 61 
5.3.6 
Tumor Response Criteria....................................................... 61 
5.3.7 
Clinical Safety Assessments.................................................. 62 
5.3.8 
Medical History and Demographics ....................................... 63 
5.3.9 
Performance Status............................................................... 64 
5.3.10 
Physical Examination ............................................................ 64 
5.3.11 
Vital Signs.............................................................................. 64 
5.3.12 
Electrocardiographic Assessment ......................................... 64 
5.3.13 
Ultrasound ............................................................................. 64 
5.4 
Laboratory Assessments ....................................................... 65 
5.4.1 
Safety Laboratory Assessments............................................ 65 
5.4.2 
Tumor Tissue Assessment .................................................... 65 
5.5 
Quality of Life Assessments .................................................. 66 
5.6 
Disease Symptom Assessment............................................. 66 
5.7 
Pharmacokinetic Assessments at Designated 
Investigative Sites.................................................................. 67 
5.7.1 
Adverse Event-Related Pharmacokinetic 
Assessments ......................................................................... 67 
5.7.2 
Post-Treatment Pharmacokinetic Assessments .................... 68 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ................................... 68 
6.1 
Dose and Schedule ............................................................... 68 
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6.1.1 
Dose Modifications, Interruptions, and Delays....................... 69 
6.2 
Preparation, Storage, and Handling of IMP ........................... 70 
6.3 
Formulation, Packaging, and Labeling .................................. 71 
6.4 
Disposal Considerations........................................................ 71 
6.5 
Blinding and Unblinding......................................................... 71 
6.6 
Accountability of IMP and Assessment of 
Compliance............................................................................ 72 
6.6.1 
Accountability of IMP ............................................................. 72 
6.6.2 
Assessment of Compliance ................................................... 72 
6.7 
Destruction of the IMP ........................................................... 72 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE.............................................. 73 
7.1 
Adverse Events and Laboratory Abnormalities...................... 73 
7.1.1 
Clinical Adverse Events (AEs)............................................... 73 
7.1.1.1 
Intensity ................................................................................. 74 
7.1.1.2 
Drug–Adverse Event Relationship......................................... 74 
7.1.1.3 
Serious Adverse Events [Immediately Reportable 
to Roche] ............................................................................... 75 
7.1.1.4 
Other Safety Findings Requiring Expedited 
Reporting............................................................................... 76 
7.1.2 
Pregnancy and Lactation....................................................... 76 
7.1.2.1 
Use in Women of Childbearing Potential ............................... 76 
7.1.2.2 
Male Patients......................................................................... 77 
7.1.2.3 
Pregnancy Reporting............................................................. 77 
7.1.3 
Abortion, Congenital Anomaly and Birth Defects................... 78 
7.1.4 
Blood Donation...................................................................... 79 
7.1.5 
Progression of Underlying Malignancy .................................. 79 
7.1.6 
Treatment and Follow-Up of Adverse Events 
(AEs)...................................................................................... 79 
7.1.7 
Laboratory Test Abnormalities............................................... 80 
7.1.8 
Follow-up of Abnormal Laboratory Test Values..................... 80 
7.2 
Handling of Safety Parameters.............................................. 80 
7.2.1 
Recording and Collection of Adverse Events......................... 80 
7.2.2 
Reporting of Serious Adverse Events 
(Immediately Reportable) ...................................................... 81 
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7.2.3 
Reporting of Non-Serious Events of Special 
Interest................................................................................... 82 
7.2.4 
PRO Data and Adverse Event Reporting............................... 82 
7.3 
Warnings and Precautions..................................................... 82 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................. 83 
8.1 
Primary and Secondary Variables ......................................... 83 
8.1.1 
Primary Variables .................................................................. 83 
8.1.2 
Secondary Variables ............................................................. 83 
8.2 
Hypothesis Testing ................................................................ 83 
8.2.1 
Types of Analyses ................................................................. 83 
8.2.1.1 
Efficacy Analysis.................................................................... 83 
8.2.1.2 
Interim Analysis ..................................................................... 85 
8.2.2 
Safety Analysis...................................................................... 85 
8.2.3 
Other Analyses...................................................................... 86 
8.2.3.1 
Subgroup Analyses ............................................................... 87 
8.2.3.2 
Quality of Life Analyses and Disease Symptoms 
Assessment........................................................................... 87 
8.2.3.3 
Exploratory Pharmacokinetic Analyses.................................. 88 
8.3 
Sample Size .......................................................................... 88 
9. 
DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE.............................................................................................. 89 
10. STUDY COMMITTEES............................................................................... 89 
11. REFERENCES ........................................................................................... 91 
12. ETHICAL ASPECTS ................................................................................... 94 
12.1 
Local Regulations/Declaration of Helsinki.............................. 94 
12.2 
Informed Consent .................................................................. 94 
12.2.1 
Main Study Informed Consent ............................................... 94 
12.3 
Independent Ethics Committees 
(IEC)/Institutional Review Board (IRB)................................... 95 
12.4 
Financial Disclosure .............................................................. 95 
13. CONDITIONS FOR MODIFYING THE PROTOCOL................................... 96 
14. CONDITIONS FOR TERMINATING THE STUDY ...................................... 96 
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15. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING.................. 96 
15.1 
Investigator's Files/Retention of Documents.......................... 96 
15.2 
Source Documents and Background Data............................. 97 
15.3 
Audits and Inspections .......................................................... 97 
15.4 
Case Report Forms or Electronic Case Report 
Forms .................................................................................... 97 
16. MONITORING THE STUDY ....................................................................... 98 
17. CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS.................................................................................................. 98 
18. CLINICAL STUDY REPORT....................................................................... 98 
19. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS................................................................................................... 98 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments........................................................... 28 
Table 2 
Adverse Event Grading (Severity) Scale..................................... 74 
Table 3 
Clopper-Pearson 95% Confidence Intervals for the Observed 
AE Incidence1............................................................................. 88 
 
 
LIST OF APPENDICES 
Appendix 1 
New Response Evaluation Criteria in Solid Tumors, Version 
1.1:  Modified Excerpt from Original Publication with 
Supplementary Explanations (1)............................................... 100 
Appendix 2 
Definition of Women of Childbearing Potential and 
Acceptable and Unacceptable Forms of Contraception............ 113 
Appendix 3 
Eastern Cooperative Oncology Group Performance Status...... 115 
Appendix 4 
International Conference on Harmonization (ICH) Guidelines 
for Clinical Safety Data Management, Definitions, and 
Standards for Expedited Reporting, Topic E2........................... 116 
Appendix 5 
Skindex-16 Quality of Life Questionnaire.................................. 118 
Appendix 6 
M.D. Anderson Symptom Inventory (MDASI)............................ 119 
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SYNOPSIS OF PROTOCOL MO25616 
 
TITLE 
STEVIE—A single-arm, open-label, phase II, 
multicenter study to assess the safety of vismodegib 
(GDC-0449) in patients with locally advanced or 
metastatic basal cell carcinoma 
 
SPONSOR 
F. Hoffmann-La Roche 
Ltd. 
 
CLINICAL 
PHASE 
 
Phase II 
INDICATION 
Locally advanced or metastatic basal cell carcinoma 
(BCC) 
 
OBJECTIVES  
Primary objective: 
• 
To assess the safety of vismodegib (also known as 
GDC-0449) in patients with locally advanced or 
metastatic BCC 
 
Secondary objectives: 
• 
To assess the overall response rate (according to 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 [RECIST, v1.1]) in those patients with 
measurable disease, as permitted by local 
regulatory requirements 
• 
To assess other efficacy parameters, such as time 
to response, duration of response, progression-free 
survival (PFS), and overall survival (OS) 
• 
To assess patient quality of life (QoL) (Skindex-16) 
• 
To assess the impact of vismodegib treatment on 
disease symptoms in patients with metastatic BCC 
who enrolled after approval of the Study Protocol, 
version 4.0, using the M.D. Anderson Symptom 
Inventory (MDASI) 
 
Exploratory objectives 
• 
To assess the status of the Hedgehog (Hh) 
pathway and/or other modifiers of vismodegib 
activity in tumor tissue obtained from patients with 
metastatic BCC who have disease progression on 
vismodegib therapy 
• 
To determine the post-treatment exposure of 
vismodegib in patients with adverse events that 
were reported to be related to vismodegib 
treatment and that are continuing at least 6  months 
after the last dose of vismodegib  
• 
To determine the post-treatment exposure of 
vismodegib in patients following daily oral dosing 
with 150 mg vismodegib for at least 2 weeks of 
consecutive dosing (steady-state exposure) and at 
3, 6, 9, and 12 months after the last dose of 
vismodegib 
 
Vismodegib—F. Hoffmann-La Roche Ltd 
13/Protocol MO25616, Version 7 


 
TRIAL DESIGN 
This is an open-label, non-comparative, multicenter, 
phase II study of vismodegib in patients with locally 
advanced BCC or metastatic BCC who are otherwise 
without satisfactory treatment options. 
 
NUMBER OF PATIENTS 
Approximately 1200 patients.  Once the enrollment of 
1200 patients is completed, an assessment of how 
many patients with metastatic BCC were enrolled under 
Protocol Amendment Version 4 (dated 8 May 2013) will 
be made.  At that time, enrollment may be extended for 
up to 15 additional metastatic BCC patients in order to 
ensure adequate collection of data regarding the effect 
of vismodegib in metastatic BCC patients, as per 
Protocol Amendment Version 4 (dated 8 May 2013). 
 
TARGET POPULATION 
The study population will consist of male or female 
patients at least 18 years of age with histologically 
confirmed diagnoses of locally advanced BCC or 
metastatic BCC.  For patients with locally advanced 
BCC, the treating physician must consider the disease 
to be inoperable or there must be a clinical 
contraindication to surgery; furthermore, radiotherapy 
must have been previously administered (unless 
radiotherapy is contraindicated or inappropriate) and 
disease must have progressed after irradiation.  For 
patients with suspected metastatic BCC, distant 
metastases must be histologically confirmed to be of 
basal cell origin.  Patients are eligible for enrollment in 
this trial with measurable and/or non-measurable 
disease, as defined by RECIST, v1.1. 
 
Inclusion Criteria: 
1. Written, signed informed consent  
2. Age ≥ 18 years 
3. Eastern Cooperative Oncology Group Performance 
Status (ECOG PS) of 0, 1, or 2 
4. For patients with metastatic BCC, histologic 
confirmation of distant BCC metastasis  
5. For patients with locally advanced BCC, at least 
one histologically confirmed lesion 10 mm or more 
in diameter and written confirmation from a surgical 
specialist that the tumor is considered inoperable 
or that surgery is contraindicated.  Examples of 
medical contraindications to surgery include but are 
not limited to: 
• 
BCC that has recurred in the same location 
after two or more surgical procedures and 
curative resection is deemed unlikely 
• 
Anticipated substantial morbidity and/or 
deformity from surgery (e.g., removal of all or 
part of a facial structure, such as nose, ear, 
eyelid, eye; or requirement for limb amputation) 
 
 
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6. For patients with locally advanced BCC, 
radiotherapy must have been previously 
administered for locally advanced BCC, unless 
radiotherapy is contraindicated or inappropriate 
(e.g., hypersensitivity to radiation due to genetic 
syndrome such as Gorlin syndrome, limitations 
because of location of tumor, or cumulative prior 
radiotherapy dose).  For patients whose locally 
advanced BCC has been irradiated, disease must 
have progressed after radiation 
7. Patients with Gorlin syndrome may enroll in this 
study but must meet the criteria for locally 
advanced or metastatic disease listed above 
8. Patients with measurable and/or non-measurable 
disease (as defined by RECIST, v1.1) are allowed 
9. Adequate organ function, as evidenced by the 
following laboratory results: 
• 
Hemoglobin > 8.5 g/dL  
• 
Granulocyte count ≥ 1000/μL 
• 
Platelet count ≥ 75,000/μL 
• 
Aspartate aminotransferase (AST [SGOT]) and 
alanine aminotransferase (ALT 
[SGPT]) ≤ 3 × upper limit of normal (ULN) 
• 
Total bilirubin ≤ 1.5 × ULN or within 3 × ULN for 
patients with documented Gilbert syndrome 
10. Women of childbearing potential must use two 
methods of acceptable contraception including one 
highly effective method and a barrier method (see 
also Appendix 2), as directed by their physician 
during treatment and for at least 9 months or as per 
approved local prescribing information for 
vismodegib (where available), whichever is longer, 
after completion of study treatment. Highly-effective 
methods of contraception are defined as those 
which result in a low failure rate (i.e., less than 
1% per year) when used consistently and correctly 
(e.g., implants, injectables, or intra-uterine devices. 
At the discretion of the Investigator, acceptable 
methods of contraception may include total 
abstinence. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, and post ovulation 
methods) and withdrawal are not acceptable 
methods of contraception (see Appendix 2) 
NOTE:  The pregnancy prevention duration for 
female patients was changed from 7 to 9 months, 
or as per approved local prescribing information, 
whichever is longer, after all patients were 
enrolled in the study. 
11. For male patients with female partners of 
childbearing potential, agreement to use a condom 
with spermicide (where available), even after 
vasectomy, during sexual intercourse with female 
partners while being treated with vismodegib and 
for 2 months or as per approved local prescribing 
information for vismodegib (where available), 
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whichever is longer,  after completion of study 
treatment 
NOTE:  The contraception duration for male 
patients was changed from 2 months to 2 months 
or as per approved local prescribing information, 
whichever is longer, after all patients were 
enrolled in the study. 
12. Agreement not to donate blood or blood products 
during the study and for at least 9 months or as per 
approved local prescribing information for 
vismodegib (where available), whichever is longer, 
after discontinuation of vismodegib. Because 
vismodegib has been detected in seminal fluid, in 
addition for men, agreement not donate sperm 
during the study or for at least 2 months or as per 
approved local prescribing information for 
vismodegib (where available), whichever is longer, 
after discontinuation of therapy 
NOTE:  The waiting time for blood donations was 
changed from 7 to 9 months or as per approved 
local prescribing information, whichever is longer, 
after all patients were enrolled in the study. 
13. Life expectancy > 12 weeks 
14. Negative serum pregnancy test within 7 days prior 
to commencement of dosing in premenopausal 
women.  Women of non-childbearing potential may 
be included if they are either surgically sterile or 
have been postmenopausal for ≥ 1 year 
 
Exclusion Criteria: 
1. Inability or unwillingness to swallow capsules 
2. Pregnancy or lactation 
3. Concurrent non–protocol-specified anti-tumor 
therapy (e.g., chemotherapy, other targeted 
therapy, radiation therapy, or photodynamic 
therapy, including participation in an experimental 
drug study; note that treatment breaks up to 
8 weeks for radiation therapy are allowed [see 
Section 6.1.1]) 
4. Completion of most recent anti-tumor therapy less 
than 21 days prior to initiation of treatment 
5. Uncontrolled medical illnesses such as infection 
requiring treatment with intravenous antibiotics 
6. 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 that 
renders the patient at high risk from treatment 
complications 
7. Assessed by the Investigator to be unable or 
unwilling to comply with the requirements of the 
protocol 
8. Patients with one of the following rare hereditary 
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conditions: galactose intolerance, primary 
hypolactasia, or glucose-galactose malabsorption 
 
LENGTH OF STUDY  
It is anticipated that approximately 1200 patients will be 
enrolled into this study over an approximately 3.5-year 
period.  Enrollment will continue only until such time as 
vismodegib becomes commercially available for this 
patient population.  Once the enrollment of 1200 
patients is completed, an assessment of how many of 
patients with metastatic BCC were enrolled under 
Protocol Amendment Version 4 (dated 8 May 2013) will 
be made.  At that time, enrollment may be extended for 
up to 15 additional metastatic BCC patients in order to 
ensure adequate collection of data regarding the effect 
of vismodegib in metastatic BCC patients, as per 
Protocol Amendment Version 4 (dated 8 May 2013). 
 
The trial will consist of a Screening Period 
(Day-28 to −1), a Treatment Phase, an End of 
Treatment Visit when the patient received the last dose 
of vismodegib and thereafter discontinues vismodegib 
(regardless of when it occurs), and five Safety 
Follow-Up Visits 1 month, 3 months, 6 months, 
9 months, and 12 months after the last dose of 
vismodegib (± 5 days), as provided by this phase II 
safety study protocol.  Day 1 of the study will be defined 
as the first day a patient receives vismodegib. 
Enrolled patients will receive study drug until 
Investigator-assessed disease progression, 
unacceptable toxicities most probably attributable to 
vismodegib, patient consent withdrawal, death, reasons 
deemed by the treating physician, or study termination 
by the Sponsor. 
 
Patients who discontinue study drug(s) for any reason 
other than disease progression or withdrawal of 
consent (e.g., an adverse event [AE]) will continue to be 
followed until the development of disease progression, 
consent withdrawal, loss to follow up, or beginning of 
another anti-cancer therapy. 
 
END OF STUDY 
Study enrollment is planned to end in the EU if 
vismodegib becomes commercially available after 
regulatory approval for the treatment of locally advanced 
or metastatic BCC.  Study enrollment is planned to end 
successively in non-EU countries participating in this 
study if vismodegib becomes commercially available 
after regulatory approval for the treatment of locally 
advanced or metastatic BCC in the respective country.  
However, patients already enrolled in this study and who 
are still benefitting from vismodegib in the opinion of the 
Investigator will continue to receive vismodegib as a 
study medication until the development of progressive 
disease (as determined by the Investigator), 
unacceptable toxicity, consent withdrawal, death, 
reasons deemed by the treating physician, or study 
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termination by the Sponsor. 
 
The study will end when the last patient on treatment 
develops progressive disease (as determined by the 
Investigator) or unacceptable toxicity, withdraws 
consent, or dies; the treating physician deems the 
patient is no longer benefitting from treatment and has 
completed the safety follow up visits, or the study is 
terminated by the Sponsor, or 12 months after the last 
dose of vismodegib in the last enrolled patient still on 
study, whichever occurs first. 
 
The Sponsor reserves the right to end study enrollment 
at any time.  If study enrollment is stopped prior to 
commercial availability of vismodegib, patients already 
enrolled will be informed of the reason for 
discontinuation of study enrollment and, in the absence 
of a significant product safety concern or other 
circumstances, will be allowed to continue vismodegib 
until disease progression, unmanageable toxicity, 
withdrawal of consent, reasons deemed by the treating 
physician, or death of the patient, whichever occurs first. 
 
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INVESTIGATIONAL MEDICAL 
PRODUCT(S) 
DOSE/ ROUTE/ REGIMEN 
Enrolled patients will receive continuous once-daily oral 
dosing of vismodegib at a dosage of 150 mg per 
administration.  One cycle of therapy is defined as 
28 days of treatment. 
 
Dosing of vismodegib will continue until one of the 
following occurs: 
• 
Investigator-assessed disease progression 
• 
Unacceptable toxicities most likely attributable to 
vismodegib 
• 
Patient consent withdrawal 
• 
Death 
• 
Reasons deemed by the treating physician  
• 
Study termination by the Sponsor 
 
No dose reductions will be allowed in this study. 
 
Treatment with vismodegib may be interrupted for up 
to: 
• 
Eight weeks if a patient becomes temporarily unable 
to swallow capsules 
• 
Eight weeks for an intolerable toxicity finding  
 
Patients with an asymptomatic or tolerable severe AE 
may continue to receive study drug provided the AE is 
manageable and the patient and the Investigator agree 
that continued study participation is acceptable. 
 
If a patient experiences two treatment interruptions, the 
Medical Monitor must be consulted before the patient 
can resume treatment. 
 
CENTERS 
This is an international multicenter study. 
NON-INVESTIGATIONAL 
MEDICAL PRODUCTS 
N.A. 
COMPARATOR “DRUG”  
(or STANDARD OF CARE) 
DOSE/ ROUTE/ REGIMEN 
No comparator 
ASSESSMENTS OF: 
 
− 
SAFETY 
Incidence, type, and severity of AEs  
Incidence and nature of serious adverse events (SAEs) 
Incidence of AEs leading to vismodegib discontinuation 
or interruption 
Cause of death on study (if not linked to disease 
progression) 
 
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− 
EFFICACY 
For patients with measurable disease at baseline, 
tumor responses categorized according to Investigator 
assessment following RECIST, v1.1, as allowed by 
local regulatory guidelines.  Information about other 
efficacy parameters, such as time to response, duration 
of response, progression-free survival, and overall 
survival, will be also collected. 
− 
PHARMACOKINETICS/ 
PHARMACODYNAMICS 
  
Adverse event-related pharmacokinetic testing will be 
performed on patients having any adverse events that 
were reported as being related to vismodegib treatment 
and that continued for at least 6 months after the last 
dose of vismodegib at selected sites.  
Post-treatment pharmacokinetic testing will be 
performed on 30 patients to further characterize the 
post-treatment elimination of vismodegib from 
steady-state exposure to 12 months after the last dose 
of vismodegib at selected sites. 
   
− 
PHARMACOECONOMICS/ 
QUALITY OF LIFE (QoL) 
 
The Skindex-16 questionnaire will be used in selected 
sites to measure patient QoL.  
− 
DISEASE SYMPTOMS 
 
The M.D. Anderson Symptom Inventory (MDASI) will be 
used to assess the impact of treatment on symptoms in 
metastatic BCC patients enrolled after approval of the 
Study Protocol, version 4.0. 
 
− 
EXPLORATORY 
BIOMARKERS  (non-
inherited) 
 
Archival tumor tissue from a metastatic BCC site will be 
collected in metastatic BCC patients who are on study 
after approval of the Study Protocol, version 4.0.  
Tumor biopsy samples will be collected from patients 
who have accessible progressing tumors (e.g., skin, 
superficial mass, or lymph node) while on vismodegib 
treatment. 
  
− 
EXPLORATORY 
BIOMARKERS (inherited) 
 
N.A. 
− 
CLINICAL GENOTYPING 
(CG) SAMPLES  
Whole-blood samples will be collected in metastatic 
BCC patients (in whom tumor biopsy samples are 
collected at progression) for the exclusive purpose of 
validating and confirming tumor specific genetic 
variants.  
 
 
PROCEDURES (SUMMARY) 
 
Informed consent must be obtained before any study related procedures are conducted. 
 
The trial will consist of a Screening Period, a Treatment Phase, an End of Treatment Visit when 
the patient received the last dose of vismodegib and thereafter discontinues vismodegib 
(regardless of when it occurs), and five Safety Follow-Up Visits 1 month, 3 months, 6 months, 
9 months, and 12 months after the last dose of vismodegib (± 5 days), as provided by this 
phase II safety study protocol. 
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Screening/Baseline Period Assessments: 
Potential participants will undergo the following screening procedures no more than 28 days 
prior to Day 1, Cycle 1 (unless they have already been conducted during this time period as part 
of the patient’s routine clinical care): 
 
• 
Informed consent 
• 
Archival tumor tissue from a metastatic BCC site in metastatic BCC patients who are on 
study after approval of the Study Protocol, version 4.0 
• 
Complete medical history (including BCC history) and demographics 
• 
Collection of metastatic BCC history, such as evidence of progression prior to 
enrollment and reason(s) for discontinuation from prior treatment, will be collected in 
patients who are on study after approval of the Study Protocol, version 4.0 
• 
Complete physical examination including weight and height at screening only. 
• 
Vital signs (body temperature, blood pressure, and pulse) 
• 
ECOG PS assessment 
• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood cell 
count including differential, platelet count, and absolute neutrophil count [ANC]) 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen [BUN], creatinine, creatine kinase [also known as creatine phosphokinase], total 
bilirubin, alkaline phosphatase, AST, and ALT) 
• 
Serum pregnancy test (within 7 days prior to the commencement of vismodegib dosing) for 
women of child bearing potential (Main Protocol Appendix 2) 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Ultrasound 
• 
Record any amenorrhea/irregular menses, relevant gynecologic medical history, and 
concurrent gynecologic conditions 
• 
Perform serum hormone evaluation, including follicle stimulating hormone (FSH), 
luteinizing hormone (LH), estradiol (E2), and thyroid stimulating hormone (TSH)  
• 
12-lead electrocardiogram (ECG) 
• 
AEs/SAEs.  After informed consent, but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected.  All AEs (either related to 
study specific procedures or otherwise) experienced after the patient has signed the 
Informed Consent Form, but before they have received study treatment, should be recorded 
as medical history  
• 
Concomitant therapy 
• 
Tumor assessment (the majority of patients in this study have locally advanced BCC and in 
this disease setting measurable tumors are accessible to evaluation by physical 
examination): 
• 
Measurable tumors accessible to evaluation by physical examination should be 
assessed within a maximum of 7 days prior to the first dose of study drug (baseline 
reading)  
• 
If assessment requires imaging, baseline computed tomography (CT) and/or magnetic 
resonance imaging (MRI) should be performed within a maximum of 28 days prior to the 
first dose of study drug  
• 
Non-measurable disease should be assessed within 28 days prior to study initiation 
• 
In selected sites, patients will complete the Skindex-16 Quality of Life questionnaire 
(see Main Protocol Section 5.5 and Appendix 5) 
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• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, 
version 4.0) will complete the M.D. Anderson Symptom Inventory (see Main Protocol, 
Section 5.6 and Appendix 6) prior to having any study-related procedures performed at the 
visit  
 
Treatment Phase Assessments: 
Day 1 of the study will be defined as the first day a patient receives vismodegib. One cycle of 
therapy is defined as 28 days of treatment.  During the Treatment Phase, all study assessments 
will be conducted on Day 1 (± 3 days from Cycle 2 onwards) of each Cycle with the exception of 
tumor evaluation, for which a window of ± 5 days will apply (see below).  The assessments 
during the Treatment Phase are:  
 
• 
Limited physical examination at every 28-Day visit 
• 
Vital signs (body temperature, blood pressure, and pulse) and weight at every 28-Day visit 
• 
ECOG PS assessment at every 28-Day visit 
• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood cell 
count including differential, platelet count, and ANC) at every 28-Day visit 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
creatine kinase [also known as creatine phosphokinase], total bilirubin, alkaline 
phosphatase, AST, and ALT) at every 28-Day visit 
• 
Urine pregnancy tests on Day 1 of each subsequent Cycle.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test 
• 
12-lead ECG (during the study if clinically indicated) 
• 
Concomitant therapy and AEs (including SAEs) throughout the study 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Ultrasound (as clinically indicated [see Schedule of Assessments]) 
• 
Assess amenorrhea/irregular menses that develops while on study:  
1. At start of amenorrhea/irregular menses, perform serum hormone evaluation at 
study site, including FSH, LH, E2, and TSH, and refer to gynecologist or appropriate 
specialist for assessment of ovaries and uterus, including ultrasound   
2. At resolution of amenorrhea/irregular menses, perform serum hormone evaluation 
at site, including FSH, LH, E2, and TSH.  Refer to gynecologist or appropriate 
specialist for follow-up ultrasound ONLY if there was abnormality identified during 
previous ultrasound   
3. If amenorrhea/irregular menses recurs, repeat evaluations at start of recurrence as 
detailed previously 
• 
Vismodegib administration throughout the study 
• 
Follow up for disease progression 
• 
Tumor assessment (the majority of the patients in this study have locally advanced BCC 
and, in this disease setting, measurable tumors are accessible to evaluation by physical 
examination).  Objective responses using RECIST, v1.1 should be confirmed by repeat 
assessments at least 4 weeks after initial documentation of response: 
• 
Measurable tumors accessible to evaluation by physical examination should be 
assessed every 4 to 8 weeks throughout the study from the time of the first dose, 
regardless of dosing delays 
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• 
If assessment requires imaging, baseline CT and/or MRI should be performed within a 
maximum of 28 days prior to the first dose of study drug and, if such scans demonstrate 
evidence of disease, follow-up imaging studies (CT and/or MRI) should be performed 
every 8 to 16 weeks from the time of the first dose, regardless of dosing delays, or per 
institutional standards.  The same imaging technique (CT or MRI) should be used for 
each patient throughout the study 
• 
In metastatic BCC patients (newly enrolled after approval of the Study Protocol, version 
4.0), imaging at baseline (CT and/or MRI scan) should be performed within a maximum 
of 28 days before the first dose.  Follow-up imaging studies (CT and/or MRI scan) 
should be performed every 8 weeks (± 5 days) from the time of the first dose, regardless 
of dosing delays.  The same imaging technique (CT or MRI) should be used for each 
patient throughout the study 
• 
Other imaging techniques may be performed as clinically indicated, but should not be 
used for determining tumor response 
• 
Patients with non-measurable disease at baseline should be assessed for disease 
progression when clinically indicated and in accordance with standard clinical practice.  
For metastatic patients, assessment of non-measurable disease should be according to 
RECIST version 1.1. 
• 
In selected sites, patients will complete the Skindex-16 Quality of Life questionnaire after 
Cycle 1 and after Cycle 6 (i.e., after 6 months of treatment) for the patients still on study 
(see Main Protocol Section 5.5. and Appendix 5) 
• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, 
version 4.0) will complete the M.D. Anderson Symptom Inventory (see Main Protocol 
Section 5.6 and Appendix 6) at every visit, prior to having any other assessments 
performed 
• 
In selected sites, post-treatment pharmacokinetic (PK) testing will be performed on patients.  
This testing requires a single blood draw for PK testing at steady-state for comparison to 
the post-treatment samples collected.  Steady-state is defined as any time point while a 
patient is taking vismodegib for at least 2 weeks continuously. 
 
End of Treatment Visit Assessments: 
The End of Treatment Visit will be performed when the patient discontinues vismodegib, 
regardless of when it occurs. 
 
• 
Limited physical examination 
• 
Vital signs (body temperature, blood pressure, and pulse) and weight 
• 
ECOG PS assessment 
• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood cell 
count including differential, platelet count, and ANC) 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
creatine kinase [also known as creatine phosphokinase], total bilirubin, alkaline 
phosphatase, AST, and ALT) 
• 
Tumor assessment 
• 
12- lead ECG (if clinically indicated) 
• 
Concomitant therapy and new anti-cancer therapy 
• 
AEs (including SAEs) 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Assess amenorrhea/irregular menses that develops while on study:  
1. At start of amenorrhea/irregular menses, perform serum hormone evaluation at 
study site, including FSH, LH, E2, and TSH, and refer to gynecologist or appropriate 
specialist for assessment of ovaries and uterus, including ultrasound   
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2. At resolution of amenorrhea/irregular menses, perform serum hormone evaluation 
at site, including FSH, LH, E2, and TSH.  Refer to gynecologist or appropriate 
specialist for follow-up ultrasound ONLY if there was abnormality identified during 
previous ultrasound   
3. If amenorrhea/irregular menses recurs, repeat evaluations at start of recurrence as 
detailed previously 
• 
Follow up for disease progression 
• 
Pregnancy test for women of childbearing potential 
• 
In selected sites, patients will complete the Skindex-16 Quality of Life questionnaire (see 
Main Protocol Section 5.5 and Appendix 5). 
• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, version 
4.0) will complete the M.D. Anderson Symptom Inventory (see Main Protocol 
Section 5.6 and Appendix 6), prior to having any other assessments performed  
• 
In metastatic BCC patients who develop tumor progression on vismodegib treatment, a 
biopsy will be performed if at least one of the progressing lesions is accessible, e.g., skin, 
superficial mass, or lymph node 
• 
Collection of whole blood in metastatic BCC patients with tumor biopsy at progression  
 
Safety Follow-Up Phase Assessments: 
Patients who discontinue vismodegib treatment will be asked to return to the clinic for a safety 
follow-up assessment 1 month, 3 months, 6 months, 9 months, and 12 months after the last 
dose of vismodegib (± 5 days), as provided by this phase II, safety study protocol. 
 
• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood cell 
count including differential, platelet count, and ANC) as clinically indicated 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
creatine kinase [also known as creatine phosphokinase], total bilirubin, alkaline 
phosphatase, AST, and ALT) as clinically indicated 
• 
Follow up for disease progression 
• 
Concomitant therapy and new anti-cancer therapy 
• 
AEs (including SAEs) 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Assess amenorrhea/irregular menses that develops while on study:  
1. At start of amenorrhea/irregular menses, perform serum hormone evaluation at 
study site, including FSH, LH, E2, and TSH, and refer to gynecologist or appropriate 
specialist for assessment of ovaries and uterus, including ultrasound   
2. At resolution of amenorrhea/irregular menses, perform serum hormone evaluation 
at site, including FSH, LH, E2, and TSH.  Refer to gynecologist or appropriate 
specialist for follow-up ultrasound ONLY if there was abnormality identified during 
previous ultrasound   
3. If amenorrhea/irregular menses recurs, repeat evaluations at start of recurrence as 
detailed previously 
• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, version 
4.0) will complete the M.D. Anderson Symptom Inventory (see Main Protocol Section 5.6 
and Appendix 6), prior to having any other assessments performed at the visits 
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• 
In selected sites, patients will have blood draws for adverse event–related PK testing if any 
adverse events that were reported to be related to vismodegib treatment continue to be 
present at least 6 months after the last dose of vismodegib.  Blood samples for the adverse 
event-related PK testing will be collected at the 6, 9, and 12 months Safety Follow-Up Visits.  
Blood samples for all time points will be collected even if the adverse event resolves after 
the 6 months Safety Follow-Up Visit.   
• 
In selected sites, post-treatment PK testing will be performed on 30 patients.  Patients, who 
previously provided a PK sample at steady-state, will have blood draws for post-treatment 
PK testing at the 3, 6, 9, and 12 months Safety Follow-up Visits. 
 
STATISTICAL ANALYSES 
The primary objective of this trial is to assess the safety of vismodegib in patients with locally 
advanced or metastatic BCC. 
 
There are no formal statistical hypothesis tests to be performed.  Continuous data will be 
summarized using mean, standard deviation, median, minimum, and maximum.  Discrete data 
will be summarized using frequencies and percentages.  No adjustments for multiplicity of 
endpoints or within-subgroup comparisons will be used in the analyses.  
 
The final analysis for safety and efficacy will be performed when the last patient on treatment 
develops progressive disease (as determined by the Investigator) or unacceptable toxicity, 
withdraws consent, or dies; the treating physician deems the patient is no longer benefitting 
from treatment; or the study is terminated by the Sponsor, or 12 months after the last dose of 
vismodegib in the last enrolled patient still on study, whichever occurs first.  
 
In addition to final analysis, there will be six interim analyses for publication of safety and 
efficacy results and DSMB reviews when the: 
First 75 patients enrolled have been treated for at least 3 months,  
First 150 patients enrolled have been treated for at least 3 months,  
First 300 patients enrolled have been treated for at least 3 months, 
First 550 patients enrolled have been treated for at least 3 months,  
First 800 patients enrolled have been treated for at least 3 months, and  
1200 patients enrolled have been treated for at least 3 months (see also Section 10).  
• 
This last interim analysis will also include analysis of 500 enrolled patients who have 
been followed for at least 1 year 
 
Safety Analyses: 
All patients who receive at least one dose of vismodegib will be included in the safety analyses.  
Safety will be assessed through summaries of AEs, SAEs, AEs Grade 3 or 4, AEs that caused 
vismodegib discontinuation and interruption, and cause of death on study.  
 
All AEs will be assessed according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 4.0 (NCI-CTCAE, v 4.0) grading system.  The analysis of 
AEs will focus on treatment-emergent AEs, i.e., AEs occurring on or after the first day of 
vismodegib administration.  Non–treatment-emergent AEs (i.e., those occurring before 
commencement of study medication) will only be listed.  The incidence, type, and severity of 
AEs will be summarized according to the primary system-organ class (SOC) and, within each 
SOC, by Medical Dictionary for Regulatory Activities (MedDRA) preferred term.  AEs of special 
interest, AEs leading to treatment interruption and discontinuation, and SAEs will be analyzed in 
a similar way to all AEs.  Cause of death will also be summarized and listed. 
Exposure to study medication will be summarized by means of descriptive statistics for the 
cumulative dose and frequency tables (percentages) by Cycles and/or Weeks of treatments.  
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The reason for the dose discontinuation, other than disease progression, will be also 
summarized.  
 
Laboratory parameters, hematology, and serum biochemistry will be presented in shift tables of 
NCI-CTCAE, v4.0 grade at baseline versus worst grade during the treatment period.  The 
laboratory parameters will be also summarized as continuous or discrete data when applicable.  
 
Vital signs, ECOG PS, physical examination, and ECG (if available) will be summarized over 
time.  Concomitant therapy will be summarized by frequency tables and percentages.  New 
anti-cancer therapy will be analyzed in a similar way to concomitant therapy at the End of 
Treatment Visit.  Protocol deviations will be listed. 
 
Medical history including demographics, (age, gender, and race as applicable), clinically 
significant diseases, previous surgeries, prior skin cancer history, prior skin cancer therapies 
and procedures, response to prior therapies, and all medications used by the patient within 
14 days preceding the screening visit) will be summarized at baseline.  
In metastatic BCC patients (who are on study after approval of the Study Protocol, version 4.0), 
evidence of tumor progression prior to enrollment on study and reasons for treatment 
discontinuation of prior therapies will be summarized.  Analysis of data regarding evidence of 
progression prior to enrollment and reasons for treatment discontinuation of prior therapies will 
be performed in metastatic BCC patients. 
 
Efficacy Analyses: 
ORR, assessed by the Investigator according to RECIST, v1.1, will be summarized.  The 
summary will be performed on patients with measureable disease at baseline.  The best overall 
response rates (complete and partial responders), together with the corresponding 95% 
Pearson-Clopper confidence intervals, will be presented.  
 
Duration of response will be defined only for patients whose confirmed best response is 
complete response (CR) or partial response (PR) and will describe the time interval between the 
date of the earliest qualifying response and the date of progressive disease (PD) or death for 
any cause.  
 
Time to response will be defined as the interval between the date of first treatment and the date 
of first documentation of confirmed CR or PR (whichever occur first).  
 
PFS will be defined as the time interval between the date of the first therapy and the date of 
progression or death for any causes, whichever occurs first.  Patients with non-measureable 
disease will be assessed for disease progression and included in this summary.  
 
OS will be defined as the time from the date of first treatment to the date of death, regardless of 
the cause of death.  Estimates for the survival function and corresponding 95% confidence 
interval for the time-to-event endpoints, PFS, OS, time to response, and duration of response 
using Kaplan-Meier estimates will be displayed by tables and graphs.  
 
Quality of Life 
The effects of skin disease on patient’s quality of life will be accessed by the 
Skindex-16 questionnaire.  Distribution of scores, mean scores, and changes from baseline for 
each domain, symptoms, emotions and function will be summarized over time by summary 
tables, line graphs with associated 95% confidence intervals, and box plots. 
 
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Vismodegib—F. Hoffma
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Screening 
Study Treatment Phase 
Safety Follow-Up 
 
Day –28 to –1 
Continuous once-daily oral dosing of 
vismodegib at a dosage of 150 mg per 
administration until one of the following occurs: 
disease progression, intolerable toxicity most 
probably attributable to vismodegib, consent 
withdrawal, death, study termination by the 
Sponsor, or other reason deemed by the 
Investigator 
Five Safety 
Follow-Up Visits 1 
month, 3 months, 
6 months, 
9 months, and 
12 months after the 
last dose of 
vismodegib 
(± 5 days) 
 
 
 
 
Treatment scheme: 
Determination of Sample Size 
Exploratory Pharmacokinetic Assessments 
Disease Symptoms 
 
 
 
Therefore, for a sample size of  1200 patients, the true AE incidence rate can be estimated to 
within 1.6%–1.8% assuming an observed incidence of 10%, i.e., within 95% Clopper-Pearson 
confidence interval of 8.4%–11.8%. 
 
 
Individual and mean plasma vismodegib concentration versus time data will be tabulated and 
plotted.  Plasma AAG concentration and unbound plasma concentration at selected time points 
will be estimated, tabulated and summarized (geometric mean, mean, standard deviation, 
coefficient of variation, median, minimum, and maximum).  Additional PK analyses may be 
conducted as appropriate.  
 
Approximately 1200 patients will be enrolled in this study.   
 
The M.D. Anderson Symptom Inventory (MDASI) will be used to assess the impact of treatment 
on symptoms in metastatic BCC patients enrolled after approval of the Study Protocol, 
version 4.0.  For these metastatic patients, incidence and type of disease symptoms will be 
summarized at baseline.  In addition, the number of metastatic BCC patients with 30% 
reduction in disease-related symptoms with baseline score of 4 or more at any time during 
treatment will be summarized for each symptom.  
Number of AE events/ 
observed AE incidence 
95% Clopper Pearson  
Confidence Interval 
12 (1%) 
0.5% – 2% 
24 (2%) 
1.3% – 3.0%  
60 (5%) 
3.8% – 6.4% 
120 (10%) 
8.4% – 11.8% 
240 (20%) 
17.8% – 22.4% 
360 (30%) 
27.4% – 32.7% 
Synopsis Table 1. Clopper-Pearson 95% Confidence Intervals for the observed AE 
incidence1 
1 Total number of patients is 1200 
nn-La Roche Ltd 
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Table 1 
Schedule of Assessments 
 
 
Screenin
g / 
Baseline 
Treatment Phase1
(Allowed Visit Window +/- 3 days from Cycle 2 onwards) 
End of 
Treatment 
Visit2
Safety Follow-Up Visits3
(1 month, 3 months, 6 months, 
9 months, 12 months after the 
last dose of vismodegib 
(GDC-0499) 
Cycle 
 
1 
2 
3 
4 
5 
6 
7 
8 onwards 
 
 
Day 
–28 to –1 
1 
29 
57 
85 
113 
141 
169 
Every 28 Days 
 
 
Informed Consent4
X 
 
 
 
 
 
 
 
 
 
 
Archival Tumor Tissue5
X 
 
 
 
 
 
 
 
 
 
 
Medical History and Demographics6
X 
 
 
 
 
 
 
 
 
 
 
Complete Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examination7
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height8 and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs9  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
As clinically indicated 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X10
X 
X 
X 
X 
X 
X 
X 
X 
X (if clinically indicated) 
Biochemistry 
X 
X10
X 
X 
X 
X 
X 
X 
X 
X 
X (if clinically indicated) 
Record Date of Last Menses11
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test12
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Hormone Evaluation13
X 
As clinically indicated 
As clinically 
indicated 
As clinically indicated 
Steady-state and post-treatment 
pharmacokinetic collection of blood 
(AT SELECTED SITES ONLY)24
 
 
One collection while taking vismodegib for at least 
2 weeks continuously 
 
At 3, 6, 9, and 12 Months 
ONLY 
QoL Assessments using Skindex-16  
(in selected sites) 
X 
 
X 
 
 
 
 
X 
 
X 
 
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Table 1 
Schedule of Assessments (cont.)  
 
 
Screenin
g / 
Baseline 
Treatment Phase1
(Allowed Visit Window +/- 3 days from Cycle 2 onwards) 
End of 
Treatment 
Visit2
Safety Follow-Up Visits3
(1 month, 3 months, 6 months, 
9 months, 12 months after the 
last dose of vismodegib 
(GDC-0499) 
Cycle 
 
1 
2 
3 
4 
5 
6 
7 
8 onwards 
 
 
Day 
–28 to –1 
1 
29 
57 
85 
113 
141 
169 
Every 28 Days 
 
 
Symptom Assessment using MDASI 14
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor Assessments (physical 
examination)15, 17
X 
Every 4 to 8 weeks from the time of the first dose (±5 days) regardless of 
dosing delays.   
X 
 
Tumor Assessments (by imaging 
techniques, if required)16, 17 
X 
Every 8 to 16 weeks from the time of the first dose (±5 days) regardless 
of dosing delays or as per institutional standards 
In metastatic BCC patients (newly enrolled after approval of the Study 
Protocol, version 4.0), every 8 weeks from time of first dose (±5 days) 
regardless of dosing delay  
X 
 
AEs / SAEs18
X 
X 
X 
X 
AE-related pharmacokinetic collection 
of blood (AT SELECTED SITES 
ONLY) 25
 
 
 
At 6, 9, and 12 Months 
ONLY 
Ultrasound19
X 
As clinically indicated 
As clinically 
indicated 
As clinically indicated 
Follow-up for disease progression  
 
X 
X 
X 
Tumor biopsy and collection of whole 
blood 20
 
 
X 
 
Concomitant medication 
X21
X 
X 
X 
New anti-cancer therapy 
 
 
X 
X 
Drug Dispensing 
 
X (first day of each Cycle) 
 
 
Drug Accountability22
Drug Dosing Exception Diary23
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Table 1 
Schedule of Assessments (cont.)  
Notes   Results of screening tests or examination performed as standard of care before obtaining informed consent and within the specified interval may be used rather than 
repeating required evaluation.  Day 1 = first dose of study drug vismodegib. 
1. 
Visits during the treatment period are to be completed on Day 1 of every 28-Day Cycle. 
2. 
End of Treatment Visit will be performed when the patient discontinues vismodegib regardless of when it occurs. 
3. 
Safety Follow-Up Visit is to be performed approximately (+/- 5 days) 1 month, 3 months, 6 months, 9 months, and 12 months after the last dose of vismodegib. 
4. 
Written, signed informed consent must be obtained prior to perform any study procedure including screening/baseline assessments. 
5. 
Archival tumor tissue from a metastatic BCC site will be collected in metastatic BCC patients (who are on study after approval of the Study Protocol, version 4.0).   
6. 
In women of childbearing potential, also record any amenorrhea/irregular menses, relevant gynecologic medical history, and concurrent gynecologic conditions.  In metastatic 
BCC patients who are on study after approval of Study Protocol, version 4.0, record evidence of disease progression prior to enrollment on study and reasons for treatment 
discontinuation of any prior metastatic BCC therapy.  
7. 
A limited physical examination should focus on organ systems that are related to a potential AE as suggested by a patient’s interim medical history and/or existing clinical and 
preclinical data for vismodegib. 
8. 
Height is only measured at screening. 
9. 
Includes body temperature, blood pressure, and pulse. 
10. Hematology and biochemistry assessments do not need to be repeated on Day 1 if performed within 7 days of first vismodegib administration.  NB: if it is necessary to repeat 
these blood tests, the results must be known before the patient receives first dose of vismodegib (to ensure inclusion/exclusion criteria related to these tests are met). 
11. In women of childbearing potential ONLY. 
12. For women of childbearing potential, including those who have had a tubal ligation.  A serum pregnancy test is required within 7 days prior to first dose of vismodegib and 
urine pregnancy tests should be performed on Day 1 of each subsequent Cycle.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
13. For women of childbearing potential ONLY.  To be performed at local laboratory.  Includes FSH, TSH, LH and E2.  Perform at Screening and at start of amenorrhea/irregular 
menses and at resolution of amenorrhea/irregular menses.  If amenorrhea/irregular menses recurs, repeat evaluations at start of recurrence as detailed previously.  
14. M.D. Anderson Symptom Inventory (MDASI) will be completed by metastatic BCC patients (newly enrolled after approval of Study Protocol, version 4.0), prior to having any 
assessments performed at each visit. 
15. Tumor assessments for patients with measurable disease (the majority of the patients in this study have locally advanced BCC and in this disease setting measurable tumors 
are accessible to evaluation by physical examination) should be performed at screening within a maximum of 7 days prior to the first dose of study drug (baseline reading), 
and then every 4-8 weeks from the time of the first dose (±5 days) regardless of dosing delays until the end of treatment.  In case of clinically measurable superficial (such as 
skin) lesions, repeated photographs should be used to document tumor response, these photos must include a ruler for documentation purposes.  Objective responses using 
RECIST should be confirmed by repeat assessments at least 4 weeks after initial documentation of response. 
16. Tumor assessments for patients with measurable disease (requiring imaging method) should be performed at screening; baseline CT/MRI scans should be performed within a 
maximum of 28 days prior to the first dose of study drug (Cycle 1, Day 1), and then every 8 to 16 weeks from the time of the first dose (±5 days) regardless of dosing delays as 
per institution standard of care thereafter but at a minimum every 16 weeks and at the end of the study.  The same imaging method(s) must be used for a patient throughout 
the study.  The same radiographic procedure used to define measurable disease sites at baseline must be used throughout the study (e.g. the same contrast protocol for CT 
scans). Objective responses using RECIST should be confirmed by repeat assessments at least 4 weeks after initial documentation of response.  In metastatic BCC patients 
(enrolled after approval of the Study Protocol, version 4.0), tumor assessments should be performed at screening; baseline CT/MRI scans should be performed within a 
maximum of 28 days prior to the first dose of study drug (Cycle 1, Day 1), and then every 8 weeks from time of first dose (±5 days) regardless of dosing delay. 


 
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Table 1 
Schedule of Assessments (cont.)  
17. Non- measurable disease should be assessed within 28 days prior to study initiation, and thereafter as clinically indicated and in accordance with standard clinical practice. 
For metastatic patients assessment of non-measurable disease should be according to RECIST version 1.1.  
18. AEs will be collected on Day 1 of each Cycle and at the follow-up or early termination visit.  After informed consent, but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected.  All AEs (either related to study specific procedures or otherwise) experienced after the patient has signed the 
Informed Consent form but before they have received study treatment, should be recorded as medical history.  All AEs experienced after the patient has started study 
treatment must be recorded on the AE form of the eCRF, as well as all new AEs experienced during the study and up to 1 month, 3 months, 6 months, 9 months, 12 months 
after the last dose of study treatment (± 5 days).  Additionally, non-serious, new AEs considered related to study drug which occur approximately (+/- 5 days) 1 month, 
3 months, 6 months, 9 months, 12 months after the last dose of study drug should also be reported.  SAEs considered related to study drug should be reported indefinitely. 
19. In women of childbearing potential ONLY.  At start of amenorrhea/irregular menses, refer to gynecologist or appropriate specialist for assessment of ovaries and uterus, 
including ultrasound.  At resolution of amenorrhea/irregular menses, refer to gynecologist or appropriate specialist for follow-up ultrasound ONLY if there was abnormality 
identified during previous ultrasound.  If amenorrhea/irregular menses recurs, repeat evaluations at start of recurrence as detailed previously.  Obtain copy of results from 
ultrasound and enter any abnormal findings into the CRF. 
20. In metastatic BCC patients who develop tumor progression on vismodegib treatment, a biopsy will be performed if at least one of the progressing lesions is accessible, 
e.g., skin, superficial mass, or lymph node and a whole blood sample will be collected. 
21. All concomitant medications used within 14 days before study treatment and up to the end of treatment and approximately (± 5 days) 1 month, 3 months, 6 months, 9 months, 
and 12 months after the last dose of vismodegib at the Safety Follow-Up Visit must be recorded. 
22. Study drug vismodegib accountability will be performed at every study visit from Cycle 2 onwards and at the End of Treatment Visit. 
23. Patients will keep a diary to record ONLY those occasions when a vismodegib dose was missed.  The patient will bring this diary with him/her to each study visit to allow 
missed doses to be recorded by the Investigator. 
24. A total of 30 patients will have blood collected for steady-state and post-treatment pharmacokinetic testing.  
25. Collect blood if any adverse events that were reported to be related to vismodegib treatment continue to be present at least 6 months after the last dose of vismodegib.  Blood 
samples for the adverse event-related PK testing will be collected at the 6, 9, and 12 months Safety Follow-Up Visits even if the adverse event resolves after the 6 months 
Safety Follow-Up Visit.  
 


 
GLOSSARY OF ABBREVIATIONS 
AAG 
alpha 1 acid glycoprotein 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase 
AST (SGOT) 
aspartate aminotransferase 
AUC 
area under the curve 
BCC 
basal cell carcinoma 
BP 
blood pressure 
BORR 
best overall response rate 
ºC 
degrees Celsius 
CI 
confidence interval 
Cmax
maximum concentration 
CR 
complete response 
eCRF 
electronic Case Report Form 
CT 
computer tomography 
DDI 
drug-drug interaction 
DSMB 
Data Safety Monitoring Board 
E2 
Estradiol 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
Electronic Data Capture 
ESF 
Eligibility Screening Form 
EU 
European Union 
F 
Fahrenheit 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
Hh 
Hedgehog 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product  
IRF 
Independent Review Facility 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ITT 
intent to treat 
KM 
Kaplan-Meier 
LH 
Luteinizing hormone 
MDASI 
M.D. Anderson Symptom Inventory 
MRI 
magnetic resonance image 
mm 
millimeter 
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NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse 
Events 
ORR 
objective response rate 
OS 
overall survival 
P-gp 
P-glycoprotein 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
 
 
PR 
partial response 
QoL 
Quality of Life 
RECIST, v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
SAE 
serious adverse event 
SD 
stable disease 
SMO 
smoothened 
SOC 
system organ class 
SUSAR 
Suspected Unexpected Serious Adverse Events Reactions 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US FDA 
United States Food and Drug Administration 
USP/NF 
United States Pharmacopeia/National Formulary  
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PART I: STUDY DESIGN AND CONDUCT 
1. 
BACKGROUND, RATIONALE, AND BENEFIT-RISK 
1.1 
BACKGROUND 
1.1.1 
Advanced Basal Cell Carcinoma 
Basal cell carcinoma (BCC) is the most common malignancy; for example, of the more 
than 1 million cases of non-melanoma skin cancer reported in the United States in 2007, 
approximately 80% are BCC (1-3).  Almost all of these cases are small BCCs that can 
be effectively treated by dermatologists using several surgical modalities.  However, in a 
small 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 is no approved 
therapy and no standard of care exists.  Although palliative radiation therapy may be 
used, its use may be limited by the location of the tumor and the involved structures, as 
well as prior cumulative radiation dosage.  Locally advanced BCC 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 
(4, 5). 
Metastatic BCC is extremely rare, with a reported metastasis rate ranging from 
0.0028% to 0.55%; most believe the true metastasis rate to be significantly less than 
0.1% (6).  A total of approximately 300 cases of metastatic BCC have been reported in 
the literature.  The most common sites of metastasis are the lymph nodes, lung, bone, 
liver, other viscera, and soft tissue (7).  Once metastasis is detected, survival can be 
short for some patients, with a range of 8 to 14 months reported by some Investigators.  
However, a 5-year survival rate of approximately 10% has also been reported, and 
individual patients have been reported to live for as many as 25 years with metastatic 
disease (8-10).  No standard therapy for metastatic BCC exists, although there is 
anecdotal use of chemotherapeutic agents such as platinum compounds (11). 
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 (12).  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 GLI transcription factors and induction of Hh target 
genes, many of which are involved in proliferation, survival, and differentiation.  
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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 led to ligand-independent activation of SMO and constitutive activity of the Hh 
pathway (13).  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 (14, 15).  Two mutations commonly found in BCC result from either the inactivation 
of the PTCH1 receptor or the activation of SMO protein (16).  Both have the same 
functional consequence, i.e., the uncontrolled activation of the Hh signaling pathway in 
the absence of the Hh protein.  High expression levels of Hh target genes, such as GLI1 
and PTCH1, are found in nearly all cases of human BCC examined (17, 18), suggesting 
that activation of this pathway is a causal event 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 (19). 
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 (20).  Cyclopamine, a steroidal alkaloid isolated from 
this plant, was shown to induce midline deformities, including cyclopia, by blocking 
SMO signaling in the developing lamb fetuses (21).  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 (22, 23). 
1.1.2 
Vismodegib 
Vismodegib (also known as GDC-0449) is a small molecule antagonist of the Hh 
signaling 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 binds to and inhibits SMO, thereby preventing the Hh signal.  Vismodegib 
has proven to be efficacious in nonclinical tumor models of both mutated and 
ligand-overexpressing tumors. 
1.1.2.1 
Vismodegib Pharmacokinetics 
The pharmacokinetics of vismodegib was evaluated in multiple clinical studies in patients 
with advanced solid tumors, advanced basal cell carcinoma (BCC), and in healthy 
volunteers. 
1.1.2.1.1 
Single and Multiple Dose Pharmacokinetics 
After a single oral dose, vismodegib demonstrates a unique pharmacokinetic (PK) profile 
with high, sustained plasma levels and an estimated terminal half-life of 12 days.  
Parallel concentration−time profiles are observed in the terminal elimination phase 
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following oral and intravenous (IV) dosing, indicative of elimination rate-limited 
pharmacokinetics. 
After continuous once-daily dosing, steady-state plasma concentrations in patients are 
typically achieved within approximately 7 days of continuous daily dosing.  Increasing 
the daily dose from 150 mg to 270 or 540 mg does not result in higher steady-state 
plasma concentrations. 
1.1.2.1.2 
Absorption 
Vismodegib is a highly permeable compound with low aqueous solubility 
(Biopharmaceutics Classification System Class 2).  The single-dose absolute 
bioavailability of vismodegib is 31.8%.  Under clinically relevant conditions (steady-
state), the pharmacokinetics of vismodegib is not affected by food (see the Investigator’s 
Brochure). 
1.1.2.1.3 
Distribution 
The single-dose volume of distribution for vismodegib is 16.4 L and it increases 
(62% higher relative to single dose) with continuous daily dosing.  In vitro binding of 
vismodegib to human plasma proteins is high (97%) and independent of vismodegib 
concentrations at clinically relevant levels.  Vismodegib binds to both human serum 
albumin (HSA) and α-1-acid glycoprotein (AAG).  In vitro binding to AAG is saturable at 
concentrations > 25 μM.  Ex vivo plasma protein binding in humans is  > 99%.  
Vismodegib concentrations are strongly correlated with AAG levels, showing parallel 
fluctuations of AAG and total drug over time and consistently low unbound drug levels. 
1.1.2.1.4 
Metabolism 
Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and 
uncommon pyridine ring cleavage.  The major oxidative metabolite recovered in feces 
(M3) is produced by recombinant cytochrome P450 (CYP) 2C9 and to a lesser extent by 
CYP3A4/5, while another oxidative metabolite (M1) is formed primarily by recombinant 
CYP3A4/5.  However, multiple isoforms are capable of forming both metabolites.  These 
findings indicate that vismodegib and any associated metabolic products are eliminated 
primarily by the hepatic route.  Vismodegib is predominantly found in plasma, with 
concentrations representing greater than 98% of the total circulating drug-related 
components. 
1.1.2.1.5 
Excretion 
After oral administration of radiolabeled drug, vismodegib is absorbed and slowly 
eliminated by a combination of metabolism and excretion of parent drug, the majority of 
which is recovered in the feces (82% of the administered dose), with 4.4% of the 
administered dose recovered in urine. 
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1.1.2.1.6 
Nonlinear Pharmacokinetics of Vismodegib 
The pharmacokinetics of vismodegib are characterized by less than dose proportional 
increases in plasma concentration with increasing dose and lower than expected 
accumulation after continuous daily dosing; these observations are suggestive of 
nonlinear pharmacokinetics. 
The nonlinear pharmacokinetics of vismodegib result from two separate, nonlinear 
processes: 1) saturable absorption; and 2) high-affinity, saturable protein binding.  
Nonlinear absorption is consistent with the poor solubility of vismodegib at physiologic 
pH and likely resulted in a lack of dose-proportional increase in exposure after a single 
dose of 270 and 540 mg vismodegib.  The more clinically relevant nonlinear process for 
vismodegib is saturable binding to alpha-1-acid glycoprotein, which results in 
concentration-dependent changes in the pharmacokinetics of vismodegib. 
Following intravenous (IV) administration at oral steady-state, mean vismodegib CL and 
volume of distribution increase > 50%, suggestive of concentration-dependent changes 
in pharmacokinetics.  The fraction unbound of vismodegib increases approximately 
3-fold after once-daily dosing relative to a single dose, which can account for the 
increase in vismodegib CL and volume of distribution after repeated dosing.  With less 
frequent dosing of 150 mg vismodegib (three times a week [TIW] or once a week [QW]), 
total plasma vismodegib levels decrease in a less-than-dose-proportional fashion as 
compared with once-daily dosing, consistent with nonlinear pharmacokinetics.  The 
decrease in unbound plasma vismodegib concentrations with less frequent dosing is 
more pronounced than for total drug and is proportional to the decrease in weekly dose 
amount. 
1.1.2.1.7 
Population Pharmacokinetics 
The population PK analysis suggests that vismodegib pharmacokinetics at the clinical 
dose range can be adequately described by a one-compartment model with first-order 
absorption, first-order elimination (of unbound), and saturable binding to AAG with fast 
equilibrium.  Overall, vismodegib pharmacokinetics are highly dependent on AAG 
concentration.  None of the other covariates evaluated showed clinically relevant impact 
on steady-state vismodegib concentration.  Sex, body mass index, baseline tumor 
burden, albumin, creatinine clearance, and hepatic function (alanine aminotransferase 
[ALT], aspartate aminotransferase [AST], total protein, and total bilirubin) did not appear 
to affect the pharmacokinetics of vismodegib.  Age and body weight were identified as 
statistically significant covariates for the vismodegib disposition (unbound clearance and 
volume of distribution, respectively), but sensitivity analysis suggested that neither of 
these effects had a clinically significant impact on vismodegib concentration at 
steady-state.  Patients with cancer showed slower drug absorption (lower ka) than 
healthy volunteers, but with no significant impact on vismodegib exposure at steady 
state. 
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No clinically relevant exposure-response relationship was observed for the most 
frequently reported adverse events of weight loss, alopecia, dysgeusia, fatigue, muscle 
spasms, or nausea.  Furthermore, there was no evidence of an effect of vismodegib 
plasma concentration on QTc interval prolongation. 
1.1.2.2 
Clinical Development Program in BCC 
1.1.2.2.1 
Study SHH3925g 
Study SHH3925g was an open-label, multicenter, two-stage phase I trial to evaluate the 
safety and tolerability of vismodegib in patients with a variety of solid tumors who were 
refractory to standard therapy (24).  In total, 68 patients enrolled in the study at three 
centers, of whom 33 had advanced BCC.  This study was closed in November 2009. 
Enrollment in this study occurred in two stages.  Stage 1 of the trial, the dose escalation 
portion of the study, was designed to estimate the safety, tolerability, pharmacokinetics, 
pharmacodynamics, and maximum tolerated dose of vismodegib.  Patients received a 
single oral dose of vismodegib on Day 1, followed by a 7-day PK observation period, 
then daily administration at the same dose beginning on Day 8.  Seven patients were 
assigned to receive 150 mg per day, nine patients 270 mg per day, and four patients 
540 mg per day; each dose cohort included one patient with advanced BCC.  No 
dose-limiting toxic effects were observed.  On the basis of this study, the recommended 
phase II dose was set at 150 mg per day because PK analyses indicated that doses 
greater than this did not result in higher plasma concentrations of the drug. 
Stage 2 of the study included an expansion cohort that received the recommended 
phase II dose, with the goal of obtaining additional information on PK and safety; 
12 patients (none with advanced BCC) enrolled in this cohort, and all received 
150 mg per day.  The study was amended to include two further cohorts in Stage 2.  The 
first of these cohorts was added because of evidence of clinical benefit in two patients 
with advanced BCC during Stage 1; this cohort consisted of 20 patients with advanced 
BCC, who were treated with 150 mg per day or 270 mg per day (with the dose chosen 
on the basis of drug availability) to evaluate the activity and safety of vismodegib in this 
population.  The second additional cohort, which consisted of 16 patients with solid 
tumors (including 10 with advanced BCC), was added to investigate the PK properties of 
a new formulation of vismodegib at 150 mg per day.  In Stage 2, all patients received 
continuous daily administration of the drug beginning on Day 1 and were treated until 
disease progression, the occurrence of intolerable toxic effects, or withdrawal from the 
study. 
Between January 2007 and February 2010, 33 patients with locally advanced BCC or 
metastatic BCC enrolled in SHH3925g and received oral vismodegib: 17 patients 
received 150 mg per day, 15 patients received 270 mg per day, and one patient received 
540 mg per day.  Of these 33 patients, 19 had an objective response (OR) to vismodegib, 
according to assessment on imaging (seven patients), physical examination 
(ten patients), or both (one patient).  Of the patients who had a response, two had a 
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complete response (CR) and 17 had a partial response (PR).  The other 14 patients had 
either stable disease (SD; 10 patients) or progressive disease (PD; four patients).  As of 
the data cutoff date (February 25th, 2010), the Kaplan–Meier estimate of the median time 
of participation in the study was 11.2 months and ongoing, and the median duration of 
response was 12.8 months and ongoing.  At the time of study closure, 12 of 33 BCC 
patients had been on study for durations of 8.5 to 26.5 months.  These 12 patients were 
enrolled onto the extension study SHH4437g to continue receiving vismodegib. 
Of the 15 patients with locally advanced tumors, 13 were assessed on physical 
examination (clinical response), and two with measurable disease were assessed by 
imaging using the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST, v1.1).  Of these 15 patients, two had a complete clinical response, and seven 
had a partial clinical response; four patients had SD as the best response, with a 
duration of participation in the study ranging from 2.1 to 19.0 months; two of the patients 
had PD.  Overall, the response rate in patients with locally advanced tumors was 
60% (95% confidence interval [CI], 33% to 83%). 
Of the 18 patients with metastatic tumors, 15 had radiologically measurable disease, and 
seven of these patients had a PR, as assessed on imaging only (with six responses 
confirmed and one unconfirmed at the time of the data cutoff).  Two other patients with 
metastatic tumors had PRs, one assessed on both imaging and physical examination 
and the other on physical examination only.  Seven patients with metastatic tumors had 
SD (with six patients assessed with the use of RECIST, v1.1 and one on physical 
examination), and two had PD as the best response.  The overall response rate (ORR) 
among the 18 patients with metastatic tumors was 50% (95% CI, 29–71%). 
Eleven Grade 3 AEs that were deemed to be possibly related to the study drug were 
reported in six patients with advanced BCC, including five with fatigue, three with 
hyponatremia, one with muscle spasm, one with weight loss, and one with atrial 
fibrillation.  In addition, one episode of Grade 4 paranoia and one case of Grade 4 
pancreatic andenocarcinoma were considered to be related to vismodegib.  One 
Grade 4 event, asymptomatic hyponatremia, was judged to be unrelated to vismodegib.  
One patient withdrew from the study because of AEs. 
1.1.2.2.2 
ERIVANCE BCC (SHH4476g) 
ERIVANCE BCC (SHH4476g) was a pivotal, phase II, single-arm, multicenter, 
open-label trial evaluating the efficacy and safety of vismodegib in patients 18 years of 
age or older with advanced BCC (25).  The trial included two cohorts: 1) patients with 
histologically-confirmed locally advanced BCC that was either unresectable or 
inappropriate for surgery; and 2) patients with metastatic BCC with 
histologically-confirmed and radiographically-measurable disease.  Patients in the trial 
received 150 mg of oral vismodegib once-daily until evidence of progression, intolerable 
toxicities most probably attributable to vismodegib, or withdrawal from the study.  One 
hundred and four patients enrolled at 34 study sites in the United States, England, 
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France, Germany, Belgium, and Australia.  Ninety six were evaluable for efficacy, of 
whom 63 (65.6%) had locally advanced and 33 (34.4%) had metastatic disease.  
In the cohort with locally advanced BCC, 27 patients responded for an ORR (primary 
efficacy variable) of 42.9% (95% CI, 30.5–56.0%; p<0.0001).  Twenty-four patients 
(38.1%) exhibited stable disease and 8 patients (12.7%) exhibited disease progression.  
The clinical benefit rate was 75% (defined as the percentage of patients experiencing an 
objective response prior to or after onset of progressive disease plus the percentage of 
patients who experienced stable disease lasting ≥ 24 weeks).  Median duration of 
response and PFS were 7.6 and 9.5 months, respectively.  The median duration of 
therapy was 9.7 months (range, 1.1–18.7 months), with 45.1% of patients remaining on 
treatment as of the data cutoff date, which occurred 9 months after the last patient had 
enrolled. 
In the cohort with metastatic BCC, 10 patients responded to therapy for an ORR 
of 30.3% (95% CI, 15.6–48.2%; p=0.0011).  Twenty-one patients (63.6%) exhibited 
stable disease and 1 patient (3.0%) exhibited disease progression.  The clinical benefit 
rate was 76%.  Median duration of response and PFS were again 7.6 and 9.5 months.  
Finally, the median duration of therapy was 10.0 months (range, 0.7–16.4 months), 
with 57.6% of patients remaining on treatment as of the data cutoff date. 
The most common AEs were muscle spasms (68%), alopecia (64%), dysgeusia (51%), 
weight loss (46%), fatigue (36%), nausea (29%), decreased appetite (23%), and 
diarrhea (22%); the large majority of these events were mild to moderate in intensity.  
Serious AEs were reported in 26 patients (25%), 4 (4%) of whom experienced SAEs 
possibly related to vismodegib administration (cholestasis [n=1], pulmonary embolism 
[n=1], syncope [n=1], and cardiac failure and pneumonia [n=1]).  Fatal AEs were 
reported in 7 patients (7%; unknown cause [n=3], acute myocardial infarction [n=1], 
ischemic stroke [n=1], meningeal disorder [n=1], and hypovolemic shock [n=1]).  In all 
patients who died on study, pre-existing risk factors and comorbid conditions had been 
present (30, 31).  
1.2 
RATIONALE FOR THE STUDY  
Surgery cures most cases of BCC, but a few patients may exhibit progression to 
life-threatening, unresectable, locally advanced disease or metastatic tumors 
(5, 6, 11, 26).  There is no standard therapy for locally advanced or metastatic BCC and, 
consequently, opportunities remain to improve outcomes for these patients. 
In the Phase I study SHH3925g, a tumor response to vismodegib was observed in 
> 50% of patients with advanced BCC.  Thus, of 33 patients with locally advanced or 
metastatic tumors, 18 had an OR to vismodegib.  Of the remaining 15 patients, 11 had 
SD for up to 10.8 months and 4 had PD.  There were no dose-limiting toxic effects or 
Grade 5 AEs, and only one Grade 4 AE occurred during continuous daily administration 
of vismodegib for up to 19 months. 
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The encouraging results from the Phase I study have generated significant interest and 
increased demand for access to vismodegib because of the unmet medical need in this 
patient population.  However, since ERIVANCE BCC (SHH4476g) is now closed, no 
clinical studies of vismodegib are currently open to patients with advanced BCC.  
Therefore, because patients with advanced BCC do not have satisfactory therapeutic 
options, and because there is a need to establish a broader safety evidence for 
vismodegib when given to patients with locally advanced or metastatic BCC, this phase 
II study will enroll patients who qualify as having an unmet medical need.  The study is 
expected to enroll approximately 1200 patients over an approximately 3.5-year period 
and will continue enrollment until such time as vismodegib becomes commercially 
available for this patient population.  
1.3 
BENEFIT-RISK  
Potential Benefits of the Study 
In general terms, the key benefit from this study will be an increase in our knowledge 
base for vismodegib.  In particular, with its focus on safety (the primary objective), the 
trial should provide new data that can be used in future studies to optimize safe 
administration of vismodegib.  Other analyses described in this protocol will serve to test 
the reproducibility of prior safety and efficacy results and to add new information on 
patient QoL. 
Significant potential benefit is also expected to accrue to patients who enroll in the study.  
As described in earlier sections, locally advanced BCC can be associated with 
significant morbidity as a result of chronic pain, bacterial infection and sepsis, 
bleeding/oozing, and/or compromise of function; moreover, in some cases, death can 
result from local invasion of critical organs, such as the meninges, brain, and spinal cord 
(4, 5).  Metastatic BCC also has a grim prognosis, with a median survival estimated by 
some investigators to be only 8 to 14 months (8).  For patients lacking other therapeutic 
options, vismodegib may provide substantial utility as an anti-cancer agent of last resort, 
given its encouraging efficacy results in previous clinical trials.  
Potential Risks of the Study 
An important risk associated with this study, as with any clinical trial, is the potential 
enrollment of inappropriate patients.  Minimization of this risk has been attempted via 
judicious choice of inclusion and exclusion criteria.  Thus, for patients with locally 
advanced BCC, disease must be histologically confirmed and enrollees must have 
exhausted all other therapeutic options, i.e., only patients who are contraindicated for 
surgery and have undergone previous radiotherapy (or are inappropriate for 
radiotherapy) are eligible.  Similarly, for those patients with metastatic disease, 
histological confirmation of distant metastasis is required.  
As is true of any investigational agent, vismodegib may pose some safety risks for 
patients participating in the trial.  These risks will be managed by careful monitoring of 
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AEs and laboratory tests throughout the study period.  In addition, an independent Data 
Safety Monitoring Board (DSMB) will be established that will be responsible for 
monitoring patient safety data during the course of the study (see Section 10). 
Finally, small-molecule inhibitors of the Hedgehog pathway are known teratogens that 
result in midline malformations and other severe developmental defects in mammalian 
model systems (see the Vismodegib Investigator Brochure).  Consequently, to be 
eligible for this trial, female patients of childbearing potential must use two methods of 
acceptable contraception, including one highly effective means of contraception and one 
barrier method during treatment and for at least 9 months or as per approved local 
prescribing information for vismodegib (where available), whichever is longer,  after 
completion of treatment.  Fertile male patients must utilize a condom with spermicide 
(where available), even if he has had a vasectomy, during treatment.  Additionally, 
female patients must exhibit negative serum pregnancy tests within 7 days prior to 
dosing and throughout the trial.  After discontinuing treatment, female patients of 
childbearing potential must continue to use an effective method of contraception for at 
least 9 months or as per approved local prescribing information for vismodegib (where 
available), whichever is longer.  Acceptable contraception and duration of contraceptive 
use should comply with locally approved vismodegib (Erivedge®, the trade name for 
vismodegib) Pregnancy Prevention Program or prescribing information where 
vismodegib is commercially available. 
With these risk mitigation safeguards in place, the potential benefits of the study 
(see previous section) encourage moving ahead with the trial. 
2. 
OBJECTIVES  
2.1 
PRIMARY OBJECTIVE 
To assess the safety of vismodegib in patients with locally advanced or metastatic BCC 
2.2 
SECONDARY OBJECTIVES 
• 
To assess the overall response rate (ORR; according to RECIST, v1.1) in those 
patients with measurable disease, as permitted by local regulatory requirement 
• 
To assess other efficacy parameters, such as time to response, duration of 
response, progression-free survival (PFS), and overall survival (OS) 
• 
To assess patient quality of life (QoL) (Skindex-16) 
• 
To assess the impact of vismodegib treatment on disease symptoms in patients with 
metastatic BCC who enrolled after approval of the Study Protocol, version 4.0, using 
the M.D. Anderson Symptom Inventory (MDASI) 
2.3 
EXPLORATORY OBJECTIVES 
• 
To assess the status of the Hh pathway and/or other modifiers of vismodegib activity 
in tumor tissue obtained from patients with metastatic BCC who have disease 
progression on vismodegib therapy 
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• 
To determine the post-treatment exposure of vismodegib in patients with adverse 
events that were reported to be related to vismodegib treatment and that are 
continuing at least 6 months after the last dose of vismodegib  
• 
To determine the post-treatment exposure of vismodegib in patients following daily 
oral dosing with 150 mg vismodegib for at least 2 weeks of consecutive dosing 
(steady-state exposure) and at 3, 6, 9, and 12 months after the last dose of 
vismodegib 
 
3. 
STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN 
This is an open-label, non-comparative, multicenter, phase II study of vismodegib in 
patients with locally advanced BCC or metastatic BCC who are otherwise without 
satisfactory treatment options. 
The study population will consist of male or female patients at least 18 years of age with 
histologically confirmed diagnoses of locally advanced BCC or metastatic BCC.  For 
patients with locally advanced BCC, the treating physician must consider the disease to 
be inoperable or there must be a clinical contraindication to surgery; furthermore, 
radiotherapy must have been previously administered (unless radiotherapy is 
contraindicated or inappropriate) and disease must have progressed after irradiation.  
For patients with suspected metastatic BCC, distant metastases must be histologically 
confirmed to be of basal cell origin.  Patients are eligible for enrollment in this trial with 
measurable and/or non-measurable disease, as defined by RECIST, v1.1. 
Enrolled patients will receive continuous once-daily oral dosing of vismodegib at a 
dosage of 150 mg per administration.  One cycle of therapy will be defined as 28 days of 
treatment.  All patients will receive study drug until the development of PD (as 
determined by the Investigator), unacceptable toxicity, consent withdrawal, death, 
reasons deemed by the treating physician, or study termination by the Sponsor.  Dose 
reduction of vismodegib is not permitted, as there is only a 150-mg capsule strength 
available.  Temporary discontinuation of drug for up to 8 weeks is allowed.  Temporary 
discontinuation longer than 8 weeks must be discussed with the Roche Medical Monitor 
or his/her designee.  
The trial will consist of a Screening Period (Day –28 to –1), a Treatment Phase, an End 
of Treatment Visit when the patient received the last dose of vismodegib and thereafter 
discontinues vismodegib (regardless of when it occurs), and five Safety Follow-Up Visits 
1 month, 3 months, 6 months, 9 months and 12 months after the last dose of vismodegib 
(± 5 days), as provided by this phase II safety study protocol.  Day 1 of the study will be 
defined as the first day a patient receives vismodegib.  During the Treatment Phase, all 
study assessments will be conducted on Day 1 (± 3 days, from Cycle 2 onwards) of 
each Cycle with the exception of computed tomography (CT) and/or magnetic resonance 
imaging (MRI) for tumor evaluation, which should occur every 8 to 16 weeks or as per 
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institutional standards (see below).  For a list of study assessments, see the Study 
Flowchart (Table 1. Schedule of Assessments). 
Assessment of safety, the primary objective of this trial, will occur by examining the 
incidence, type, and severity of AEs; the incidence and nature of serious AEs (SAEs); 
the incidence of AEs leading to vismodegib discontinuation or interruption; and the 
cause of death on study (if not linked to disease progression). 
The pharmacokinetics of vismodegib will be assessed in an exploratory manner at 
selected sites.  Adverse event-related PK testing will be performed on patients having 
any adverse events that were reported as being related to vismodegib treatment and 
that continued for at least 6 months after the last dose of vismodegib.  This PK sample 
collection will occur at 6 months, 9 months, and 12 months after the last dose of 
vismodegib (± 5 days).  In addition, post-treatment PK testing will be performed on 
30 patients to further characterize the post-treatment elimination of vismodegib from 
steady-state exposure to 12 months after the last dose of vismodegib, with PK sample 
collection occurring at 3 months, 6 months, 9 months, and 12 months after the last dose 
of vismodegib (± 5 days).   
Efficacy will be assessed according to RECIST, v1.1.  Measurable tumors accessible to 
evaluation by physical examination should be assessed within a maximum of 7 days 
prior to the first dose of study drug (baseline reading) and every 4 to 8 weeks thereafter.  
If assessment requires imaging, baseline CT and/or MRI should be performed within a 
maximum of 28 days prior to the first dose of study drug and, if such scans demonstrate 
evidence of disease, follow-up imaging studies (CT and/or MRI) should be performed 
every 8 to 16 weeks or as per institutional standards from the time of the first dose, 
regardless of dosing delays.  Other imaging techniques may be performed as clinically 
indicated, but should not be used for determining tumor response.  Objective responses 
using RECIST, v1.1 should be confirmed by repeat assessments at least 4 weeks after 
initial documentation of response.  
In metastatic BCC patients (newly enrolled after approval of the Study Protocol, 
version 4.0), imaging at baseline (CT and/or MRI scan) should be performed within a 
maximum of 28 days before the first dose.  Follow-up imaging studies (CT and/or 
MRI scan) should be performed every 8 weeks (± 5 days) from the time of the first dose, 
regardless of dosing delays.  The same imaging technique (CT or MRI) should be used 
for each patient throughout the study. 
Non-measurable disease should be assessed within 28 days prior to study initiation.  
Patients with non-measurable disease at baseline should be assessed for disease 
progression when clinically indicated and in accordance with standard clinical practice.  
For metastatic patients, assessment of non-measurable disease should be according to 
RECIST version 1.1. 
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In addition to safety and efficacy assessments, skin-related quality of life will be 
assessed at selected sites using the Skindex-16 questionnaire, a validated QoL 
instrument (27) that has been shown to be useful in patients with non-melanoma skin 
cancers, including BCC, although data in patients with higher-burden tumors are limited 
(28, 29).  In patients with metastatic BCC who have enrolled after approval of the Study 
Protocol, version 4, symptoms will also be assessed using the M.D. Anderson Symptom 
Inventory. 
Study enrollment will end in the European Union (EU) if vismodegib becomes 
commercially available after regulatory approval for the treatment of locally advanced or 
metastatic BCC.  Study enrollment will end successively in non-EU countries 
participating in this study if vismodegib becomes commercially available after regulatory 
approval for the treatment of locally advanced or metastatic BCC in the respective 
country.  However, patients already enrolled in this study and who are still benefitting 
from vismodegib, in the opinion of the Investigator, will continue to receive vismodegib 
as a study medication until the development of PD (as determined by the Investigator), 
unacceptable toxicity, consent withdrawal, death, reasons deemed by the treating 
physician or study termination by the Sponsor. 
It is anticipated that approximately 1200 patients will be enrolled over approximately 
3.5 years.  The study will end when the last patient enrolled in this study develops 
Progressive Disease (PD) (as determined by the Investigator), unacceptable toxicity, 
withdraws consent, dies, or the treating physician deems that patient is no longer 
benefitting from treatment or the study is terminated by the Sponsor, or 12 months after 
the last dose of vismodegib in the last enrolled patient still on study, whichever occurs 
first.  
The Sponsor reserves the right to end enrollment at any time.  If study enrollment is 
discontinued prior to commercial availability of vismodegib, patients already enrolled will 
be informed of the reason for discontinuation of study enrollment and, in the absence of 
a significant product safety concern or other circumstances, will be allowed to continue 
vismodegib until disease progression, unmanageable toxicity, withdrawal of consent, 
reasons deemed by the treating physician or death of the patient, whichever occurs first. 
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Treatment scheme:   
 
Screening 
Study Treatment Phase 
Safety Follow-Up 
Day –28 to –1 
Continuous once-daily oral dosing of vismodegib 
at a dosage of 150 mg per administration 
once-daily until one of the following occurs: 
disease progression, intolerable toxicity most 
probably attributable to vismodegib, consent 
withdrawal, death, study termination by the 
Sponsor, or other reason deemed by 
Investigator 
Five Safety 
Follow-Up 
Visits 1 month, 
3 months, 
6 months, 
9 months, and 
12 months after 
the last dose of 
vismodegib 
(± 5 days) 
 
 
 
 
3.1.1 
Rationale for Study Design 
The primary objective of this phase II study is to assess the safety of vismodegib in 
patients with locally advanced BCC or metastatic BCC.  The potential utility of 
vismodegib for treatment of advanced BCC was established in the phase I Study 
SHH3925g and phase II Study ERIVANCE BCC (SHH4476g), both of which 
demonstrated significant antitumor activity for vismodegib in this patient population 
(24, 25). 
Based on these results and still limited information about the safety profile of vismodegib 
in locally advanced or metastatic BCC (vismodegib has not been approved for use in this 
patient population), safety will be carefully assessed within a phase II study setting.  For 
patients with measurable disease and at least two tumor assessments during the study 
period, objective tumor response (according to RECIST, v1.1) will also be assessed, as 
permitted by local regulatory requirements. 
3.1.2 
Rationale for Dose Selection 
The recommended dose for vismodegib is 150 mg given orally on a continuous daily 
schedule.  It was chosen based on the SHH3925g study, which was an open-label, 
multicenter, two-stage phase I trial that evaluated the safety and tolerability of 
vismodegib in patients with a variety of solid tumors refractory to standard therapy (24).  
This dosing regimen was also used in ERIVANCE BCC (SHH4476g).   
3.1.3 
Rationale for Disease Symptom Assessment 
Disease-related symptoms associated with metastatic BCC and the impact of 
vismodegib treatment on disease-related symptoms are not well described.  To collect 
data addressing these questions, the M.D. Anderson Symptom Inventory will be used in 
metastatic BCC patients who were newly enrolled after approval of the Study Protocol, 
version 4. 
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3.1.4 
Rationale for Biomarker Assessments 
Despite the clinical benefit observed with vismodegib, a subset of advanced BCC 
patients who initially responded to vismodegib discontinue therapy due to disease 
progression, indicating potential resistance to vismodegib.  Acquired resistance to 
vismodegib has also been observed in a metastatic medulloblastoma patient who 
exhibited an initial response to therapy in a phase I study (35).  Efforts to understand the 
mechanism(s) underlying acquired resistance in preclinical models of Hh-driven 
medulloblastoma have led to the identification of mutations in SMO that impact 
vismodegib binding, as well as gene amplifications in downstream signaling components 
that bypass the effects of SMO inhibition with vismodegib (36).  However, no such 
molecular events have been observed to date in tissue obtained at progression from a 
limited number of advanced BCC patients treated with vismodegib.  Genotyping of tissue 
samples from patients with metastatic BCC, as they are most likely to progress while on 
treatment, could identify novel mechanisms that lead to vismodegib resistance and 
hence impact future approaches to overcome the development of resistance in BCC 
patients.  
 
 
 
 
 
 
 
 
 
 
3.1.5 
Rationale for Pharmacokinetic Assessments at Designated 
Investigative Sites 
Vismodegib is a teratogen and a threshold for plasma concentrations of vismodegib in 
patients has been established.  Currently available post-treatment discontinuation PK 
data for vismodegib is limited to 56 days.  Based on the elimination kinetics of 
vismodegib in plasma after treatment discontinuation, it is predicted that the vast 
majority of patients will have plasma concentrations below the threshold for 
teratogenicity after 7 months.  Notably, there is some uncertainty in this extrapolation, 
and until additional post-treatment discontinuation PK data are available, the duration for 
pregnancy prevention measures in female patients taking vismodegib has been 
prolonged to 24 months in the EU.  The PK data obtained from this study will be utilized 
to inform and possibly revise the current recommended duration for pregnancy 
prevention measures after discontinuation of vismodegib treatment. 
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Acceptable contraception and duration of contraceptive use and waiting time for blood 
donations should comply with locally approved vismodegib Pregnancy Prevention 
Program or prescribing information where vismodegib is commercially available. 
3.1.6 
End of Study 
Study enrollment will end in the EU if vismodegib becomes commercially available after 
regulatory approval for the treatment of locally advanced or metastatic BCC.  Study 
enrollment will end successively in non-EU countries participating in this study if 
vismodegib becomes commercially available after regulatory approval for the treatment 
of locally advanced or metastatic BCC in the respective country.  However, patients 
already enrolled in this study and who are still benefitting from vismodegib in the opinion 
of the Investigator will continue to receive vismodegib until the development of 
progressive disease (as determined by the Investigator), unacceptable toxicity, consent 
withdrawal, death, reasons deemed by the treating physician, or study termination by the 
Sponsor. 
It is anticipated that approximately 1200 patients will be enrolled over approximately 
3.5 years.  Once the enrollment of 1200 patients is completed, an assessment of how 
many patients with metastatic BCC were enrolled under Protocol Amendment Version 4 
(dated 8 May 2013) will be made.  At that time, enrollment may be extended for up to 
15 additional metastatic BCC patients in order to ensure adequate collection of data 
regarding the effect of vismodegib in metastatic BCC patients, as per Protocol 
Amendment Version 4 (dated 8 May 2013).  The study will end when the last patient on 
treatment develops progressive disease (as determined by the Investigator), 
unacceptable toxicity, withdraws consent, or dies; the treating physician deems that the 
patient is no longer benefitting from treatment; or the study is terminated by the Sponsor, 
or 12 months after the last dose of vismodegib in the last enrolled patient still on study, 
whichever occurs first. 
The Sponsor reserves the right to end study enrollment at any time.  If study enrollment 
is stopped prior to commercial availability of vismodegib, patients already enrolled will be 
informed of the reason for discontinuation of study enrollment and, in the absence of a 
significant product safety concern, will be allowed to continue on vismodegib until 
disease progression, unmanageable toxicity, withdrawal of consent, reasons deemed by 
the treating physician, or death of the patient, whichever occurs first. 
3.2 
NUMBER OF PATIENTS 
It is anticipated that approximately 1200 patients will be enrolled over approximately 
3.5 years.  Once the enrollment of 1200 patients is completed, an assessment of how 
many patients with metastatic BCC were enrolled under Protocol Amendment Version 4 
(dated 8 May 2013) will be made.  At that time, enrollment may be extended for up to 
15 additional metastatic BCC patients in order to ensure adequate collection of data 
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regarding the effect of vismodegib in metastatic BCC patients, as per Protocol 
Amendment Version 4 (dated 8 May 2013). 
3.3 
CENTERS 
This is an international multicenter study. 
4. 
STUDY POPULATION 
4.1 
OVERVIEW 
The study population will consist of male or female patients at least 18 years of age with 
histologically confirmed diagnoses of locally advanced BCC or metastatic BCC.  For 
patients with locally advanced BCC, the treating physician must consider the disease to 
be inoperable or there must be a clinical contraindication to surgery; furthermore, 
radiotherapy must have been previously administered (unless radiotherapy is 
contraindicated or inappropriate) and disease must have progressed after irradiation.  
For patients with suspected metastatic BCC, distant metastases must be histologically 
confirmed to be of basal cell origin.  Patients are eligible for enrollment in this trial with 
measurable and/or non-measurable disease, as defined by RECIST, v1.1. 
Under no circumstances are patients who enroll in this study permitted to re-enroll into 
this study for a second course of treatment. 
4.2 
INCLUSION CRITERIA 
A patient may be included if the answer to all of the following statements is "yes." 
1. 
Written informed consent  
2. 
Age ≥ 18 years 
3. 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0, 1, or 2 
4. 
For patients with metastatic BCC, histologic confirmation of distant BCC metastasis  
5. 
For patients with locally advanced BCC, at least one histologically confirmed lesion 
10 mm or more in diameter and written confirmation from a surgical specialist that 
the tumor is considered inoperable or that surgery is contraindicated.  Examples of 
medical contraindications to surgery include but are not limited to:  
• 
BCC that has recurred in the same location after two or more surgical 
procedures and curative resection is deemed unlikely  
• 
Anticipated substantial morbidity and/or deformity from surgery (e.g., removal of 
all or part of a facial structure, such as nose, ear, eyelid, eye; or requirement for 
limb amputation) 
6. 
For patients with locally advanced BCC, radiotherapy must have been previously 
administered for locally advanced BCC, unless radiotherapy is contraindicated or 
inappropriate (e.g., hypersensitivity to radiation due to genetic syndrome such as 
Gorlin syndrome, limitations because of location of tumor, or cumulative prior 
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radiotherapy dose).  For patients whose locally advanced BCC has been irradiated, 
disease must have progressed after radiation 
7. 
Patients with Gorlin syndrome may enroll in this study but must meet the criteria for 
locally advanced or metastatic disease listed above 
8. 
Patients with measurable and/or non-measurable disease (as defined by 
RECIST, v1.1) are allowed. 
9. 
Adequate organ function, as evidenced by the following laboratory results: 
• 
Hemoglobin > 8.5 g/dL 
• 
Granulocyte count ≥ 1000/μL 
• 
Platelet count ≥ 75,000/μL 
• 
Aspartate transaminase (AST [SGOT]) and alanine transaminase 
(ALT [SGPT]) ≤ 3 × upper limit of normal (ULN) 
• 
Total bilirubin ≤ 1.5 × ULN or within 3 × ULN for patients with documented 
Gilbert syndrome 
10. Women of childbearing potential must use two methods of acceptable contraception 
including one highly effective method and a barrier method (see also Appendix 2), 
as directed by their physician during treatment and for at least 9 months or as per 
approved local prescribing information for vismodegib (where available), whichever 
is longer, after completion of study treatment.  Highly-effective methods of 
contraception are defined as those which result in a low failure rate (i.e., less than 
1% per year) when used consistently and correctly (e.g., implants, injectables, or 
intra-uterine devices.  At the discretion of the Investigator, acceptable methods of 
contraception may include total abstinence.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, and postovulation methods) and withdrawal are not 
acceptable methods of contraception (see Appendix 2) 
NOTE:  The pregnancy prevention duration for female patients was changed from 
7 to 9 months or as per approved local prescribing information, whichever is longer, 
after all patients were enrolled in the study. 
11. For male patients with female partners of childbearing potential, agreement to use a 
condom with spermicide (where available), even after vasectomy, during sexual 
intercourse with female partners while being treated with vismodegib and for 
2 months or as per approved local prescribing information for vismodegib (where 
available), whichever is longer,  after completion of study treatment 
NOTE:  The contraception duration for male patients was changed from 2 months 
to 2 months or as per approved local prescribing information, whichever is longer, 
after all patients were enrolled in the study. 
12. Agreement not to donate blood or blood products during the study and for at least 
9 months or as per approved local prescribing information for vismodegib (where 
available), whichever is longer after discontinuation of vismodegib.  Because 
vismodegib has been detected in seminal fluid, in addition for men, agreement not 
donate sperm during the study or for at least 2 months or as per approved local 
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prescribing information for vismodegib (where available), whichever is longer after 
discontinuation of therapy 
NOTE:  The waiting time for blood donations was changed from 7 to 9 months or 
as per approved local prescribing information, whichever is longer, after all 
patients were enrolled in the study. 
13. Life expectancy > 12 weeks. 
14. Negative serum pregnancy test within 7 days prior to commencement of dosing in 
premenopausal women.  Women of non-childbearing potential may be included if 
they are either surgically sterile or have been postmenopausal for ≥ 1 year 
 
4.3 
EXCLUSION CRITERIA 
A patient will be excluded if the answer to any of the following statements is "yes." 
1. 
Inability or unwillingness to swallow capsules 
2. 
Pregnancy or lactation 
3. 
Concurrent non–protocol-specified anti-tumor therapy (e.g., chemotherapy, other 
targeted therapy, radiation therapy, or photodynamic therapy, including participation 
in an experimental drug study; note that treatment breaks up to 8 weeks for 
radiation therapy are allowed [see Section 6.1.1]) 
4. 
Completion of most recent anti-tumor therapy less than 21 days prior to initiation of 
treatment 
5. 
Uncontrolled medical illnesses such as infection requiring treatment with 
intravenous antibiotics 
6. 
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 that renders the patient at high risk from treatment 
complications 
7. 
Assessed by the Investigator to be unable or unwilling to comply with the 
requirements of the protocol 
8. 
Patients with one of the following rare hereditary conditions: galactose intolerance, 
primary hypolactasia, or glucose-galactose malabsorption 
 
4.4 
CONCOMITANT MEDICATION AND TREATMENT 
4.4.1 
Concomitant Therapy  
Concomitant therapy includes any prescription medications or over the counter 
preparations used by a patient between the 14 days preceding the screening evaluation 
and the 12 months Safety Follow-up visit.  All concomitant medications should be 
reported to the Investigator and recorded on the appropriate electronic case report form 
(eCRF). 
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Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.  Results of a drug-drug interaction study 
conducted in cancer patients demonstrated that the systemic exposure of ethinyl 
estradiol and norethindrone is not altered when co-administered with vismodegib.  
However, the interaction study was of only 7 days duration, and it cannot be excluded 
that vismodegib upon longer treatment is a mild inducer of enzymes that metabolize 
ethinyl estradiol contraceptive steroids.  This modest induction might lead to a decrease 
in systemic exposure of this contraceptive steroid, and thereby reduced contraceptive 
efficacy. 
4.4.2 
Excluded Therapy and Potential Interactions With Concomitant 
Drugs 
Coadministration of St John's wort (Hypericum perforatum) and other concomitant 
anti-tumor therapies are prohibited during this study. 
Medicinal products that alter the pH of the upper gastrointestinal tract (e.g., proton pump 
inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib 
and reduce its bioavailability.  However, no formal clinical trial has been conducted to 
evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib.  
Increasing the dose of vismodegib when co-administered with such agents is not likely to 
compensate for the loss of exposure.  Therefore, when vismodegib is co-administered 
with a proton pump inhibitor, H2-receptor antagonist, or antacid, systemic exposure of 
vismodegib may be decreased, and the effect on efficacy of vismodegib is unknown.  
Patients with achlorhydria would be subject to the same potential effect. 
In vitro studies indicate that vismodegib is a substrate of the efflux transporter 
P-glycoprotein (P-gp) and the drug metabolizing enzymes CYP2C9 and CYP3A4. When 
vismodegib is co-administered with medicinal products that inhibit P-gp 
(e.g., clarithromycin, erythromycin, azithromycin, verapamil, cyclosporine), CYP2C9 (e.g., 
amiodarone, fluconazole, miconazole), or CYP3A4 (e.g., boceprevir, clarithromycin, 
coniraptan, indinavir, traconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), systemic 
exposure of vismodegib and incidence of adverse events of vismodegib may be 
increased.  When vismodegib is administered with CYP inducers (e.g., rifampin, 
carbemazepine, phenytoin, St. John’s wort) exposure to vismodegib may be decreased. 
Results of a drug-drug interaction study conducted in cancer patients demonstrated that 
the systemic exposure of ethinyl estradiol and norethindrone is not altered when 
co-administered with vismodegib.  However, the interaction study was of only 7 days 
duration, and it cannot be excluded that vismodegib upon longer treatment is a mild 
inducer of enzymes that metabolize ethinyl estradiol contraceptive steroids.  This modest 
induction might lead to a decrease in systemic exposure of this contraceptive steroid, 
and thereby reduced contraceptive efficacy. 
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In vitro studies indicate that vismodegib has the potential to act as an inhibitor of breast 
cancer resistance protein (BCRP).  In vivo interaction data are not available.  It may not 
be excluded that vismodegib may give rise to increased exposure of drugs transported 
by this protein, such as rosuvastatin, topotecan, and sulfasalazin.  Concomitant 
administration should be performed with caution and a dose adjustment may be 
necessary. 
In vitro, CYP2C8 was the most sensitive CYP isoform for vismodegib inhibition.  
However, results of a drug-drug interaction study conducted in cancer patients 
demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) is not 
altered when either agent is co-administered with vismodegib.  Thus, inhibition of CYP 
enzymes by vismodegib in vivo may be excluded (33). 
4.5 
CRITERIA FOR PREMATURE STUDY WITHDRAWAL 
Patients have the right to withdraw from the study at any time for any reason. 
In the case that the patient decides to prematurely discontinue study treatment (“refuses 
treatment”), he/she should be asked if he/she can still be contacted for further 
information.  The outcome of that discussion should be documented in both the medical 
records and in the eCRF.  If lost to follow-up, the Investigator should contact the patient 
or a responsible relative by telephone followed by registered mail or through a personal 
visit to establish as completely as possible the reason for the withdrawal.  A complete 
final evaluation at the time of the patient’s withdrawal should be made with an 
explanation of why the patient is withdrawing from the study. 
When applicable, patients should be informed of circumstances under which their 
participation may be terminated by the Investigator without the patient’s consent.  The 
Investigator may withdraw patients from the study in the event of intercurrent illness, 
AEs, treatment failure after a prescribed procedure, lack of compliance with the study 
and/or study procedures (e.g., dosing instructions, study visits), cure, or any reason 
where it is felt by the Investigator that it is in the best interest of the patient to be 
terminated from the study.  Any administrative or other reasons for withdrawal must be 
documented and explained to the patient. 
If the reason for the removal of a patient from the study is an AE, then the principal 
specific event will be recorded on the eCRF.  The patient should be followed until the AE 
has resolved, if possible. 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of patients should be avoided.  Should a patient decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
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5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
All scheduled study assessments are outlined in Table 1 (Schedule of Assessments). 
All Screening/Baseline assessments, as outlined in Table 1, must be performed within 
28 days prior to the first administration of vismodegib on Day 1, Cycle 1.  Results of tests 
or examinations performed as standard of care before obtaining informed consent and 
within the 28 days prior to commencing vismodegib may be used.  Tumor assessment 
by physical examination should be performed within a maximum of 7 days prior to the 
first dose of study drug (baseline reading).  If tumor assessment requires imaging, 
baseline CT/MRI scans should be performed within a maximum of 28 days prior to the 
first dose of study drug (on Cycle 1, Day 1).  Non-measurable disease should be 
assessed within 28 days prior to study initiation.   
All assessments during the Treatment Phase must be performed within a 
window ± 3 days, from Cycle 2 onwards of the day indicated on the schedule of 
assessment, with the exception of tumor assessments.  The majority of the patients in 
this study have locally advanced BCC and in this disease setting measurable tumors are 
accessible to evaluation by physical examination every 4 to 8 weeks (± 5 days).  If 
assessment requires imaging, CT and/or MRI scans should occur every 8 to 16 weeks 
(± 5 days) or as per institutional standards. 
Eligibility for the study will be determined by the Investigator from the mandatory 
Screening/Baseline assessments performed during screening and according to the study 
inclusion/exclusion criteria.  First dosing of vismodegib will be determined by the 
patient’s eligibility and the laboratory assessments on Day 1 prior to dosing. 
The treatment period will begin on Day 1, and patients will be followed until 
Investigator-assessed disease progression, unacceptable toxicities most probably 
attributable to vismodegib, patient consent withdrawal, death, reasons deemed by the 
treating physician, or study termination by the Sponsor.  In addition, five Safety 
Follow-Up Visits 1 month, 3 months, 6 months, 9 months, and 12 months will occur after 
the last dose of vismodegib (± 5 days), as provided by this phase II safety study protocol.  
The first anti-cancer therapy received by the patient after discontinuation of study drug 
will also be recorded. 
5.1 
SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM 
All patients must provide written informed consent before any study-specific 
assessments or procedures are performed. 
Screening /baseline evaluations must be performed between Day −28 and −1.  Patients 
who fulfill all the inclusion and none of the exclusion criteria will be accepted into the 
study. 
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An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator. 
A log must be maintained by the Investigator of all patients who fail screening.  For those 
patients from whom Informed Consent has been obtained but who do not meet the 
Inclusion and Exclusion criteria on Day 1, only the Screening Log pages, demographics, 
and reason for screening failure will be collected. 
5.2 
PROCEDURES FOR ENROLLMENT OF ELIGIBLE PATIENTS 
A patient who has fulfilled the entry criteria will attend on the morning of Day 1, at which 
time a patient number will be allocated by the Interactive Web-Based/Voice Response 
System, which has been established for the purpose of this study. 
Under no circumstances will patients who enroll in this study and have completed 
treatment as specified be permitted to re-enroll in the study. 
A Patient Enrollment and Identification Code List must be maintained by the Investigator.  
5.3 
CLINICAL ASSESSMENTS AND PROCEDURES 
The following clinical assessments and procedures must be completed for all patients 
enrolled in this study at screening/baseline and during study visits.  
All assessments must be performed within a window of 3 days prior to and after the 
scheduled visit date from Cycle 2 onwards of the day indicated on the schedule of 
assessment, except for tumor evaluations (see Section 5.3.1), for which a window 
of ± 5 days will apply.  Please refer to Table 1 (Schedule of Assessments) for specific 
details and time points collected on clinical assessments and procedures outlined below: 
5.3.1 
Screening/Baseline Period Assessments 
Potential participants will undergo the following screening procedures no more than 
28 days prior to Day 1, Cycle 1 (unless they have already been conducted during this 
time period as part of the patient’s routine clinical care):  
• 
Informed consent 
• 
Archival tumor tissue from a metastatic BCC site in metastatic BCC patients who 
are on study after approval of the Study Protocol, version 4.0 
• 
Complete medical history (including BCC history) and demographics  
• 
Collection of metastatic BCC history, such as evidence of progression prior to 
enrollment and reason(s) for discontinuation from prior treatment, will be 
collected in patients who are on study after approval of the Study Protocol, 
version 4.0 
• 
Complete physical examination including weight and height at screening only 
• 
Vital signs (body temperature, blood pressure, and pulse) 
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• 
ECOG PS assessment 
• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood 
cell count including differential, platelet count, and absolute neutrophil count [ANC]) 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, creatine kinase [also known as creatine phosphokinase], 
total bilirubin, alkaline phosphatase, AST, and ALT) 
• 
Serum pregnancy test (within 7 days prior to the commencement of dosing) for 
women of child bearing potential (see Appendix 2) 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Ultrasound 
• 
Record any amenorrhea/irregular menses, relevant gynecologic medical history, 
and concurrent gynecologic conditions 
• 
Perform serum hormone evaluation, including follicle stimulating hormone 
(FSH), luteinizing hormone (LH), estradiol (E2), and thyroid stimulating 
hormone (TSH) 
• 
12-lead electrocardiogram (ECG) 
• 
AEs/SAEs.  After informed consent, but prior to initiation of study medications, only 
SAEs caused by a protocol-mandated intervention will be collected.  All AEs (either 
related to study-specific procedures or otherwise) experienced after the patient has 
signed the Informed Consent form, but before they have received study treatment, 
should be recorded as medical history  
• 
Concomitant therapy 
• 
Tumor assessment (the majority of patients in this study have locally advanced BCC 
and in this disease setting measurable tumors are accessible to evaluation by 
physical examination): 
• 
Measurable tumors accessible to evaluation by physical examination should be 
assessed within a maximum of 7 days prior to the first dose of study drug 
(baseline reading)  
• 
If assessment requires imaging, baseline CT and/or MRI should be performed 
within a maximum of 28 days prior to the first dose of study drug 
• 
Non-measurable disease should be assessed within 28 days prior to study 
initiation 
• 
In selected sites, patients will complete the Skindex-16 Quality of Life questionnaire 
(see Section 5.5 and Appendix 5) 
• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, 
version 4.0) will complete the M.D. Anderson Symptom Inventory (see Main 
Protocol, Section 5.6 and Appendix 6) prior to having any study-related procedures 
performed at the visit 
 
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5.3.2 
Treatment Phase Assessments 
Day 1 of the study will be defined as the first day a patient receives vismodegib.  One 
cycle of therapy is defined as 28 days of treatment.  During the Treatment Phase, all 
study assessments will be conducted on Day 1 (± 3 days) of each Cycle, with the 
exception of tumor evaluation, for which a window of ± 5 days will apply (see below).  
The assessments during the treatment period are:  
• 
Limited physical examination at every 28-day visit 
• 
Vital signs (body temperature, blood pressure, and pulse) and weight at every 
28-day visit 
• 
ECOG PS assessment at every 28-day visit 
• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood 
cell count including differential, platelet count, and ANC) at every 28-day visit 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, creatine kinase [also known as creatine phosphokinase], 
total bilirubin, alkaline phosphatase, AST, and ALT) at every 28-day visit 
• 
Urine pregnancy tests on Day 1 of each subsequent Cycle.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test 
• 
12-lead ECG (during the study if clinically indicated) 
• 
Concomitant therapy and AEs (including SAEs) throughout the study 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Ultrasound (as clinically indicated [see Schedule of Assessments]) 
• 
Assess amenorrhea/irregular menses that develops while on study:  
1. 
At start of amenorrhea/irregular menses, perform serum hormone 
evaluation at study site, including FSH, LH, E2, and TSH, and refer to 
gynecologist or appropriate specialist for assessment of ovaries and uterus, 
including ultrasound 
2. 
At resolution of amenorrhea/irregular menses, perform serum hormone 
evaluation at site, including FSH, LH, E2, and TSH.  Refer to gynecologist 
or appropriate specialist for follow-up ultrasound ONLY if there was 
abnormality identified during previous ultrasound 
3. 
If amenorrhea/irregular menses recurs, repeat evaluations at start of 
recurrence as detailed previously 
• 
Vismodegib administration throughout the study 
• 
Tumor assessment (the majority of the patients in this study have locally advanced 
BCC and in this disease setting measurable tumors are accessible to evaluation by 
physical examination).  Objective responses using RECIST, v1.1 should be 
confirmed by repeat assessments at least 4 weeks after initial documentation of 
response: 
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• 
Measurable tumors accessible to evaluation by physical examination should be 
assessed every 4 to 8 weeks throughout the study from the time of the first 
dose, regardless of dosing delays 
• 
If assessment requires imaging, baseline CT and/or MRI should be performed 
within a maximum of 28 days prior to the first dose of study drug and, if such 
scans demonstrate evidence of disease, follow-up imaging studies (CT and/or 
MRI) should be performed every 8 to 16 weeks from the time of the first dose, 
regardless of dosing delays, or per institutional standards.  The same imaging 
technique (CT or MRI) should be used for each patient throughout the study 
• 
In metastatic BCC patients (newly enrolled after approval of the Study Protocol, 
version 4.0), imaging at baseline (CT and/or MRI scan) should be performed 
within a maximum of 28 days before the first dose.  Follow-up imaging studies 
(CT and/or MRI scan) should be performed every 8 weeks (± 5 days) from the 
time of the first dose, regardless of dosing delays.  The same imaging 
technique (CT or MRI) should be used for each patient throughout the study 
• 
Other imaging techniques may be performed as clinically indicated, but should 
not be used for determining tumor response 
• 
Patients with non-measurable disease at baseline should be assessed for 
disease progression when clinically indicated and in accordance with standard 
clinical practice.  For metastatic patients, assessment of non-measurable 
disease should be according to RECIST, version 1.1. 
• 
Follow up for disease progression 
• 
In selected sites, patients will complete the Skindex-16 Quality of Life questionnaire 
after Cycle 1 and after Cycle 6 (at 6 months of treatment) for the patients still on 
study (see Section 5.5 and Appendix 5) 
• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, 
version 4.0) will complete the M.D. Anderson Symptom Inventory 
(see Section 5.6  and Appendix 6) at every visit, prior to having any other 
assessments performed 
• 
In selected sites, post-treatment PK testing will be performed on 30 patients.  This 
testing requires a single blood draw for PK testing at steady-state for comparison to 
the post-treatment samples collected.  Steady-state is defined as any time point 
while a patient is taking vismodegib for at least 2 weeks continuously. 
 
5.3.3 
End of Treatment Visit Assessments 
The End of Treatment Visit will be performed when the patient discontinues vismodegib, 
regardless of when it occurs. 
The following evaluations will be conducted at the End of Treatment Visit: 
• 
Limited physical examination 
• 
Vital signs (body temperature, blood pressure, and pulse) and weight 
• 
ECOG PS assessment 
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• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood 
cell count including differential, platelet count, and ANC) 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen, creatinine, creatine kinase [also known as creatine phosphokinase], 
total bilirubin, alkaline phosphatase, AST, and ALT) 
• 
Tumor assessment 
• 
12- lead ECG (if clinically indicated) 
• 
Concomitant therapy and new anti-cancer therapy 
• 
AEs (including SAEs) 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Assess amenorrhea/irregular menses that develops while on study:  
1. 
At start of amenorrhea/irregular menses, perform serum hormone 
evaluation at study site, including FSH, LH, E2, and TSH, and refer to 
gynecologist or appropriate specialist for assessment of ovaries and uterus, 
including ultrasound 
2. 
At resolution of amenorrhea/irregular menses, perform serum hormone 
evaluation at site, including FSH, LH, E2, and TSH.  Refer to gynecologist 
or appropriate specialist for follow-up ultrasound ONLY if there was 
abnormality identified during previous ultrasound 
3. 
If amenorrhea/irregular menses recurs, repeat evaluations at start of 
recurrence as detailed previously 
• 
Follow up for disease progression 
• 
Pregnancy test for women of childbearing potential 
• 
In selected sites, patients will complete the Skindex-16 Quality of Life questionnaire 
(see Section 5.5 and Appendix 5).  
• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, 
version 4.0) will complete the M.D. Anderson Symptom Inventory 
(see Section 5.6  and Appendix 6), prior to having any other assessments 
performed 
• 
In metastatic BCC patients who develop tumor progression on vismodegib treatment, 
a biopsy will be performed if at least one of the progressing lesions is accessible, 
e.g., skin, superficial mass, or lymph node 
• 
Collection of whole blood in metastatic BCC patients with tumor biopsy at 
progression 
 
5.3.4 
Safety Follow-Up Phase Assessments 
Patients who discontinue from the study will be asked to return to the clinic for a safety 
follow-up assessment 1 month, 3 months, 6 months, 9 months, and 12 months after the 
last dose of vismodegib (+/- 5 days), as provided by this phase II, safety study protocol, 
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or upon initiation of new non-permitted anti-cancer therapy.  The assessments will 
include: 
• 
Hematology (including hemoglobin, hematocrit, red blood cell count, full white blood 
cell count including differential, platelet count, and ANC) as clinically indicated 
• 
Biochemistry (including glucose, sodium, potassium, chloride, bicarbonate, BUN, 
creatinine, creatine kinase [also known as creatine phosphokinase], total bilirubin, 
alkaline phosphatase, AST, and ALT) as clinically indicated 
• 
Follow up for disease progression 
• 
Concomitant therapy and new anti-cancer therapy 
• 
AEs (including SAEs) 
• 
For women of childbearing potential: 
• 
Record date of last menses 
• 
Assess amenorrhea/irregular menses that develops while on study:  
1. 
At start of amenorrhea/irregular menses, perform serum hormone 
evaluation at study site, including FSH, LH, E2, and TSH, and refer to 
gynecologist or appropriate specialist for assessment of ovaries and uterus, 
including ultrasound   
2. 
At resolution of amenorrhea/irregular menses, perform serum hormone 
evaluation at site, including FSH, LH, E2, and TSH.  Refer to gynecologist 
or appropriate specialist for follow-up ultrasound ONLY if there was 
abnormality identified during previous ultrasound   
3. 
If amenorrhea/irregular menses recurs, repeat evaluations at start of 
recurrence as detailed previously 
• 
Patients with metastatic BCC (newly enrolled after approval of the Study Protocol, 
version 4.0) will complete the M.D. Anderson Symptom Inventory 
(see Section 5.6  and Appendix 6), prior to having any other assessments 
performed at the visits 
• 
In selected sites, patients will have blood draws for adverse event–related PK 
testing if any adverse events that were reported to be related to vismodegib 
treatment continue to be present at least 6 months after the last dose of vismodegib.  
Blood samples for the adverse event-related PK testing will be collected at the 6, 9, 
and 12 months Safety Follow-Up Visits.  Blood samples for all time points will be 
collected even if the adverse event resolves after the 6 months Safety Follow-Up 
Visit.   
• 
In selected sites, post-treatment PK testing will be performed on 30 patients.  
Patients, who previously provided a PK sample at steady-state, will have blood 
draws for post-treatment PK testing at the 3, 6, 9, and 12 months Safety Follow-up 
Visits.  
 
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5.3.5 
Post-Study Pregnancy Assessments 
Female patients of childbearing potential must continue to use an effective method of 
contraception for 9 months after the last dose of vismodegib.  Acceptable contraception 
and duration of contraceptive use should comply with locally approved vismodegib 
(Erivedge®, the trade name for vismodegib) Pregnancy Prevention Program or 
prescribing information where vismodegib is commercially available.  If a pregnancy 
occurs within 9 months or within the designated window per approved local prescribing 
information for vismodegib (where available), whichever is longer, of the last dose of 
vismodegib, the Investigator should report to the Sponsor (refer to Sections 7.1.1.4 
and 7.1.2).  The Investigator should counsel the patient, discussing the risks of 
continuing with the pregnancy and the possible effects on the fetus.  Monitoring of the 
patient should continue until conclusion of the pregnancy. 
5.3.6 
Tumor Response Criteria 
Tumor response will be evaluated according to the RECIST, v1.1 criteria (Appendix 1).  
The majority of patients in this study have locally advanced BCC and in this disease 
setting measurable tumors are accessible to evaluation by physical examination.  This 
study allows for more than two target skin lesions, which takes into account patient with 
multiple BCC. 
In this study, tumor response will be measured for patients with measurable disease by 
physical examination and/or imaging (CT and/or MRI scans), at the Investigator’s 
discretion.  Other imaging techniques may be performed as clinically indicated, but 
should not be used for determining tumor response.  For each patient, the same method 
of assessment and the same technique must be used to evaluate each lesion 
throughout the entire study.  If more than one method is used, the most accurate method 
according to RECIST should be selected when recording data. 
Patients with non-measurable disease should be assessed for disease progression 
when clinically indicated and in accordance with standard clinical practice.  For 
metastatic patients, assessment of non-measurable disease should be carried out 
according to RECIST, version 1.1. 
For both metastatic and locally advanced BCC cohorts, a new cutaneous BCC will be 
considered as PD if the lesion is > 5 mm and can be clearly documented as not being 
previously present, unless it is confirmed on biopsy not to be consistent with BCC. 
Consistency of consecutive CT-scans, X-rays, or MRIs should be ensured during all 
assessments for each patient, with the same technique being used for evaluating lesions 
throughout the treatment period.  (Use of spiral CT or MRI is required for baseline 
lesions < 20 mm and must be documented in medical records and used consistently 
throughout the study.)  The use of oral and IV contrast, etc., should be kept consistent 
as long as it is clinically possible.  Tumor measurements should be made by the same 
Investigator/radiologist for each patient during the study to the extent that this is feasible.  
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In case of clinically measurable superficial lesions (such as skin), repeated photographs 
should be used to document tumor response.  These photos must include a ruler for 
documentation purposes. 
Tumor response will be confirmed a minimum of 4 weeks after the initial response was 
noted, or at the next scheduled tumor assessment if it is to occur more than 4 weeks 
after the initial response. 
Scheduling of Tumor Assessments 
The majority of patients in this study have locally advanced BCC, and in this disease 
setting measurable tumors are accessible to evaluation by physical examination. 
Tumor assessment by physical examination should be performed within a maximum of 
7 days prior to the first dose of study drug (baseline reading).  If tumor assessment 
requires imaging, baseline CT/MRI scans should be performed within a maximum of 
28 days prior to the first dose of study drug (on Cycle 1, Day 1).  Non-measurable 
disease should be assessed within 28 days prior to study initiation. 
Post-baseline measurable tumors accessible to evaluation by physical examination are 
to be performed every 4 to 8 weeks (± 5 days).  For tumor assessment requiring imaging 
and if the baseline scans demonstrate evidence of disease, CT and/or MRI scans should 
occur every 8 to 16 weeks (± 5 days) or as per institutional standards.  The same 
imaging technique must be used for a patient throughout the study.   
In metastatic BCC patients who are newly enrolled after approval of the Study Protocol, 
version 4.0, imaging at baseline (CT and/or MRI scan) should be performed within a 
maximum of 28 days before first dose.  Follow-up imaging studies (CT and/or MRI scan) 
should be performed every 8 weeks (± 5 days) from the time of the first dose, regardless 
of dosing delays.  The same imaging technique (CT or MRI) should be used for each 
patient throughout the study. 
If there is suspicion of disease progression based on clinical or laboratory findings 
before the next scheduled assessment, an unscheduled assessment should be 
performed. 
All tumor assessments after baseline will be done within ± 5 days of the scheduled visit.  
If a patient inadvertently misses a prescribed tumor evaluation or a technical error 
prevents the evaluation, the patient may continue treatment until the next scheduled 
assessment, unless signs of clinical progression are present. 
5.3.7 
Clinical Safety Assessments 
The National Cancer Institute Common Terminology for Adverse Events, Version 4.0 
(NCI-CTCAE, v4.0) will be used to evaluate the clinical safety of the treatment in this 
study (available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html).  All patients who 
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receive at least one dose of vismodegib will be included in the safety analyses.  Safety 
will be assessed through summaries of AEs, SAEs, AEs grade 3 or 4, AEs that caused 
vismodegib discontinuation and interruption, and cause of death on study. 
All AEs will be assessed according to the NCI-CTCAE, v4.0 grading system.  The 
analysis of AEs will focus on treatment-emergent AEs, i.e., AEs occurring on or after the 
first day of vismodegib administration.  Non–treatment-emergent AEs (i.e., those 
occurring before commencement of study medication) will only be listed.  The incidence, 
type, and severity of AEs will be summarized according to the primary system-organ 
class (SOC) and within each SOC, by Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term.  AEs of special interest, AEs leading to treatment interruption 
and discontinuation, and SAEs will be analyzed in a similar way to all AEs.  Cause of 
death will also be summarized and listed. 
Exposure to study medication will be summarized by means of descriptive statistics for 
the cumulative dose and frequency tables (percentages) by Cycles and/or Week of 
treatments.  The reason for the dose discontinuation, other than disease progression, 
will also be summarized.  
Laboratory parameters, hematology, and serum biochemistry will be presented in shift 
tables of NCI-CTCAE, v4.0 grade at baseline versus worst grade during treatment period.  
The laboratory parameters will be also summarized as continuous or discrete data when 
applicable. 
Vital signs, ECOG PS, physical examination, and ECG (if available) will be summarized 
over time.  Concomitant therapy will be summarized by frequency tables and 
percentages.  New anti-cancer therapy will be analyzed in a similar way to concomitant 
therapy at the End of Treatment Visit.  Protocol deviations will be listed. 
5.3.8 
Medical History and Demographics 
Medical history includes all clinically significant diseases, previous surgeries, prior skin 
cancer history (especially BCC), prior skin cancer therapies, procedures, and responses 
to prior therapies (especially BCC).  It will also include all medications used by the 
patient within 14 days preceding the screening visit.  In women of childbearing potential, 
medical history will also include a record of any amenorrhea/irregular menses, relevant 
gynecologic medical history, and concurrent gynecologic conditions, as well as the date 
of last menses prior to study drug administration.  In metastatic BCC patients who 
enrolled after approval of the Study Protocol, version 4.0, medical history will also 
include evidence of progression prior to enrollment on study and the reason for 
discontinuation from prior treatments (if applicable).  
Demographic information will include age, gender, and race as applicable. 
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5.3.9 
Performance Status 
Performance status will be measured using the ECOG PS scale (see Appendix 3). 
It is recommended, where possible, that a patient’s performance status will be assessed 
by the same person throughout the study.  
Performance status will be assessed at each visit, except in the Safety Follow-Up Visit. 
5.3.10 
 Physical Examination 
The initial complete physical examination should include the evaluation of the head, 
eyes, ears, nose and throat; and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, and neurological systems.  Height and weight will also be 
recorded.  Subsequent limited physical examinations for assessment of toxicity may be 
restricted to evaluation of specific systems or areas of interest, including those with 
previously abnormal findings or associated with symptomatic or laboratory evidence of 
toxicity.  Changes from baseline abnormalities should be recorded at each subsequent 
physical examination.  New or worsened abnormalities should be recorded as AEs if 
appropriate. 
In women of childbearing potential, the date of last menses should be recorded at each 
visit. 
5.3.11 
Vital Signs 
Vital signs will be recorded for all patients and will include blood pressure (BP), 
temperature (°C), and pulse.  Vital signs will be obtained at baseline (Day 1 pre-dose), at 
each monthly visit, and at the End of Treatment Visit. 
5.3.12 
Electrocardiographic Assessment 
Electrical activity of the heart will be assessed by standard twelve-lead 
electrocardiograms (ECGs).  ECGs will be performed at screening and thereafter 
throughout the study and at the End of Treatment Visit, as clinically indicated. 
5.3.13 
Ultrasound 
If women of childbearing potential develop amenorrhea/irregular menses while on study, 
they will be referred to a gynecologist or appropriate specialist at the start of 
amenorrhea/irregular menses for assessment of their ovaries and uterus by ultrasound.  
At resolution of amenorrhea/irregular menses, they will be referred to a gynecologist or 
appropriate specialist for a follow-up ultrasound ONLY if there was abnormality identified 
during the prior ultrasound.  Ultrasound analyses will be repeated if the 
amenorrhea/irregular menses recurs.  The ultrasound report/results must be forwarded 
to the study site and any abnormal findings recorded in the CRF. 
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5.4 
LABORATORY ASSESSMENTS 
Samples for hematology, serum chemistry, and pregnancy will be analyzed at the study 
site’s local laboratory.  Normal ranges for the study laboratory parameters must be 
supplied to Roche before the study starts.  Changes to the normal ranges during the 
course of the study should be notified to Roche as soon as possible. 
Laboratory assessments will be performed at screening/baseline, at each 28-Day visit, at 
the End of Treatment Visit, and at five Safety Follow-Up Visits 1 month, 3 months, 
6 months, 9 months, and 12 months after the last dose of vismodegib (± 5 days), as 
provided by this phase II safety study protocol for hematology and biochemistry, if 
clinically indicated. 
The total volume of blood loss for laboratory assessments will be approximately 220 mL 
throughout the duration of the study (slightly higher for women of childbearing potential). 
5.4.1 
Safety Laboratory Assessments 
Samples for hematology, biochemistry, pregnancy, and serum hormone evaluation (in 
women of childbearing potential) will be analyzed at the study site’s local laboratory. 
• 
Hematology (hemoglobin, hematocrit, platelet count, white blood cell count, and 
percent or absolute differential count [neutrophils, eosinophils, lymphocytes, 
monocytes, basophils, and other cells]) 
• 
Biochemistry (including glucose, BUN, creatinine, creatine kinase [also known as 
creatine phosphokinase], sodium, potassium, chloride, bicarbonate (if routinely 
performed on venous blood samples), total bilirubin, alkaline phosphatase, AST, 
and ALT) 
• 
Pregnancy test for all women of childbearing potential (including those who have 
had a tubal ligation).  Women will have a serum pregnancy test within 7 days prior to 
the first dose of vismodegib, followed by urine pregnancy tests on Day 1 and every 
4 weeks.  A positive urine pregnancy test must be confirmed with a serum 
pregnancy test.  Women of non-childbearing potential may be included if they are 
either surgically sterile or have been postmenopausal for ≥ 1 year 
• 
Serum hormone evaluation, including FSH, LH, E2, and TSH, for all women of 
childbearing potential at Screening.  The serum hormone evaluation will be repeated 
at the start of amenorrhea/irregular menses and at the resolution of 
amenorrhea/irregular menses 
 
5.4.2 
Tumor Tissue Assessment 
In metastatic BCC patients who are on study after approval of Study Protocol, version 
4.0, archival tissue from a metastatic BCC site will be collected.  In metastatic BCC 
patients who develop tumor progression on vismodegib treatment, a biopsy will be 
performed if at least one of the progressing lesions is accessible (e.g., skin, superficial 
mass, or lymph node).  One or more biopsies of ONE representative progressing lesion 
is required per patient.  
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The archival and progression tumor-tissue samples will be reviewed for tumor histology.  
In addition, genome-wide technologies to identify somatic gene mutations (e.g., SMO 
mutations), copy number changes, or gene expression patterns will be carried out on 
DNA/RNA extracted from these tissues.  DNA collected from whole blood will serve as a 
control for addressing tumor-specific genetic variants.   
For sampling procedures and shipping instructions, see the laboratory manual.  
Assessments will be performed by the Sponsor or a Sponsor-selected vendor.  
5.5 
QUALITY OF LIFE ASSESSMENTS 
In selected sites, QoL assessments using the Skindex-16 tool (Appendix 5) will be 
performed up to 4 times.  Eligible patients will be asked to complete the questionnaire at 
baseline, i.e., before the start of treatment with vismodegib, after completion of Cycle 1, 
after completion of Cycle 6, and at the End of Treatment Visit. 
Patients should complete the questionnaire at the beginning of each visit, before any 
extensive contact and consultation with the clinician/study Investigator, as the 
consultation may bias the patient’s perceptions about his or her skin condition-related 
QoL.  
Skindex-16 measures the effect of skin disease on patients’ QoL through three major 
domains: skin symptom, effect on emotions, and effect on physical and social 
functioning.  It has been shown to be useful in patients with non-melanoma skin cancers, 
including BCC (27, 29), but there are limited data in patients with higher burden tumors.  
Clinicians can use this tool to complement their own assessment of the severity of 
disease and response to therapy.  
5.6 
DISEASE SYMPTOM ASSESSMENT 
The M.D. Anderson Symptom Inventory (MDASI, See Appendix 6) will be used to 
assess the impact of treatment on symptoms in patients with metastatic BCC who 
enrolled after approval of the Study Protocol, version 4.0.  Eligible patients will be asked 
to complete the questionnaire at baseline, i.e., before the start of treatment with 
vismodegib, at every clinic visit while receiving vismodegib, at the End of Treatment Visit, 
and at every Safety Follow-Up Visit. 
Patients should complete the questionnaire at the beginning of each visit, before any 
extensive contact and consultation with the clinician/study investigator, as the 
consultation may bias the patient’s perceptions about his or her disease symptom(s).  
The MDASI core instrument is a 19-item, valid, and reliable self-report questionnaire (34) 
that consists of two scales that assess symptom severity and symptom interference with 
different aspects of a patient’s life.  For 13 items (pain, fatigue, nausea, disturbed sleep, 
distress, shortness of breath, difficulty remembering things, lack of appetite, drowsiness, 
dry mouth, sadness, vomiting, and numbness or tingling), patients are asked to rate how 
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severe the symptoms were when “at their worst” in the last 24 hours.  For an additional 
six items, patients are asked to rate how much the symptoms have interfered with 
six areas of functioning (i.e., general activity, walking, work, mood, relations with other 
people, and enjoyment of life) in the last 24 hours.  In addition to the core set of items in 
the MDASI, one additional symptom related to metastatic BCC will be included 
(coughing from the Lung Cancer module).  The MDASI items are rated from 0 to 10, with 
0 indicating that the symptom is either not present or does not interfere with the patient’s 
activities and 10 indicating that the symptom is “as bad as you can imagine” or 
“interfered completely” with the patient’s life. 
In metastatic patients (enrolled before approval of the Study Protocol, version 4.0), 
disease symptoms will be assessed based on a retrospective review.  A comparison of 
concurrent conditions and sites of metastatic disease at baseline will be used to 
determine disease symptoms related to metastatic disease. 
5.7 
PHARMACOKINETIC ASSESSMENTS AT DESIGNATED 
INVESTIGATIVE SITES 
At selected sites that have the capability for pharmacokinetic sample collection and 
processing, samples for pharmacokinetic testing, will be analyzed at a central laboratory.  
Samples will be collected and shipped to a central laboratory or to Genentech for 
measuring the concentrations of the following: 
• 
Total vismodegib  
• 
Unbound vismodegib  
• 
AAG 
 
Instruction manuals and supply kits will be provided for all pharmacokinetic 
assessments.  
5.7.1 
Adverse Event-Related Pharmacokinetic Assessments 
Patients will have blood draws for adverse event–related PK testing if any adverse 
events that were reported to be related to vismodegib treatment continue to be present 
at least 6 months after the last dose of vismodegib.  Site personnel must ensure that a 
thorough review of all ongoing adverse events that have been recorded in the medical 
chart and eCRF is performed with the patients at the 6 months Safety Follow-up Visit to 
ensure that all required PK samples are collected.  Blood samples (5 mL each) for the 
adverse event-related PK testing will be collected at the 6, 9, and 12 months Safety 
Follow-Up Visits.  
The total volume of blood loss for adverse event-related PK assessments will be 
approximately 15 mL throughout the duration of the study. 
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5.7.2 
Post-Treatment Pharmacokinetic Assessments 
Post-treatment PK testing will be performed on 30 patients to further characterize the 
post-treatment elimination of vismodegib from steady-state exposure to 12 months 
post-treatment discontinuation.  Patients will have a single blood draw (5 mL) for PK 
testing at steady-state, defined as any time point while taking vismodegib for at least 
2 weeks continuously, followed by blood draws  (5 mL each) for post-treatment PK 
testing at the 3, 6, 9, and 12 months Safety Follow-up Visits.  
The total volume of blood loss for post-treatment PK assessments will be approximately 
25 mL throughout the duration of the study. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
6.1 
DOSE AND SCHEDULE 
Enrolled patients will receive continuous once-daily oral dosing of vismodegib at a 
dosage of 150 mg per administration.  One cycle of therapy is defined as 28 days of 
treatment.  Dose reduction of vismodegib is not permitted, as there is only a 150-mg 
capsule strength available.   
Dosing of vismodegib will continue until one of the following occurs: 
• 
Investigator-assessed disease progression 
• 
Unacceptable toxicities most likely attributable to vismodegib 
• 
Patient consent withdrawal 
• 
Death 
• 
Reasons deemed by the treating physician  
• 
Study termination by the Sponsor 
 
If there is objective evidence of progressive disease, but the Investigator believes the 
patient is still deriving benefit from treatment, treatment with vismodegib may be 
continued after consultation with the medical monitor.  However, if there is evidence of 
further disease progression at the next tumor assessment, vismodegib should be 
discontinued. 
At each study visit, patients will be given enough capsules for dosing until the next study 
visit.  The Investigator is required to confirm that any female patient of childbearing 
potential has a negative pregnancy test, understands the teratogenic potential of 
vismodegib, and is using an effective method of contraception prior to dispensing 
vismodegib.  Patients will be instructed to take one 150 mg capsule per day.  
Vismodegib should be taken at approximately the same time each day, with or without 
food.  Capsules must be swallowed whole and must not be opened under any 
circumstances.  If a patient misses a dose (e.g., due to emesis), he or she should be 
instructed not to take or make up that dose and to resume dosing with the next 
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scheduled dose.  Missed doses will not be made up.  Patients will be instructed to bring 
all unused capsules to each study visit for assessment of compliance. 
If a patient is suspected to be pregnant, vismodegib must be immediately discontinued.  
If it is subsequently confirmed that the patient is not pregnant, dosing may be resumed. 
The terminal half-life of vismodegib has been determined to be 10–14 days in humans, 
based on preliminary findings in healthy patients.  If plasma concentrations of 
vismodegib need to be lowered emergently, animal studies suggest that oral 
administration of activated charcoal may lower plasma drug levels more quickly than 
dose cessation alone. 
6.1.1 
Dose Modifications, Interruptions, and Delays  
No dose reductions will be allowed in this study. 
Treatment with vismodegib may be interrupted for up to: 
• 
Eight weeks if a patient becomes temporarily unable to swallow capsules 
• 
Eight weeks for an intolerable toxicity finding  
Any other proposed reasons for interruption of treatment should be discussed in 
advance with the Medical Monitor.  The Medical Monitor must be consulted in all cases 
where study drug will be interrupted. 
Intolerable toxicities are defined as new (not present at baseline) Grade 3 or 4 AEs 
considered related to vismodegib that are likely to be life-threatening or irreversible and, 
in the opinion of the Investigator, the risk outweighs the benefit of continued treatment 
with vismodegib.  The following AEs 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 
(e.g., basal cell carcinoma and nevoid basal cell carcinoma [Gorlin] syndrome) 
• 
Nausea, vomiting, or diarrhea that are 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 AE may continue to receive study 
drug provided the AE is manageable and the patient and the Investigator agree that 
continued study participation is acceptable. 
If a patient experiences two treatment interruptions, the Medical Monitor must be 
consulted before the patient can resume treatment. 
6.2 
PREPARATION, STORAGE, AND HANDLING OF IMP 
Vismodegib will be supplied as capsules to the study sites. 
Vismodegib capsules will be stored in a secured location at the clinical site at room 
temperature conditions (between 59°F and 86°F [15°C and 30°C]).  Patients will be 
requested to store vismodegib at the recommended storage conditions noted on the 
label, out of reach of children. 
In case of accidental capsule breakage, these instructions should be followed by sites 
and/or patients: 
• 
Keep your face away from the open container 
• 
Close the container and return the medication to the pharmacists for proper 
handling 
• 
In case of eye or skin contact or accidental inhalation follow first aid measures 
(see below) 
• 
If the contents of the capsule have spilled outside the container, wear protective 
gloves and protective mask, remove the spilled material with a wet towel, wash the 
area with soap and water, and dispose any material that had contact with the 
substance in a closed container 
• 
Observe local/national regulations regarding waste disposal 
• 
Do not allow drug to enter drains or waterways 
 
First-aid measures 
• 
Eye contact: Rinse immediately with tap water for 10 minutes; open eyelids forcibly 
• 
Skin contact: Remove immediately contaminated clothes, wash affected skin with 
water and soap.  Do not use any solvents 
• 
Inhalation: Take fresh air and keep calm.  In the event of symptoms, seek medical 
treatment. 
 
Note to physician: Treat symptomatically after accidental exposure.  Women of 
childbearing potential who are not taking vismodegib actively or pregnant women should 
get medical advice from a physician.  For women of childbearing potential who are not 
taking vismodegib actively or pregnant women, preserve blood and urine samples and 
notify Roche Drug Safety immediately. 
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6.3 
FORMULATION, PACKAGING, AND LABELING 
The formulated drug product vismodegib is provided in hard gelatin capsules of 150 mg.  
The 150-mg capsules are Size 1 with a grey-colored cap and a pink-colored body.  Two 
black stripes may be printed on the capsule shell using a commercial, compendial grade 
black ink.  Excipients included in the capsule formulations are microcrystalline cellulose, 
United States Pharmacopeia/National Formulary (USP/NF); lactose monohydrate, 
USP/NF; sodium lauryl sulfate, USP/NF; Povidone, USP/NF; Talc, USP; sodium 
glycolate, USP/NF; and magnesium stearate, USP/NF.  Capsules are packaged in 
75-mL round, white, high-density polyethylene (High-density polyethylene [HDPE]) 
bottles with two-piece HDPE child-resistant caps.  The bottles are induction sealed and 
labeled for clinical trial use only.  Each bottle contains 32 capsules.  For additional batch 
specific instructions and information for vismodegib capsules, see the packaging. 
For further details, see the Vismodegib Investigator Brochure.  
The packaging and labeling of the study medication will be in accordance with Roche 
standards and local regulations.  Vismodegib will be labeled in compliance with Good 
Manufacturing Practice (GMP). 
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, batch 
number, storage conditions, drug identification and dosage, and the statement, “For 
Clinical Trial Use Only.” 
The study drug must be stored according to the details on the product label.  The drug 
label indicates the storage temperature. 
Local packaging in some countries may be different. 
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions, 
and report any deviations or product complaints to the monitor upon discovery. 
6.4 
DISPOSAL CONSIDERATIONS 
Observe local/national regulations regarding waste disposal.  Incinerate in a qualified 
installation with flue gas scrubbing. 
6.5 
BLINDING AND UNBLINDING 
Not applicable.  This is an open-label non-comparative study. 
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6.6 
ACCOUNTABILITY OF IMP AND ASSESSMENT OF 
COMPLIANCE 
6.6.1 
Accountability of IMP 
The Investigator is responsible for the control of drugs under investigation.  Adequate 
records for the receipts (e.g., Drug Receipt Record) and disposition (e.g., Drug 
Dispensing Log) of the study drug must be maintained.  Accountability and patient 
compliance will be assessed by maintaining adequate “drug dispensing” and return 
records. 
Accurate records must be kept for each study drug provided by the Sponsor.  These 
records must contain the following information: 
• 
Documentation of drug shipments received from the Sponsor (date received, 
quantity, and batch number) 
• 
Disposition of unused study drug not dispensed to patient 
 
A Drug Dispensing Log must be kept current and should contain the following 
information:  
• 
The identification of the patient to whom the study medication was dispensed 
• 
The date(s), quantity and batch number of the study medication dispensed to the 
patient 
• 
The date(s), quantity and batch number of the study medication returned by the 
patient 
 
All records and drug supplies must be available for inspection by the Monitor at every 
monitoring visit. 
Patients will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance. 
This inventory must be available for inspection by the Monitor.  All supplies, including 
partially used or empty containers and copies of the dispensing and inventory logs, must 
be returned to the Monitor at the end of the study, unless alternate destruction has been 
authorized by Roche or required by local or institutional regulations (Section 6.6). 
6.6.2 
Assessment of Compliance 
Patient compliance will be assessed by maintaining adequate study drug dispensing 
records.  The Investigator is responsible for ensuring that dosing is administered in 
compliance with the protocol.  Delegation of this task must be clearly documented and 
approved by the Investigator. 
6.7 
DESTRUCTION OF THE IMP 
Local or institutional regulations may require immediate destruction of used IMP for 
safety reasons, e.g., cytotoxicity.  In these cases, it may be acceptable for investigational 
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site staff to destroy dispensed IMP before a monitoring inspection provided that source 
document verification is performed on the remaining inventory and reconciled against 
the documentation of quantity shipped, dispensed, returned, and destroyed.  Written 
authorization must be obtained from the Sponsor at study start up before destruction. 
Written documentation of destruction must contain the following: 
• 
Identity (batch numbers and patient numbers) of investigational product(s) 
destroyed 
• 
Quantity of investigational product(s) destroyed 
• 
Date of destruction (date discarded in designated hazardous container for 
destruction) 
• 
Method of destruction (the site must provide the Sponsor with documentation of 
their institutional policy and procedures for handling and disposing of hazardous 
drugs) 
• 
Name and signature of responsible person who discarded the investigational 
product in a hazardous container for destruction 
 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
Safety assessments will consist of monitoring and recording protocol-defined AEs and 
SAEs; measurement of protocol-specified hematology and clinical chemistry variables; 
measurement of protocol-specified vital signs; and other protocol-specified tests that are 
deemed critical to the safety evaluation of the study drug. 
7.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
7.1.1 
Clinical Adverse Events (AEs) 
According to the International Conference of Harmonization (ICH), an AE is any 
untoward medical occurrence in a patient or clinical investigation subject (patient) 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product.  Pre-existing conditions 
which worsen during a study are to be reported as AEs. 
This includes the following: 
• 
AEs not previously observed in the patient that emerge during the protocol-specified 
AE reporting period, including signs or symptoms associated with locally advanced 
or metastatic BCC that were not present prior to the AE reporting period 
(see Section 7.2.1) 
• 
Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as biopsies) 
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• 
AEs that occur prior to assignment of study treatment that are related to a 
protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
medication washout, or no treatment run-in)  
• 
Pre-existing medical conditions that are judged by the Investigator to have 
worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period 
 
7.1.1.1 
Intensity  
Intensity of all AEs will be graded according to the NCI-CTCAE, v4.0 on a five-point 
scale (Grade 1 to 5) and reported in detail on the eCRF.  
AEs not listed on the CTCAE should be graded as follows:  
Table 2 
Adverse Event Grading (Severity) Scale 
CTC Grade 
Equivalent To: 
Definition 
Discomfort noticed but no disruption of normal daily 
activity  
Grade 1 
Mild 
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated although 
this could improve the overall well-being or symptoms of 
the subject 
Grade 2 
Moderate 
Inability to work or perform normal daily activity; treatment 
or medical intervention is indicated in order to improve the 
overall well-being or symptoms; delaying the onset of 
treatment is not putting the survival of the subject at direct 
risk. 
Grade 3 
Severe 
An immediate threat to life or leading to a permanent 
mental or physical conditions that prevents work or 
performing normal daily activities; treatment or medical 
intervention is required in order to maintain survival. 
Grade 4 
Life threatening/ 
disabling 
AE resulting in death  
Grade 5 
Death  
AE = adverse event; CTC = common terminology criteria. 
 
7.1.1.2 
Drug–Adverse Event Relationship 
The causality relationship of study drug to the AE will be assessed by the Investigator as 
either: 
Yes or No 
If there is a reasonable suspected causal relationship to the study medication, i.e., there 
are facts (evidence) or arguments to suggest a causal relationship, drug–event 
relationship should be assessed as Yes. 
The following criteria should be considered in order to assess the relationship as Yes: 
• 
Reasonable temporal association with drug administration 
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• 
It may or may not have been produced by the patient’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to the patient 
• 
Known response pattern to suspected drug 
• 
Disappears or decreases on cessation or reduction in dose 
• 
Reappears on rechallenge 
 
The following criteria should be considered in order to assess the relationship as No: 
• 
It does not follow a reasonable temporal sequence from administration of the drug 
• 
It may readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient 
• 
It does not follow a known pattern of response to the suspected drug 
• 
It does not reappear or worsen when the drug is re-administered 
 
7.1.1.3 
Serious Adverse Events [Immediately Reportable to Roche] 
A serious AE (SAE) is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  These must be reported to Roche within 
24 hours of the Investigator becoming aware of the event through the eSAE page in the 
eCRF.  An SAE is any adverse event that at any dose fulfills at least one of the following 
criteria:  
• 
Is fatal; (results in death**; NOTE: death is an outcome, not an event) 
• 
Is life-threatening (NOTE: the term "life-threatening" refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused a death had it been more severe) 
• 
Required in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
**The term sudden death should be used only when the cause of a cardiac origin as per 
standard definition.  The term death and sudden death are clearly distinct and must not 
be used interchangeably.  
Deaths that occur during the protocol-specified AE reporting period (see Section 7.2.1) 
that are attributed by the Investigator solely to progression of advanced BCC will be 
recorded only on the Study Discontinuation eCRF.  All other on-study deaths, regardless 
of attribution except PD, will be recorded as an SAE on the AE eCRF and expeditiously 
reported to the Sponsor. 
The study will comply with all local regulatory requirements and adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2 (Appendix 4). 
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After informed consent, but prior to initiation of study medications, only SAEs caused by 
a protocol-mandated intervention will be collected (e.g., SAEs related to invasive 
procedures such as biopsies, medication washout, or no treatment run-in). 
7.1.1.4 
Other Safety Findings Requiring Expedited Reporting 
Other safety findings may require expedited reporting depending on local legislation. 
The following events are events of special interest and will need to be reported to the 
Sponsor expeditiously (see Section 7.1.2 for reporting instructions), irrespective of 
regulatory seriousness criteria: 
7.1.2 
Pregnancy and Lactation 
Small-molecule inhibitors of the Hedgehog pathway are known teratogens that result in 
midline malformations, such as holoprosencephaly, cyclopia, and other severe 
developmental defects.  The teratogenic potential of vismodegib has been confirmed in 
an embryo-fetal development study in rats (please see the updated Vismodegib 
Investigator Brochure).  Women who plan to become pregnant (during a study or for 
9 months after the last dose or within the designated window per approved local 
prescribing information for vismodegib [where available], whichever is longer) are 
excluded from all vismodegib clinical studies.  Please refer to the Vismodegib 
Investigator Brochure for further information regarding the teratogenic potential of 
vismodegib. 
• 
Pregnant women: Vismodegib is contraindicated in pregnant women or women 
planning to become pregnant during treatment and for 9 months or within the 
designated window per approved local prescribing information for vismodegib 
(where available), whichever is longer, after the last dose. 
• 
Nursing mothers: Vismodegib is contraindicated in nursing mothers.  The extent to 
which vismodegib or any of its metabolites are excreted in breast milk is not known. 
 
7.1.2.1 
Use in Women of Childbearing Potential 
As of the data cutoff date of 15 December 2011, there have been no reports of 
pregnancy in female patients treated with vismodegib. 
To prevent pregnancy and the risk of fetal exposure to vismodegib, female patients 
should not become pregnant or plan to become pregnant during treatment with 
vismodegib and for 9 months or within the designated window per approved local 
prescribing information for vismodegib (where available), whichever is longer, after the 
last dose. 
Specific actions are required when treating female patients of childbearing potential.  
Patients should be thoroughly counseled and informed of the teratogenic potential of 
vismodegib.  All pregnancy prevention measures for women of childbearing potential 
must be followed for the duration of the study and for 9 months or within the designated 
window per approved local prescribing information for vismodegib (where  available), 
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whichever is longer,  after the last dose.  Patients should be counseled on the use of 
contraception before beginning treatment with vismodegib.  As appropriate, the treating 
physician should refer the subject to her gynecologist or other healthcare provider to 
ensure proper understanding of the use of her chosen contraceptive method.  
Acceptable contraception and duration of contraceptive use should comply with locally 
approved vismodegib (Erivedge®, the trade name for vismodegib) Pregnancy Prevention 
Program or prescribing information where vismodegib is commercially available. 
Please refer to Appendix 2 for a definition of women of childbearing potential and a list of 
acceptable and unacceptable forms of contraception. 
Women of childbearing potential are required to have a negative medically-supervised 
serum or urine pregnancy test (sensitivity of at least 50 mIU/mL) within 7 days prior to 
the first dose of vismodegib.  Every 4 weeks thereafter, medically supervised serum or 
urine pregnancy tests are required for women of childbearing potential, and the test must 
be negative within 7 days prior to receiving her supply of vismodegib capsules. 
Treating physicians must confirm (with documentation in the medical record) a negative 
pregnancy test and non-childbearing status (both outlined above), that the patient is 
using two acceptable forms of contraception, that the patient understands the risk of 
teratogenicity with vismodegib, and that the patient has signed the informed consent 
understanding the pregnancy prevention program. 
Patients must notify the treating physician if they have changed their forms of 
contraception from the previous month. 
If a woman of childbearing potential believes that her contraceptive method has failed, 
she must immediately stop taking vismodegib, notify her treating physician immediately, 
and discuss available management options.  For female patients outside of the United 
States, the patient should immediately consult with her physician or 
obstetrician/gynecologist (OB/GYN) regarding options for pregnancy testing, 
management, and treatment. 
7.1.2.2 
Male Patients 
It is not known if vismodegib that may be present in seminal fluid would cause 
teratogenic effects in a fetus born to the female partner of a male subject.  Therefore, 
sexually active male patients must utilize a barrier form of contraception, even if he has 
had a vasectomy, during vismodegib treatment and for 2 months or as per approved 
local prescribing information for vismodegib (where available), whichever is longer, 
after the last dose.   
7.1.2.3 
Pregnancy Reporting 
If a female patient becomes pregnant while receiving investigational therapy with 
vismodegib or within 9 months or within the designated window per approved local 
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prescribing information for vismodegib (where available), whichever is longer, after the 
last dose, the Investigator must report all pregnancies immediately i.e., no more than 
24 hours after learning of the event to the Sponsor. 
A female patient must be instructed to stop taking the test “drug” and immediately inform 
the Investigator if she becomes pregnant during the study.  The Investigator should 
report all pregnancies immediately i.e., no more than 24 hours after learning of the event 
to the Sponsor, using the Clinical Trial Pregnancy Reporting Form.  The Investigator 
should counsel the patient, discussing the risks of continuing with the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Pregnancies occurring up to 9 months or within the designated 
window per approved local prescribing information for vismodegib (where available), 
whichever is longer, after the completion of the study medication must also be reported 
to the Investigator. 
If a female partner of a male patient becomes pregnant during vismodegib treatment or 
within 2 months or within the designated window per approved local prescribing 
information for vismodegib (where available), whichever is longer, after the last dose of 
vismodegib, the pregnancy must be reported to the Investigator and the Sponsor and 
alert the female partner to consult with her physician.  The partner should be counseled 
and the risks of continuing the pregnancy discussed, as well as the possible effects on 
the fetus.  Monitoring of the female partner should continue until conclusion of the 
pregnancy.  
NOTE: The Investigator should fill out a Pregnancy Reporting Form only if the pregnant 
partner has signed a Pregnant Partner Data Release Form.  
7.1.3 
Abortion, Congenital Anomaly and Birth Defects 
Abortions, congenital anomalies and birth defects are events of special interest and will 
need to be reported to the Sponsor immediately i.e., no more than 24 hours after 
learning of the event (see Section 7.1.2 for reporting instructions). 
Abortion, whether therapeutic or spontaneous, should always be classified as serious 
(as the Sponsor considers these medically significant), recorded on an SAE eCRF page, 
and reported to the Sponsor immediately i.e., no more than 24 hours after learning of the 
event. 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to the investigational product should be recorded and reported 
as an SAE to the Sponsor immediately i.e., no more than 24 hours after learning of the 
event.  
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7.1.4 
Blood Donation 
Patients must not donate blood or blood products while on study and for 9 months or as 
per approved local prescribing information for vismodegib (where available), whichever 
is longer, after discontinuation of vismodegib.  Where vismodegib is commercially 
available, avoidance of blood donation should comply with locally approved prescribing 
information. 
7.1.5 
Progression of Underlying Malignancy 
Progression of underlying malignancy is not reported as an AE if it is clearly 
consistent with the suspected progression of the underlying cancer, as defined by 
RECIST criteria or other criteria as determined by protocol.  Hospitalization due solely to 
the progression of underlying malignancy should not be reported as an SAE.  Clinical 
symptoms of progression may be reported as AEs if the symptoms cannot be 
determined to be exclusively due to the progression of the underlying malignancy, or do 
not fit the expected pattern of progression for the disease under study. 
Symptomatic deterioration may occur in some patients.  In this situation, progression is 
evident in the patient’s clinical symptoms, but is not supported by the tumor 
measurements.  Or, the disease progression is so evident that the Investigator may elect 
not to perform further disease assessments.  In such cases, the determination of clinical 
progression is based on symptomatic deterioration.  These determinations should be a 
rare exception, as every effort should be made to document the objective progression of 
underlying malignancy. 
If there is any uncertainty about an AE being due only to the disease under study, it 
should be reported as an AE or SAE. 
7.1.6 
Treatment and Follow-Up of Adverse Events (AEs)  
After the five Safety Follow-Up Visits 1 month, 3 months, 6 months, 9 months, and 
12 months from the last dose of study drug continue to follow up AEs as follows: 
Related SAEs are to be reported indefinitely. 
Related AEs.  Follow until one of the following occurs: 
• 
Resolved or improved to baseline 
• 
Relationship is reassessed as unrelated 
• 
Death 
• 
Start of new anti-cancer regimen  
• 
Investigator confirms that no further improvement can be expected  
• 
Clinical or safety data will no longer be collected, or final database closure 
 
Unrelated severe or life threatening AEs.  Follow until one of the following occurs: 
• 
Resolved or improved to baseline 
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• 
Severity improved to Grade 2 
• 
Death 
• 
Start of new anti-cancer regimen  
• 
Investigator confirms that no further improvement can be expected  
• 
Clinical or safety data will no longer be collected, or final database closure 
 
Unrelated Grade 1 or Grade 2 AEs.  Follow until 30 days from the last dose of study 
drug. 
The final outcome of each AE must be recorded on the eCRF. 
7.1.7 
Laboratory Test Abnormalities 
Local laboratories will be used for all laboratory tests.  Laboratory test abnormalities will 
be recorded on the AEs pages of the eCRF. 
Any laboratory result abnormality fulfilling the criteria for an SAE should be reported as 
such, in addition to being recorded as an AE in the eCRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the AE page in the eCRF: 
• 
Accompanied by clinical symptoms 
• 
Leading to a change in study medication (e.g., dose modification, interruption, or 
permanent discontinuation) 
• 
Requiring a change in concomitant therapy (e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, or 
treatment) 
 
7.1.8 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  If a clear explanation is 
established it should be recorded on the eCRF. 
7.2 
HANDLING OF SAFETY PARAMETERS 
7.2.1 
Recording and Collection of Adverse Events 
Information about all AEs, whether volunteered by the patient, discovered by Investigator 
questioning, or detected through physical examination, laboratory test, or other means, 
will be collected on the Adverse Event eCRF page, documented in the patient’s medical 
records, and followed as appropriate. 
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All AEs and SAEs, regardless of the relationship to the trial drug, will be recorded in the 
eCRF. 
All AE reports should contain a brief description of the event, date and time of onset, 
date and time of resolution, intensity, treatment required, relationship to trial drug, action 
taken with the trial drug, outcome, and whether the AE is classified as serious. 
All AEs experienced after the patient has started study treatment must be recorded on 
the AE form of the eCRF, as well as all new AEs experienced during the study and 
during further five Safety Follow-Up Visits 1 month, 3 months, 6 months, 9 months, and 
12 months after the last dose of study treatment (± 5 days).  SAEs considered related to 
study drug are to be reported indefinitely. 
A pre-existing medical condition that is present at the start of the study should be 
recorded on the Medical History eCRF. 
Worsening and/or progression of advanced BCC should not be recorded as an AE or 
SAE.  These data will be captured as efficacy assessment data only. 
If a female patient becomes pregnant while receiving investigational therapy or within 
9 months or within the designated window per approved local prescribing information 
for vismodegib (where available), whichever is longer, after the last dose of 
investigational product, the Investigator should report to the Sponsor immediately within 
one working day (24 hours) of learning of the pregnancy. 
Abortion, whether therapeutic or spontaneous, should always be classified as serious 
(as the Sponsor considers these medically significant), recorded on the eCRF, and 
expeditiously reported to the Sponsor. 
7.2.2 
Reporting of Serious Adverse Events (Immediately Reportable) 
Any clinical AE or abnormal laboratory test value that is serious and which occurs during 
the course of the study (as defined in Section 7.1.1.3 above), must be reported to Roche 
within 24 hours of the Investigator becoming aware of the event (expedited reporting).  
The following proviso applies: 
• 
During the Screening Period, after written informed consent has been signed 
only SAEs related to protocol procedures will be reported. 
• 
From the first administration of vismodegib, all SAEs must be reported. 
 
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Related SAEs MUST be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed.  Suspected 
Unexpected Serious Adverse Reactions (SUSARs) are reported to Investigators at each 
site and associated Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
when the following conditions occur: 
• 
The event must be a SAE 
• 
There must be a certain degree of probability that the event is an adverse reaction 
from the administered drug 
• 
The adverse reaction must be unexpected, that is to say, not foreseen in the 
Investigator’s Brochure (for an unauthorized medicinal product)  
 
When all patients at a particular site are off treatment as defined by the protocol:  
• 
Only individual SUSAR reports originating in that particular trial will be forwarded to 
the site and associated IRB/IEC on an expedited basis 
• 
Individual SUSARs considered to be a significant safety issue and/or which result in 
Roche recommending a change to the ICF, will be reported in an expedited manner 
to all Investigators and IRBs/IECs 
• 
SUSAR reports originating from other trials using the same IMP will be provided as 
6-monthly SUSAR Reports to Investigators and IRBs/IECs where long-term 
follow-up studies are carried out, unless they are considered significant 
 
Unrelated SAEs must be collected and reported during the study and for up to 
12 months after the last dose of study medication. 
This study adheres to the definition and reporting requirements of ICH Guideline for 
Clinical Safety Data Management, Definitions and Standards for Expedited 
Reporting, Topic E2.  Complete information can be found in Appendix 4. 
7.2.3 
Reporting of Non-Serious Events of Special Interest  
Not applicable. 
7.2.4 
PRO Data and Adverse Event Reporting 
Adverse event reports will not be derived from PRO data.  However, if any patient 
responses suggestive of a possible adverse event are identified during site review of the 
PRO questionnaires, site staff will alert the investigator, who will determine if the criteria 
for an adverse event have been met and will document the outcome of this assessment 
in the patient's medical record per site practice.  If the event meets the criteria for an 
adverse event, it will be reported on the Adverse Event eCRF. 
7.3 
WARNINGS AND PRECAUTIONS  
No evidence available at the time of the approval of this study protocol indicated that 
special warnings or precautions were appropriate, other than those noted in the 
Investigators’ Brochure.  
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8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
8.1 
PRIMARY AND SECONDARY VARIABLES 
The final analysis for safety and efficacy will be performed when the last patient on 
treatment develops progressive disease (as determined by the Investigator) or 
unacceptable toxicity, withdraws consent, or dies; the treating physician deems the 
patient is no longer benefitting from treatment; or the study is terminated by the Sponsor, 
or 12 months after the last dose of vismodegib in the last enrolled patient still on study, 
whichever occurs first.   
Additional interim analyses will be performed as described in Section 8.2.1.2. 
8.1.1 
Primary Variables 
The primary objective of this trial is to assess the safety of vismodegib in patients with 
locally advanced or metastatic BCC.  
Consequently, the following safety variables are primary variables: all AEs, AEs 
Grade 3 or 4, AEs leading to drug interruptions or discontinuations, SAEs, cause of 
death on study, premature discontinuation from study and treatment, laboratory 
parameters (hematology and serum chemistry), and exposure to study medication. 
Continuous data will be summarized using mean, standard deviation, median, minimum, 
and maximum.  Discrete data will be summarized using frequencies and percentages.  
No adjustments for multiplicity of endpoints or within-subgroup comparisons will be used 
in the analyses. 
8.1.2 
Secondary Variables 
Other safety secondary variables are:  physical examinations, vital signs (body 
temperature, blood pressure, pulse and respiratory rate), electrocardiogram, ECOG PS, 
and concomitant therapies. 
The following efficacy variables will also be secondary variables:  ORR, duration of 
response, time to response, PFS, OS, QoL, and disease symptom.  
8.2 
HYPOTHESIS TESTING 
No formal hypothesis testing is planned. 
8.2.1 
Types of Analyses 
8.2.1.1 
Efficacy Analysis 
The efficacy summaries will be presented for the ITT population, which will include all 
patients enrolled in the study. 
The efficacy variable of primary interest for this study is the overall response rate (ORR), 
as assessed by the Investigator according to RECIST, v1.1.  The summary will be 
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performed on patients with measureable disease at baseline.  The best overall response 
rate (BORR) will be reported.  BORR is defined as the number of patients whose best 
objective response is CR or PR divided by the total number of treated patients in the 
group for which the BORR is estimated. 
Duration of response is the key secondary efficacy variable.  It is defined only for the 
patients whose confirmed best response is CR or PR as the time interval between the 
date of the earliest qualifying response and the date of PD or death for any cause.  For 
patients who are alive without progression following the qualifying response, duration of 
response will be censored on the date of last evaluable tumor assessment or last 
follow-up for progression of disease.  This will be done based on Investigator’s 
assessments.  
Time to response is defined as the interval between the date of first treatment and the 
date of first documentation of confirmed CR or PR (whichever occur first).  This will be 
done based on Investigator’s assessments. 
Progression Free Survival (PFS) is defined as the time interval between the date of the 
first therapy and the date of progression or death for any causes, whichever occurs first.  
A patient who died without a reported progression will be considered as an event on the 
date of death.  Patients who have neither progressed nor died will be censored on the 
date of last evaluable tumor assessment.  This will be done based on Investigator’s 
assessments.  Patients with non-measureable disease will be assessed for disease 
progression and included in this summary. 
Overall survival (OS) is defined as the time from the date of first treatment to the date of 
death, regardless of the cause of death.  For patients who are alive at the time of 
analysis, OS time will be censored at the last date the patient was known to be alive.  
Patients with no post baseline information will be censored at the time of first treatment 
with vismodegib. 
The best ORRs (confirmed complete and confirmed partial responders) together with the 
corresponding 95% Pearson-Clopper confidence intervals will be presented.  A listing of 
tumor assessments and best overall response will also be presented. 
Estimates for the survivor function for the time-to-event endpoints, including PFS, OS, 
time to response, and duration of response, will be displayed graphically using 
Kaplan-Meier (KM) curves.  Estimates for the median time to event and the 
corresponding two-sided 95% confidence interval will be presented with the estimates 
for the other quartiles and the associated ranges (minimum, maximum).  The estimates 
and KM curves will be presented for the ITT population. 
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8.2.1.2 
Interim Analysis 
In addition to final analysis, there will be six interim analyses for publication of safety and 
efficacy results and DSMB reviews when the: 
• 
First 75 patients enrolled have been treated for at least 3 months,  
• 
First 150 patients enrolled have been treated for at least 3 months,  
• 
First 300 patients enrolled have been treated for at least 3 months, 
• 
First 550 patients enrolled have been treated for at least 3 months, 
• 
First 800 patients enrolled have been treated for at least 3 months, and  
• 
1200 patients enrolled have been treated for at least 3 months (see also Section 10).  
• 
This last interim analysis will also include analysis of 500 enrolled patients who 
have been followed for at least 1 year. 
Relevant details will be described in the DSMB charter and Statistical Analysis Plan. 
8.2.2 
Safety Analysis 
The safety variables will be summarized for the safety population, where the safety 
population will include all patients who received at least one dose of study medication.  
If the safety population differs by less than 5 patients from the ITT population, then all 
summaries will be presented only for the safety population. 
AEs, AE Grade 3 or 4, AEs leading to drug interruptions or discontinuation and SAEs 
All AEs will be assessed according to the NCI-CTCAE, v4.0 grading system. 
The analysis of AEs will focus on treatment-emergent AEs, i.e., AEs occurring on or after 
the first day of vismodegib administration.  Non–treatment-emergent AEs (i.e., those 
occurring before commencement of study medication) will only be listed. 
The incidence, type, and severity of AEs will be summarized according to the primary 
system organ class (SOC) and within each SOC by the Medical Dictionary for 
Regulatory Activities (MedDRA) preferred term.  Summary tables might be presented for 
time to first onset of the AE of special interest. 
SAEs and AEs leading to drug interruptions or discontinuation will be analyzed similarly.  
Cause of death will also be summarized and listed. 
Premature withdrawal from study and treatment 
The number of patients who prematurely discontinued treatment, along with the 
corresponding reason(s) for discontinuation, will be summarized and listed.  The 
discontinuation from study will be also summarized and listed.  
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Exposure to Study Medication 
The exposure of vismodegib will be summarized by means of descriptive statistics for 
the cumulative dose and frequency tables (percentages) by Cycles and/or Weeks of 
treatment.  The reason for the dose discontinuation other than disease progression will 
be also summarized. 
Laboratory parameters 
Laboratory parameters, hematology, and serum chemistry will be presented in shift 
tables of NCI-CTCAE grade at baseline versus worst grade during the treatment period.  
Summary of laboratory parameters will be presented by means, standard deviation, 
minimum, and maximum.  Graphical presentations of the mean value of selected 
laboratory parameters might be also displayed.  
Physical Examination 
Physical examination variables will be summarized over time by visit and reported in 
patient listings. 
Vital Signs and ECG 
Vital signs and ECG will be summarized over time by means of mean, median, and 
range (mean and maximum), and will be presented graphically over time. 
ECOG PS 
The ECOG PS will be summarized by frequency tables over time, and the percentage of 
patients in different categories will be presented by bar charts at different time points. 
Concomitant therapy and new anticancer-therapy 
Concomitant therapy recorded during the study and new anticancer therapy at the End 
of Treatment Visit will be summarized for the safety population and presented by 
frequency tables and percentages. 
8.2.3 
Other Analyses 
Medical history, including demographics, (age, sex, and race as applicable), clinically 
significant diseases, previous surgeries, prior skin cancer history, prior skin cancer 
therapies and procedures, response to prior therapies, and all medications used by the 
patient within 14 days preceding the screening visit will be summarized at baseline for 
the ITT and safety populations.  
In metastatic BCC patients (who are on study after approval of the Study Protocol, 
version 4.0), evidence of tumor progression prior to enrollment on study and reasons for 
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treatment discontinuation of prior therapies will be summarized.  Analysis of data 
regarding evidence of progression prior to enrollment and reasons for treatment 
discontinuation of prior therapies will be performed in metastatic BCC patients. 
The following exploratory analyses will be performed: 
• 
In metastatic BCC patients, measures of pathway signaling may include, but will not 
be limited to, one or more of the following:  1) quantitative RT PCR profiling of Hh 
ligands, the target of vismodegib (SMO), and transcriptional target genes; and 
2) any other assessments related to the understanding of vismodegib resistance 
mechanism.  Analyses of mutational status of relevant pathway may be performed 
to determine their possible role in the development of acquired resistance in 
metastatic BCC patients treated with vismodegib. 
• 
In patients with any adverse events that were reported to be related to vismodegib 
treatment and that are continuing at least 6 months after the last dose of vismodegib, 
PK analyses will be performed to determine if vismodegib is still present and may 
correlate with the continuing adverse event at 6, 9, and 12 months after the last 
dose of vismodegib. 
• 
In 30 patients, post-treatment PK analyses will be performed to characterize the 
elimination of vismodegib from steady-state to 3, 6, 9, and 12 months after the last 
dose of vismodegib. 
 
Protocol deviations will be listed. 
8.2.3.1 
Subgroup Analyses 
Exploratory subgroup analyses might be performed, e.g., younger versus elderly, ECOG 
performance status (PS 0–1 vs. PS > 1), etc. 
8.2.3.2 
Quality of Life Analyses and Disease Symptoms Assessment 
Skindex-16 
The effects of skin disease on patient’s quality of life (QoL) will be accessed by the 
Skindex-16 questionnaire.  The Skindex-16 includes three domains: symptoms, 
emotions and function.  For ease of interpretation of scores, responses will be 
transformed to a linear scale of 100 varying from 0 (never bothered, i.e., best) to 
100 (always bothers, i.e., worst).  Distribution of scores for each domain over time will be 
presented by box plots and summary tables for continuous variables by means of mean, 
standard deviation, median, minimum, maximum, and 25th and 75th percentile.  The 
mean scores will be presented by line graphs and corresponding 95% confidence 
intervals over time.  Changes from baseline will be summarized by descriptive statistics 
and displayed together with associated 95% confidence intervals.  Individual items of 
interest for each domain might also be summarized by frequency tables and presented 
by bar charts.  
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M.D. Anderson Symptom Inventory 
The MDASI instrument will be used to determine the rate and the number of patients 
who have a 30% reduction in disease-related symptoms in metastatic BCC patients 
(e.g. pain, fatigue, shortness of breath, lack of appetite, dry mouth and coughing) 
following treatment with vismodegib in patients who have at least a score of 4 points at 
baseline. 
QoL will be analyzed for the ITT population.  If the safety population differs by more than 
5 patients from the ITT population, then some QoL summaries might be presented for 
the safety population, as well. 
More details will be presented in the statistical analysis plan. 
8.2.3.3 
Exploratory Pharmacokinetic Analyses 
Individual and mean plasma vismodegib concentration versus time data will be tabulated 
and plotted.  Plasma AAG concentration and unbound plasma concentration at selected 
time points will be estimated, tabulated and summarized (geometric mean, mean, 
standard deviation, coefficient of variation, median, minimum, and maximum).  
Additional PK analyses may be conducted as appropriate.  
8.3 
SAMPLE SIZE 
Approximately 1200 patients will be enrolled in this study. 
Table 3 
Clopper-Pearson 95% Confidence Intervals for the Observed AE 
Incidence1 
Number of AE events/ 
observed AE incidence 
95% Clopper Pearson 
Confidence Interval 
12 (1%) 
0.5%-2% 
24 (2%) 
1.3%-3.0% 
60 (5%) 
3.8%-6.4% 
120 (10%) 
 8.4%-11.8% 
240 (20%) 
17.8%-22.4% 
360 (30%) 
27.4%-32.7% 
1 Total number of patients is 1200 
 
Therefore, for a sample size of 1200 patients, the true AE incidence rate can be 
estimated to within 1.6%–1.8% assuming an observed incidence of 10%, i.e., within 95% 
Clopper-Pearson confidence interval of 8.4%–11.8%. 
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9. 
DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
Data for this study will be recorded via an Electronic Data Capture (EDC) system using 
electronic CRF.  It will be transcribed by the site from the paper source documents onto 
the CRF.  In no case is the eCRF to be considered as source data for this trial. 
Accurate and reliable data collection will be assured by verification and cross-check of 
the eCRFs against the Investigator’s records by the study monitor (source document 
verification), and the maintenance of a drug-dispensing log by the Investigator. 
A comprehensive validation check program utilizing front-end checks in the eCRF and 
back-end checks in the Roche database will verify the data and discrepancies will be 
generated accordingly.  These are transferred electronically to the eCRF at the site for 
resolution by the Investigator. 
The result of the analysis must not be released with individual identification of the patient 
until the database is closed. 
Assignment of Preferred Terms and Original Terminology 
For classification purposes, preferred terms will be assigned by the Sponsor to the 
original terms entered on the CRF, using the most up-to-date version of the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology for AEs and diseases and the 
International Non-proprietary Name Drug Terms and Procedures Dictionary for 
treatments and surgical and medical procedures Study Committees. 
10. 
STUDY COMMITTEES 
A Data Safety Monitoring Board (DSMB) will be established for this study.  The DSMB 
will be responsible for monitoring patient efficacy and safety data during the course of 
the study.  The DSMB will meet to review safety data after:  
• 
First 75 patients enrolled have been treated for at least 3 months,  
• 
First 150 patients enrolled have been treated for at least 3 months,  
• 
First 300 patients enrolled have been treated for at least 3 months, 
• 
First 550 patients enrolled have been treated for at least 3 months, 
• 
First 800 patients enrolled have been treated for at least 3 months, and  
• 
1200 patients enrolled have been treated for at least 3 months and as per DSMB’s 
recommendation. 
 
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The DSMB will be responsible for independently evaluating the safety and efficacy of the 
patients participating in the trial and will be led by a medically qualified Chairperson.  
Following each meeting, the DSMB will recommend to the Sponsor that the study 
continues according to the protocol or suggest changes to the protocol based on the 
outcome of the data review.  
Further details of the DSMB responsibilities and logistics will be documented in the 
DSMB Charter. 
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11. 
REFERENCES 
1. 
American Cancer Society. Cancer Facts & Figures. 2011  [cited 2011 August]; 
Available from: http://www.cancer.org/Research/CancerFactsFigures/index 
2. 
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA 
Cancer J Clin. 2007;57:43-66. 
3. 
Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005;353:2262-
9. 
4. 
Cohen B, Weiss G, Yin H. Basal cell carcinoma (BCC) causing spinal cord 
compression. Dermatol Online J. 2000;6:12. 
5. 
Kovarik CL, Stewart D, Barnard JJ. Lethal basal cell carcinoma secondary to 
cerebral invasion. J Am Acad Dermatol. 2005;52:149-51. 
6. 
Wadhera A, Fazio M, Bricca G, Stanton O. Metastatic basal cell carcinoma: a case 
report and literature review. How accurate is our incidence data? Dermatol Online J. 
2006;12:7. 
7. 
Snow SN, Sahl W, Lo JS, Mohs FE, Warner T, Dekkinga JA, et al. Metastatic basal 
cell carcinoma. Report of five cases. Cancer. 1994;73:328-35. 
8. 
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. 
9. 
Lo JS, Snow SN, Reizner GT, Mohs FE, Larson PO, Hruza GJ. Metastatic basal cell 
carcinoma: report of twelve cases with a review of the literature. J Am Acad 
Dermatol. 1991;24:715-9. 
10. Spates ST, Mellette JR, Jr., Fitzpatrick J. Metastatic basal cell carcinoma. Dermatol 
Surg. 2003;29:650-2. 
11. Pfeiffer P, Hansen O, Rose C. Systemic cytotoxic therapy of basal cell carcinoma. A 
review of the literature. Eur J Cancer. 1990;26:73-7. 
12. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms 
and principles. Genes Dev. 2001;15:3059-87. 
13. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human 
homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 
1996;272:1668-71. 
14. Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman 
C, et al. The role of the human homologue of Drosophila patched in sporadic basal 
cell carcinomas. Nat Genet. 1996;14:78-81. 
15. Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, et al. 
Identification of mutations in the human PATCHED gene in sporadic basal cell 
carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 
1998;110:885-8. 
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16. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating Smoothened 
mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90-2. 
17. Dahmane N, Lee J, Robins P, Heller P, Ruiz i Altaba A. Activation of the 
transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. 
Nature. 1997;389:876-81. 
18. Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, Stahle-Backdahl M. Human 
patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial 
and sporadic basal cell carcinoma. Cancer Res. 1997;57:2336-40. 
19. Williams JA. Hedgehog signaling pathway as a target for therapeutic intervention in 
basal cell carcinoma. Drug News Perspect. 2003;16:657-62. 
20. Binns W, James LF, Shupe JL, Everett G. A congenital cyclopian-type malformation 
in lambs induced by maternal ingestion of a range plant, Veratrum californicum. Am 
J Vet Res. 1963;24:1164-75. 
21. Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of Hedgehog signaling by 
direct binding of cyclopamine to Smoothened. Genes Dev. 2002;16:2743-8. 
22. Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, et al. 
Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 
2003;425:851-6. 
23. Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, et al. 
Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 
2004;431:707-12. 
24. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, et al. 
Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 
2009;361:1164-72. 
25. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis K, Hainsworth JD, et al. CO14. A 
pivotal study evaluating efficacy and safety of the hedgehog pathway inhibitor (HPI) 
vismodegib (GDC-0449) in patients with locally advanced (la) or metastatic (m) 
basal cell carcinoma (BCC). Melanoma Res. 2011;21:e9. 
26. Walling HW, Fosko SW, Geraminejad PA, Whitaker DC, Arpey CJ. Aggressive 
basal cell carcinoma: presentation, pathogenesis, and management. Cancer 
Metastasis Rev. 2004;23:389-402. 
27. Chren MM, Lasek RJ, Sahay AP, Sands LP. Measurement properties of Skindex-16: 
a brief quality-of-life measure for patients with skin diseases. J Cutan Med Surg. 
2001;5:105-10. 
28. Chen T, Bertenthal D, Sahay A, Sen S, Chren MM. Predictors of skin-related quality 
of life after treatment of cutaneous basal cell carcinoma and squamous cell 
carcinoma. Arch Dermatol. 2007;143:1386-92. 
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29. Chren MM, Sahay AP, Bertenthal DS, Sen S, Landefeld CS. Quality-of-life 
outcomes of treatments for cutaneous basal cell carcinoma and squamous cell 
carcinoma. J Invest Dermatol. 2007;127:1351-7. 
30. Sekulic A., Migden MR, Oro AE, Dirix, L, Lewis KD Hainsworth JD et al.  Efficacy 
and Safety of Vismodegib in Advanced Basal-Cell Carcinoma. N Engl J Med. 
2012;366:2171-9. 
31. Dirix L. A pivotal multicentre trial evaluating efficacy and safety of the Hedgehog 
pathway inhibitor (HPI) vismodegib in patients with advanced basal cell carcinoma.  
Oral presentation at the European Multidisciplinary Cancer Congress.  Stockholm, 
Sweden, 23-27 September, 2011. 
32. Vismodegib Core Data Sheet, Version1.1, April 2012 
33. Erivedge Summary of Product Characteristics (Draft Version), February 2013. 
34. Cleeland CS, The M.D. Anderson Symptom Inventory User Guide 2010, 
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-
tools/MDASI_userguide.pdf 
35. Rudin, C. M. et al. Treatment of medulloblastoma with Hedgehog pathway inhibitor 
GDC-0449. N. Engl. J. Med. 2009;361:1173–1178. 
36. Yauch, R. L. et al. Smoothened mutation confers resistance to a Hedgehog pathway 
inhibitor in medulloblastoma. Science 2009;326, 572–574. 
 
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Part II: 
Ethics and General Study Administration 
12. 
ETHICAL ASPECTS 
12.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI 
The Investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the patient.  For studies conducted in the EU/EEA countries, the 
Investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC].  
In other countries where the “Guideline for Good Clinical Practice” exists Roche and the 
Investigators will strictly ensure adherence to the stated provisions. 
12.2 
INFORMED CONSENT 
12.2.1 
Main Study Informed Consent 
It is the responsibility of the Investigator, or a person designated by the 
Investigator (if acceptable by local regulations), to obtain signed informed 
consent from each patient prior to participating in this study after adequate 
explanation of the aims, methods, anticipated benefits and potential hazards of 
the study.  
The Investigator or designee must also explain that the patients are completely free to 
refuse to enter the study or to withdraw from it at any time, for any reason.  
The Case Report Forms for this study contain a section for documenting patient 
informed consent, and this must be completed appropriately.  If new safety information 
results in significant changes in the benefit-risk assessment, the consent form should 
be reviewed and updated if necessary.  All patients (including those already being 
treated) should be informed of the new information, given a copy of the revised form and 
give their consent to continue in the study. 
For the patient not qualified or incapable of giving legal consent, written consent must be 
obtained from the legally acceptable representative.  In the case where both the patient 
and his/her legally acceptable representative are unable to read, an impartial witness 
should be present during the entire informed consent discussion.  After the patient and 
representative have orally consented to participation in the trial, the witness’ signature 
on the form will attest that the information in the consent form was accurately explained 
and understood.  
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12.3 
INDEPENDENT ETHICS COMMITTEES (IEC)/INSTITUTIONAL 
REVIEW BOARD (IRB)  
Independent Ethics Committees [non-US]:  This protocol and any accompanying 
material provided to the patient [such as patient information sheets or descriptions of the 
study used to obtain informed consent] will be submitted by the Investigator to an 
Independent Ethics Committee.  An approval letter or certificate (specifying the protocol 
number and title) from the IEC/IRB must be obtained before starting the study, and 
should be documented in a letter to the Investigator specifying the date on which the 
committee met and granted the approval.  This applies whenever subsequent 
amendments/modifications are made to the protocol. 
Any modifications made to the protocol, informed consent or material provided to the 
patient after receipt of the IEC/IRB approval must also be submitted by the Investigator 
to the Committee in accordance with local procedures and regulatory requirements. 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments 
will be submitted to the IRB/EC and to Regulatory Authorities in accordance with 
local regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 
When no local review board exists, the Investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the Investigator 
in submitting the protocol to the European Ethics Review Committee. 
Roche shall also submit an Annual Safety Report once a year to the IEC and Competent 
Authorities (CAs) according to local regulatory requirements and timelines of each 
country participating in the study. 
12.4 
FINANCIAL DISCLOSURE 
The Investigator(s) will provide the Sponsor with sufficient accurate financial information 
(PD35) to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities.  The Investigator is 
responsible to promptly update any information provided to the Sponsor if relevant 
changes occur in the course of the investigation and for 1 year following the completion 
of the study (last patient, last visit). 
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13. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Requests from Investigators to modify the protocol to ongoing studies will be considered 
only by consultation between an appropriate representative of the Sponsor and the 
Investigator (Investigator representative[s] in the case of a multicenter trial).  Protocol 
modifications must be prepared by a representative of the Sponsor and initially reviewed 
and approved by the International Medical Leader and Biostatistician. 
All protocol modifications must be submitted to the appropriate IEC or IRB for information 
and approval in accordance with local requirements, and to Regulatory Agencies if 
required.  Approval must be obtained before any changes can be implemented, except for 
changes necessary to eliminate an immediate hazard to trial patients, or when the 
change(s) involves only logistical or administrative aspects of the trial, e.g., change in 
monitor[s], change of telephone number[s]. 
14. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the Sponsor and the Investigator reserve the right to terminate the study at any 
time.  Should this be necessary, both parties will arrange the procedures on an individual 
study basis after review and consultation.  In terminating the study, Roche and the 
Investigator will assure that adequate consideration is given to the protection of the 
patient’s interests.  The appropriate IRB/IEC and Regulatory Agencies should be 
informed accordingly. 
15. 
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING 
15.1 
INVESTIGATOR'S FILES/RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into two different separate categories: 1) Investigator's 
Study File, and 2) patient clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, Case Report and 
Query Forms and schedule of assessments, Independent Ethics 
Committee/Institutional Review Board and governmental approval with 
correspondence, sample informed consent, drug records, staff curriculum vitae and 
authorization forms and other appropriate documents/correspondence, etc.  In addition, 
at the end of the study the Investigator will receive the patient data, which includes an 
audit trail containing a complete record of all changes to data, query resolution 
correspondence and reasons for changes, in human readable format on compact disc, 
which also has to be kept with the Investigator’s Study File. 
Patient clinical source documents (usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs) would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
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laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and patient screening and enrollment logs.  
The Investigator must keep the two categories of documents as described above 
(including the archival CD) on file for at least 15 years after completion or discontinuation 
of the study.  After that period of time the documents may be destroyed, patient to local 
regulations. 
Should the Investigator wish to assign the study records to another party or move them 
to another location, Roche must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container(s) outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
ICH GCP guidelines require that Investigators maintain information in the study patient’s 
records which corroborate data collected on the CRF(s).  Completed CRFs will be 
forwarded to Roche. 
15.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
The Investigator shall supply the Sponsor on request with any required background data 
from the study documentation or clinic records.  This is particularly important when 
errors in data transcription are suspected.  In case of special problems and/or 
governmental queries or requests for audit inspections, it is also necessary to have 
access to the complete study records, provided that patient confidentiality is protected. 
15.3 
AUDITS AND INSPECTIONS 
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Quality Assurance or its 
designees, or to health authority inspectors after appropriate notification.  The 
verification of the CRF data must be by direct inspection of source documents. 
15.4 
CASE REPORT FORMS OR ELECTRONIC CASE REPORT 
FORMS 
Data for this study will be captured via an Electronic Data Capture (EDC) system by 
using an online eCRFs.  An audit trail will maintain a record of initial entries and changes 
made; reasons for change; time and date of entry; and user name of person authorizing 
entry or change.  
For each patient enrolled, an eCRF must be completed and electronically signed by the 
principal Investigator or authorized delegate from the study staff.  This also applies to 
records for those patients who fail to complete the study.  If a patient withdraws from the 
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study, the reason must be noted on the eCRF.  If a patient is withdrawn from the study 
because of a treatment-limiting AE, thorough efforts should be made to clearly document 
the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor in the eCRFs and in all required reports. 
16. 
MONITORING THE STUDY 
It is understood that the responsible Monitor will contact and visit the Investigator 
regularly and will be allowed, on request, to inspect the various records of the trial 
(eCRFs, source notes and other pertinent data) provided that patient confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor should have access to 
laboratory test reports and other patient records needed to verify the entries on the 
eCRF.  The Investigator (or his/her deputy) agrees to cooperate with the monitor to 
ensure that any problems detected in the course of these monitoring visits are resolved. 
17. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS 
The Investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On CRFs or other documents 
submitted to the Sponsor, patients should not be identified by their names, but by an 
identification code.  The Investigator should keep a patient enrolment log showing codes, 
names and addresses. 
18. 
CLINICAL STUDY REPORT  
A clinical study report will be written and distributed to Health Authorities as required by 
applicable regulatory requirements.  
19. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Roche will comply with the requirements for publication of study results. 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission.  This allows the Sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
Investigator. 
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In accordance with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors (ICMJE) authorship requirements.  Any formal 
publication of the study in which input of Roche personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Roche personnel. 
 
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Appendix 1 New Response Evaluation Criteria in Solid Tumors, 
Version 1.1:  Modified Excerpt from Original Publication with 
Supplementary Explanations (1) 
1. MEASURABILITY OF TUMOR AT BASELINE  
1.1 DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows: 
1.1.1 Measurable Tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:  
• 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater than 
5 mm); 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable); 
• 
20 mm by chest X-ray.  
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be not greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.  See also section 2.2 below on ‘Baseline 
documentation of target and non-target lesions’ for information on lymph node 
measurement.  
1.1.2 Non-measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with  ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inf ammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, or abdominal 
masses/abdominal organomegaly identif ed by physical exam that is not measurable by 
reproducible imaging techniques.  
1.1.3 Special considerations regarding lesion measurability  
Bone and cystic lesions, and lesions previously treated with local therapy require 
particular comment:  
Bone lesions: 
• 
Bone scan, positron emission tomography (PET) scan or plain f lms are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to conf rm the presence or disappearance of bone lesions.  
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Appendix 1 New Response Evaluation Criteria in Solid Tumors, 
Version 1.1:  Modified Excerpt from Original Publication with 
Supplementary Explanations (1) (cont.) 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identif able soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI, can be considered as measurable lesions if the soft tissue component 
meets the def nition of measurability described above 
• 
Blastic bone lesions are non-measurable 
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically def ned simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by def nition, simple cysts 
• 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the def nition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions 
 
Lesions with prior local treatment:  
Tumor lesions situated in a previously irradiated area, or in an area patiented to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
1.2 TARGET LESIONS:  SPECIFICATIONS BY METHODS OF 
MEASUREMENTS  
1.2.1 Measurement of lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.  
1.2.2 Method of assessment  
The same method of assessment and the same technique should be used to 
characterize each identif ed and reported lesion at baseline and during study.  Imaging 
based evaluation should always be the preferred option.  
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superf cial and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
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lesions.  However, lesions on chest X-ray may be considered measurable if they are 
clearly def ned and surrounded by aerated lung. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has def ned measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 
should be twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and 
during study, should be guided by the tumor type under investigation and the anatomic 
location of the disease.  For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed, should also be based on the tumor type, 
anatomic location of the disease and should be optimized to allow for comparison to the 
prior studies if possible.  Each case should be discussed with the radiologist to 
determine if substitution of these other approaches is possible and, if not, the patient 
should be considered not evaluable from that point forward.
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  
Endoscopy, Laparoscopy, Tumor markers, Cytology, Histology:  The utilization of these 
techniques for objective tumor evaluation cannot generally be advised but will be 
dependent on the study design.  
2. TUMOR RESPONSE EVALUATION  
2.1 ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE  
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Measurable disease is def ned by the presence of at least one 
measurable lesion.  
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2.2 BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS  
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of f ve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identif ed as target lesions and will be recorded and 
measured at baseline. 
This means in instances where patients have only one or two organ sites involved, a 
maximum of two (one site) and four lesions (two sites), respectively, will be recorded.  
Other lesions (albeit measurable) in that organ will be recorded as non-measurable 
lesions (even if size is greater than 10 mm by CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be 
reproducible in repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  As noted in Section 1.1.1, 
pathological nodes which are def ned as measurable and may be identif ed as target 
lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital or coronal).  The smaller of these measures is the 
short axis.  For example, an abdominal node which is reported as being 20 mm × 30 mm 
has a short axis of 20 mm and qualif es as a malignant, measurable node.  In this 
example, 20 mm should be recorded as the node measurement.  All other pathological 
nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-target 
lesions.  Nodes that have a short axis < 10 mm are considered non-pathological and 
should not be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
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All other lesions (or sites of disease) including pathological lymph nodes should 
be identif ed as non-target lesions and should also be recorded at baseline.  
Measurements are not required and these lesions should be followed as ‘present’, 
‘absent’, or in rare cases ‘unequivocal progression’. 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the case report form (e.g. ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’).  
2.3 RESPONSE CRITERIA  
This section provides the def nitions of the criteria used to determine objective tumor 
response for target lesions.  
2.3.1 Evaluation of target lesions  
• 
Complete Response:  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm 
• 
Partial Response:  At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters 
• 
Progressive Disease:  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study including baseline (nadir).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note: the appearance of one or more new lesions is 
also considered progression) 
• 
Stable Disease:  Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD 
 
2.3.2 Special notes on the assessment of target lesions 
Lymph nodes:  Lymph nodes identif ed as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This means 
that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if CR criteria are met, since a normal lymph node is def ned as having a short 
axis of < 10 mm.  
Target lesions that become ‘too small to measure’: while on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measure 
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and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and ‘below measurable limit’ (BML) 
should be ticked (Note:  It is less likely that this rule will be used for lymph nodes 
since they usually have a def nable size when normal and are frequently surrounded 
by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked) 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that 
should be recorded, even if it is below 5 mm and in that case BML should not be 
ticked (BML is equivalent to a less than sign ‘<’). 
Lesions that split or coalesce on treatment:  when non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
2.3.3 Evaluation of non-target lesions  
This section provides the def nitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specif ed in the protocol.  
Complete Response:  Disappearance of all non-target lesions (and, if applicable, 
normalization of tumor marker level). All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease: Unequivocal progression (see section 2.3.4) of existing non-target 
lesions.  The appearance of one or more new lesions is also considered progression.  
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2.3.4 Special notes on assessment of progression of non-target disease  
When the patient also has measurable disease: in this setting, to achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be 
an overall level of substantial worsening in non-target disease in a magnitude that, 
even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in 
the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or PR of target disease will 
therefore be extremely rare.  
When the patient has only non-measurable disease:  this circumstance arises in some 
Phase III trials when it is not a criterion of study entry to have measurable disease.  The 
same general concepts apply here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantif ed (by def nition: if all lesions are truly non-measurable) a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease:  i.e., an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase in diameter in a measurable 
lesion).  Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’.  If ‘unequivocal progression’ is 
seen, the patient should be considered to have had overall PD at that point.  While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore the increase must be 
substantial.  
2.3.5 New lesions   
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specif c criteria for 
the identif cation of new radiographic lesions; however, the f nding of a new lesion 
should be unequivocal:  i.e., not attributable to differences in scanning technique and 
change in imaging modality or f ndings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or f are of pre-existing 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
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CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not.  
A lesion identif ed during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans conf rm 
there is def nitely a new lesion, then progression should be declared using the date of 
the initial scan. 
2.4 EVALUATION OF RESPONSE  
2.4.1 Time Point Response (Overall response) 
It is assumed that at each protocol specif ed time point, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each time point 
for patients who have measurable disease at baseline.  
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
Table 1 Time Point Response – Target (w/wo Non-Target) Lesions  
 
 
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Table 2 Time Point Response – Non-Target Lesions Only 
 
 
2.4.2 Missing assessments and non-evaluable designation  
When no imaging/measurement is conducted all at a particular time point, the patient is 
not evaluable at that time point.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that time point, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time point response.  This would be most likely 
to happen in the case of PD.  
For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
during the study only two lesions were assessed, but those gave a sum of 80 mm, the 
patient will have achieved PD status, regardless of the contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done, 
or could not be assessed because of poor image quality or obstructed view, the 
Response for Target Lesions should be “Unable to Assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are indicated as ‘not assessed’, 
the response for non-target lesions should be “Unable to Assess” (except where there is 
clear progression).  Overall response would be “Unable to Assess” if either the target 
response or the non-target response is “Unable to Assess” (except where this is clear 
evidence of progression) as this equates with the case being not evaluable at that time 
point. 
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Best response determination in trials where conf rmation of complete or PR IS NOT 
required:  
Best response is def ned as the best response across all time points (for example, a 
patient who has SD at f rst assessment, PR at second assessment, and PD on last 
assessment has a best overall response of PR). When SD is believed to be best 
response, it must also meet the protocol specif ed minimum time from baseline.  If the 
minimum time is not met when SD is otherwise the best time point response, the 
patient’s best response depends on the subsequent assessments.  For example, a 
patient who has SD at f rst assessment, PD at second and does not meet minimum 
duration for SD, will have a best response of PD.  The same patient lost to follow-up 
after the f rst SD assessment would be considered not evaluable.  
Best response determination in trials where conf rmation of complete or partial response 
is required: 
Complete or PRs may be claimed only if the criteria for each are met at a subsequent 
time point as specif ed in the protocol (generally 4 weeks later).  In this circumstance, the 
best overall response can be interpreted as in Table 3.  
Table 3 Best Overall Response When Confirmation is Required 
 
 
2.4.3 Special notes on response assessment  
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order, not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of ‘zero’ on the CRF.  
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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’.  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response:  it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Table 1 –Table 3.  
For equivocal f ndings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is conf rmed, the date of 
progression should be the earlier date when progression was suspected.  
In studies where patients with advanced disease are eligible (i.e., primary disease still or 
partially present), the primary tumor should be also captured under target or non-target 
lesions as appropriate.  This is to avoid wrong assessments of complete OR by 
statistical programs while the primary tumor is still present but not evaluable. 
Frequency of tumor re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specif c and 
adapted to the type and schedule of treatment.  However, in the context of phase II 
studies where the benef cial effect of therapy is not known, follow-up every 6–8 weeks 
(timed to coincide with the end of a Cycle) or as per institutional standards is reasonable.  
Smaller or greater time intervals than these could be justif ed in specif c regimens or 
circumstances.  The protocol should specify which organ sites are to be evaluated at 
baseline (usually those most likely to be involved with metastatic disease for the tumor 
type under study) and how often evaluations are repeated.  Normally, all target and non-
target sites are evaluated at each assessment.  In selected circumstances certain non-
target organs may be evaluated less frequently.  For example, bone scans may need to 
be repeated only when CR is identif ed in target disease or when progression in bone is 
suspected.   
After the end of the treatment, the need for repetitive tumor evaluations depends on 
whether the trial has as a goal the response rate or the time to an event 
(progression/death).  If ‘time to an event’ (e.g., time to progression, disease-free survival, 
PFS) is the main endpoint of the study, then routine scheduled re-evaluation of protocol 
specif ed sites of disease is warranted.  In randomized comparative trials in particular, 
the scheduled assessments should be performed as identif ed on a calendar schedule 
(for example: every 6–8 weeks on treatment or every 3–4 months after treatment) and 
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should not be affected by delays in therapy, drug holidays or any other events that might 
lead to imbalance in a treatment arm in the timing of disease assessment.  
Conf rmatory measurement/duration of response  
Conf rmation 
In non-randomized trials where response is the primary endpoint, conf rmation of PR and 
CR is required to ensure responses identif ed are not the result of measurement error.  
This will also permit appropriate interpretation of results in the context of historical data 
where response has traditionally required conf rmation in such trials.  However, in all 
other circumstances, i.e., in randomized trials (phase II or III) or studies where SD or 
progression are the primary endpoints, conf rmation of response is not required since it 
will not add value to the interpretation of trial results.  However, elimination of the 
requirement for response conf rmation may increase the importance of central review to 
protect against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general not less than 6–8 weeks, or as per institutional 
standards) that is def ned in the study protocol. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are 
f rst met for CR/PR (whichever is f rst recorded) until the f rst date that recurrent or PD is 
objectively documented (taking as reference for PD the smallest measurements 
recorded on study). 
The duration of overall CR is measured from the time measurement criteria are f rst met 
for CR until the f rst date that recurrent disease is objectively documented. 
Duration of SD 
SD is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest 
sum on study (if the baseline sum is the smallest, this is the reference for calculation of 
PD). 
References 
1. Eisenhauer, EA, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
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Appendix 1 New Response Evaluation Criteria in Solid Tumors, 
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Supplementary Explanations (1) (cont.) 
2. Bogaerts J, Ford R, Sargent D, Schwartz LH, Rubinstein L, Lacombe D, et al. 
Individual patient data analysis to assess modifications to the RECIST 
criteria. Eur J Cancer. 2009 Jan;45(2):248-60. 
 
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Appendix 2 Definition of Women of Childbearing Potential and 
Acceptable and Unacceptable Forms of Contraception 
 
Definition of childbearing potential 
Female patients who meet at least one of the following criteria are defined as women of 
non-childbearing potential: 
• 
≥ 50 years old and naturally amenorrheic for ≥ 1 year 
• 
Permanent premature ovarian failure confirmed by specialist gynecologist 
• 
Previous bilateral salpingo-oophorectomy or hysterectomy 
• 
XY karyotype, Turner’s syndrome, or uterine agenesis 
 
Female patients who do not meet at least one of the above criteria are defined as 
women of childbearing potential. 
Additionally, the parent or guardian of young female patients who have not yet started 
menstruation should verify that menstruation has not begun.  If a young female patient 
reaches menarche during the study, she is to be treated as a woman of childbearing 
potential from that time forward. 
Acceptable contraception 
Women of childbearing potential are required to use two forms of acceptable 
contraception (including one barrier method) during participation in the study and for 
9 months or as per approved local prescribing information for vismodegib (where 
available), whichever is longer, following discontinuation of vismodegib.  Acceptable 
contraception and duration of contraceptive use should comply with locally approved 
vismodegib (Erivedge®, the trade name for vismodegib) Pregnancy Prevention Program 
or prescribing information where vismodegib is commercially available. 
Acceptable forms of barrier contraception include the following: 
• 
Latex, non-latex, or any other male condom (always used with spermicide [where 
available]) 
• 
Diaphragm (always used with spermicide [where available]) 
 
Acceptable forms of secondary contraception, when used with a barrier method, include 
the following: 
• 
Combination hormonal contraceptives, hormonal patch, subcutaneous hormonal 
implant, or hormonal intramuscular contraceptives (medroxyprogesterone acetate 
depot) 
Combination hormonal contraceptives, hormonal patch, and subcutaneous hormonal 
implant are not considered acceptable in the EU and some countries that follow the EU 
prescribing information for vismodegib. 
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Appendix 2 Definition of Women of Childbearing Potential and 
Acceptable and Unacceptable Forms of Contraception (cont.)  
• 
Tubal sterilization  
 
Other acceptable forms include the following: 
• 
100% commitment to abstinence from sexual intercourse (for medical or personal 
reasons) 
 
Unacceptable contraception 
The following are unacceptable forms of contraception: 
• 
IUD progesterone T  
• 
Progestin-only contraceptives 
• 
Female condom 
• 
Natural family planning (rhythm method) or breastfeeding 
• 
Fertility awareness 
• 
Withdrawal 
• 
Cervical shield 
• 
Vaginal contraceptive ring 
• 
Combination hormonal contraceptives, hormonal patch, and subcutaneous 
hormonal implant (for countries in the EU and some countries that follow the EU 
prescribing information for vismodegib)  
 
NOTE:  Patients should be counseled on the use of contraception before 
beginning treatment with vismodegib.  As appropriate, the treating physician 
should refer the subject to her gynecologist or other healthcare provider to ensure 
proper understanding of the use of her chosen contraceptive method. 
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Appendix 3 Eastern Cooperative Oncology Group Performance 
Status 
Patients will be graded according to the Eastern Cooperative Oncology Group 
performance status scale and criteria as described below: 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
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 
1 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
3 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair 
4 
5 
Dead 
As published in:  Oken, MM, et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655. 
 
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Appendix 4 International Conference on Harmonization (ICH) 
Guidelines for Clinical Safety Data Management, Definitions, and 
Standards for Expedited Reporting, Topic E2  
A serious adverse event (SAE) is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
• 
is fatal; [results in death] [NOTE: death is an outcome, not an event] 
• 
is Life-Threatening    [NOTE: the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
• 
required in-patient hospitalization or prolongation of existing hospitalization; 
• 
results in persistent or significant disability/incapacity; 
• 
is a congenital anomaly/birth defect; 
• 
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the Sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the 
outcomes listed in the definitions above.  These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the Investigator.  For SAEs, possible causes of the 
event are indicated by selecting one or more options.  (Check all that apply)  
• 
Pre-existing/Underlying disease - specify  
• 
Study treatment – specify the drug(s) related to the event 
• 
Other treatment (concomitant or previous) – specify 
• 
Protocol-related procedure 
• 
Other (e.g., accident, new or intercurrent illness) - specify 
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Appendix 4 International Conference on Harmonization (ICH) 
Guidelines for Clinical Safety Data Management, Definitions, and 
Standards for Expedited Reporting, Topic E2 (cont.) 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious.  
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs 
page of the CRF: intensity, relationship to test substance, action taken, and outcome to 
date. 
The Investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs:  Local Monitor.  The local Monitor will 
be the initial point of contact for all study related issues.  The local monitor is responsible 
to provide administrative details and contact information of the Roche study team as 
required. 
ROCHE HEADQUARTERS CONTACT for SAEs and other medical emergencies: 
The local Monitor will be the initial point of contact for all study related issues.  The local 
monitor is responsible to provide administrative details and contact information of the 
Roche study team as required. 
See the attached Protocol Administrative and Contact Information & List of Investigators 
form [gcp_for000227], for details of administrative, contact information, and Emergency 
Medical Call Center Help Desk toll-free numbers. 
24 HOUR MEDICAL COVERAGE 
Please refer to the Emergency Medical Call Center Help Desk toll-free numbers 
provided by your local Monitor. 
 
Vismodegib—F. Hoffmann-La Roche Ltd 
117/Protocol MO25616, Version 7 


 
Appendix 5 Skindex-16 Quality of Life Questionnaire 
These questions concerns the skin condition which has bothered you the most during 
the past week.   
During the past week, how often have you been 
bothered by: 
Never Bothered                   Always Bothered 
È                                       z                          È 
__________________________________ 
 
    1. 
Your skin condition itching      .    .    .    .    .  
  0     1     2      3     4      5     6
    2. 
Your skin condition burning or stinging     .    
  0     1     2      3     4      5     6
    3. 
Your skin condition hurting    .     .    .    .    .   
  0     1     2      3     4      5     6
    4. 
Your skin condition being irritated    .    .    .  
  0     1     2      3     4      5     6
    5. 
The persistence / reoccurrence of your 
skin condition    .    .    .    .    .    .    .    .    .   
 
  0     1     2      3     4      5     6
    6. 
Worry about your skin condition   (For 
example: that it will spread, get worse, 
scar, be unpredictable, etc)    .    .    .    .    .  
 
  0     1     2      3     4      5     6
    7. 
The appearance of your skin condition   .    
  0     1     2      3     4      5     6
    8. 
Frustration about your skin condition      .    
  0     1     2      3     4      5     6
    9. 
Embarrassment about your skin condition   
  0     1     2      3     4      5     6
  10. 
Being annoyed about your skin condition     
  0     1     2      3     4      5     6
  11. 
Feeling depressed about your skin 
condition    .    .    .    .    .    .    .    .    .    .     
 
  0     1     2      3     4      5     6
  12. 
The effects of your skin condition on your 
interactions with others   (For example: 
interactions with family, friends, close 
relationships, etc)     .    .    .    .    .    .    .     
 
 
  0     1     2      3     4      5     6
  13. 
The effects of your skin condition on your 
desire to be with people    .    .    .    .    .    . 
 
  0     1     2      3     4      5     6
  14. 
Your skin condition making it hard to show 
affection.    .    .    .    .    .    .    .    .    .    .     
  0     1     2      3     4      5     6 
 
  15. 
The effects of your skin condition on your 
daily activities    .    .    .    .    .    .    .    .    .  
 
  0     1     2      3     4      5     6
  16. 
Your skin condition making it hard to work 
or do what you enjoy   .    .    .    .    .    .   .    
 
  0     1     2      3     4      5     6
                              Have you answered every item?  Yes    No   
 
Skindex16, ©MMChren,1997. 
Vismodegib—F. Hoffmann-La Roche Ltd 
118/Protocol MO25616, Version 7 


Appendix 6 M.D. Anderson Symptom Inventory (MDASI) 
 
Vismodegib—F. Hoffmann-La Roche Ltd 
119/Protocol MO25616, Version 7 


 
 
Appendix 6 M.D. Anderson Symptom Inventory (MDASI) (cont.) 
 
 
Vismodegib—F. Hoffmann-La Roche Ltd 
120/Protocol MO25616, Version 7 

SAP_001.pdf: 
 
Official Title: 
STEVIE—A SINGLE-ARM, OPEN-LABEL, PHASE II, 
MULTICENTER STUDY TO ASSESS THE SAFETY OF 
VISMODEGIB (GDC-0449) IN PATIENTS WITH LOCALLY 
ADVANCED OR METASTATIC BASAL CELL CARCINOMA 
NCT Number: 
NCT01367665 
Document Date: 
Statistical Analysis Plan: 14-Sep-15 
 
 


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Output Specifications, Version 1.0 
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Output Specification 
Study title: 
Protocol number: 
STEVIE - A single-arm, open-label, phase II, 
multicenter study to assess the safety of Vismodegib 
(GDC-0449) in patients with locally advanced or 
metastatic basal cell carcinoma 
MO25616/ NCT01367665
Author: 
 
SPA: 
 
Biostatistician: 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
General Considerations 
 
 
 
Disease Status 
Outputs are split by disease status, unless otherwise specified. This means that outputs 
should be summarized by the following cohorts: Locally Advanced BCC and Metastatic BCC 
(disease status is collected on the CRF). 
 
 
Definition of First Dose 
Earliest date of drug dispensed when the amount of drug taken is greater than 0 and the 
doses are not missed on this date, in case the dose is missed on this date then take the date 
of the day after the last dose missed amongst the first group of missed doses. A drug is 
considered ‘taken’ if there is a non-zero, non-missing ‘Taken’ record in the subject’s Drug 
Accountability CRF page. 
 
 
Definition of Last Dose 
Latest date of drug returned where amount taken is greater than 0 and the doses are not 
missed on this date, in case the dose is missed on this date then take the date of the day 
before the first dose missed  amongst the last group of missed doses. 
 
 
Reference Date (Study Day 1)  
Where derivations refer to reference date please use date of first dose as there is no 
randomization date available. 
 
 
Baseline  
Baseline is considered as the most recent time prior to treatment. If a record is collected on 
the day of first dose, then that record is considered as baseline. 
 
 
Age  
Age is collected on the CRF, but the Age used is the calculated Age. This is defined from the 
patient’s birth date and the patient’s consent to the study (both captured on the CRF). 
 
 
Visit Windowing  
Visits are windowed in this study, and all outputs should use the analysis windowed visit as 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
opposed to the collected visit unless otherwise specified. The definition of windowing is 
stored in the DAP M3 (Visit Windowing Spec tab). 
 
Unscheduled Visits 
Visits will be windowed, so any unscheduled visits will be assigned to a visit based upon the 
collection date. The information about visit windowing is discussed in the Visit Windowing 
section. 
 
 
Deaths  
Date of Death can be found on the following pages of the eCRF: 
- 
End of study treatment 
- 
Death page 
- 
Adverse event – end date of AE with grade 5 severity or AE outcome is death 
- 
Serious adverse event – SAE outcome end date; date of death 
- 
End of follow-up page 
- 
Survival follow-up page 
- 
ECOG performance status – status is Grade 5: death 
 
Take the date as defined on the Death page if the sources have different dates, as well as 
the reason defined on the Death page.  
 
Measurable/Non-Measurable Disease  
A patient is considered to have measurable disease if they have a target lesion at baseline 
according to the tumour CRF page. This is a ‘Yes’/’No’ box, but it is not a mandatory field, so 
some subjects can have a ‘missing’ result, and such subjects are not considered to have 
either measurable or non-measurable disease. Measurable/non-measurable disease 
information is also collected on the CRF disease history page as a tick box, but this 
information will not be used as the target lesion assessment page is felt to be more accurate.  
 
Histologically Confirmed Disease  
A patient is considered to have histologically confirmed disease if they have no record in 
their PDMS data that suggests that they did not have histologically confirmed disease. 
Science considered that the protocol deviation of ‘non-histologically confirmed disease’ 
stored in PDMS was more accurate than the tick box on the CRF, as the CRF page is the 
histological status at the time of collection, but the PDMS system collects information more 
often. As mentioned, histological disease confirmation information is also collected on the 
CRF as a tick box, but this information will not be used in the outputs. The reason for using 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
the PDMS system is that the information on whether a patient had histologically confirmed 
disease contained in the PDMS system is directly assessed and reviewed by Clinical 
Science. 
 
Data Cut Derivation 
The input data will have a data-cut applied prior to being stored in a VAD, but will not be 
stored anywhere as ‘cut’ raw data. The definition of the data cut is stored in the DAP M3 
(Data Cut Spec tab). 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Populations: 
 
All Subject Population (AP) 
The "All Subjects" population is any patient in the study for which their disease status 
(Locally Advanced or Metastatic, based on the disease history CRF page) is known.  
 
Enrolled Population (ENR) 
The "Enrolled" population is any patient in the study with a recorded Disease status and for 
whom actual treatment is not recorded as Screen Failure.  
 
Safety Population (SE) 
The "Safety" population is any patient who took at least one dose of study medication 
according to the dose accountability CRF page. A patient was considered dosed if they had 
a ‘number of capsules taken’ record according to the exposure CRF page that wasn’t zero or 
missing. 
 
Protocol Populations 
 
Protocol Version 4 Population (PV4ANY) 
The "Protocol Version 4" population is any patient who consented to Protocol version 4 
(or higher) at any point in the study. The protocol version is taken from the Protocol CRF 
page. 
 
Last Protocol Consented to: 1 or 2 (PV1N2) 
The "Last Protocol Consented to: 1 or 2" population includes any patient who consented 
to Protocol version 1 or 2 as their most recent version. The protocol version is taken from 
the Protocol CRF page. 
 
Last Protocol Consented to: 3 or higher (PV3PLUS) 
The "Last Protocol Consented to: 3 or higher" population includes any patient who 
consented to Protocol version 3 or higher as their most recent version. The protocol 
version is taken from the Protocol CRF page. 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Last Protocol Consented to: 5 or higher (PV5PLUS) 
The "Last Protocol Consented to: 5 or higher" population includes any patient who 
consented to Protocol version 5 or higher as their most recent version. The protocol 
version is taken from the Protocol CRF page. 
 
Protocol Version 3 (+) 12 Month Follow-up Completion (PV3COMP) 
The "Protocol Version 3 (+) 12 Month Follow-up Completion" population includes any 
patient who consented to Protocol version 3 or higher at any time (according to the 
Protocol CRF page) and completed the study according the their 12 month FU record 
from the DS CRF. 
 
 
Efficacy Populations 
Outputs will be repeated by given populations combinations as defined in the LoPO and 
in this document. 
 
Intent-to-Treat Population (IT) 
The "Intent-to-Treat" population is any patient who took at least one dose of study 
medication according to the dose accountability CRF page.  A patient was considered 
dosed if they had a ‘number of capsules taken’ record according to the exposure CRF 
page that wasn’t zero or missing. 
 
mBCC Protocol 4 (+) Population (MBCC) 
The "mBCC Protocol 4 (+)" population was any patient who had all of the following 
criteria: 
- Consented to Protocol version 4 or Higher as a first version according to the CRF. 
- Had a metastatic disease status according to the CRF. 
 
8 Weekly Tumour Assessment Population (TU8) 
The "8 Weekly Tumour Assessment" population was any patient who had all of the 
following criteria: 
- Tumour assessments every 8 weeks (+/- 10 days of the expected date of the next 
assessment) since consenting Protocol version 4. Protocol signing date taken from CRF 
page defining consent. Tumour assessment visits taken from the CRF page defining 
tumour information.  
- Did not miss ANY tumour assessments since consenting to Protocol version 4. 
The population also includes all patients from the MBCC population, regardless of 
whether they meet the aforementioned criteria.  


Study MO25616  
                                     
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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
 
Symptomatic Patients (SYMP)  
Clinical Science manually reviewed all Metastatic patients to determine which subjects 
had symptoms of the disease. This was completed by looking at numerous data 
including medical history information. The “Symptomatic Patients” population were the 
patients who were considered symptomatic by Clinical Science Review.  
 
Non-Symptomatic Patients (NSYMP) 
Clinical Science manually reviewed all Metastatic patients to determine which subjects 
had symptoms of the disease. This was completed by looking at numerous data 
including medical history information. The “Non-Symptomatic Patients” population were 
the patients who were considered non-symptomatic by Clinical Science Review. 
 
Measurable Disease Patients 
Some outputs require the subset of Measurable Disease Patients only. This subset 
would consist of patients with a target measurable disease at Baseline. This is identified 
within the titles and footnotes of the relevant outputs. 
 
Histologically Confirmed Disease Patients 
Some outputs require the subset of Histologically Confirmed Disease Patients only. This 
subset would consist of patients with histologically confirmed disease as per PDMS. This 
is identified within the titles and footnotes of the relevant outputs. 
 
Measurable and Histologically Confirmed Disease Patients 
Some outputs require the subset of Measurable and Histologically Confirmed Disease 
Patients. This subset would consist of patients with a target measurable disease at 
Baseline as well as histologically confirmed disease as per PDMS. This is identified 
within the titles and footnotes of the relevant outputs. 
 
 
 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Other Populations 
 
Potentially Reversible AE Population (PV3DSC6M) 
The “Potentially Reversible AE” population is defined as the patients who consented to 
protocol version 3 or higher at any point during the study (from the CRF), excluding: 
- Patients who discontinued treatment within 6 months of the cut (discontinue date from 
the CRF). 
- Patients who were lost to follow-up within 6 months of treatment discontinuation (both 
from CRF). 
- Patients who died within 6 months of treatment discontinuation (both from CRF). 
 
The reason for inclusion of only patients who consented to version 3 or higher is due to 
the fact that patients consenting to earlier versions were only subject to a 1 month follow 
up period.  
 
 
 
 
 
 


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Study MO25616  
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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Disposition: 
Patients will be considered to have completed the study if they have discontinued or 
completed treatment, and have completed their follow-up period (1 month for subjects who 
enrolled to protocol version 1 or 2, or 12 months for subjects who were enrolled to protocol 3 
or later). 
The reason for discontinuation of the study comes from the End of Follow Up CRF Page and 
should be listed under reasons for Study Discontinuation based on Safety and Non-safety 
categories. 
Patients discontinued from treatment for a variety of reasons (recorded in the End of Study 
Treatment CRF page), and these should be listed under reasons for treatment 
discontinuation based on Safety and Non-safety categories. 
Note: under the treatment discontinuation category, those who recorded “withdrew from 
treatment” in the CRF were assumed to have also left the study (as the investigators were 
additionally asked for study withdrawal information). As a result, patients who discontinued 
treatment but remained in follow-up were counted in the “Other” category. A footnote to the 
discontinuation table should be added to explain this idiosyncrasy. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
1. Patient Disposition 
DST01 
Output ID: t_ds_* 
● Analysis Population: Safety-Evaluable Patients 
● Column Variables:  Disease status (Locally Advanced, 
Metastatic) 
● Column Totals: Total of non-missing Disease status 
● Analysis Variables: 
             Number of Patients Completed study 
○ Follow-up of 1 month 
○ Follow-up of 12 months, 
            Number of Patients discontinued from Study , 
○ Safety 
○ Non-Safety 
            Number of Patients Ongoing in Study 
○ In Follow-Up 
○ On Treatment, 
           Number of Patients discontinued from Treatment 
○ Safety 
○ Non-Safety 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
Programming Note: 
1. Patients  are considered as completers (i.e. included in the row Number of Patients 
Completed Study) if an End of Follow-Up (EOFU) page is present, or (for patients 
whose EOFU page was missing due to a known database issue where the EOFU 
page was not available), one of the following conditions is met: 
a. for subjects whose latest protocol version consented to was 1 or 2, they were 
alive at the date of their 30 day FU visit. 
b. for subjects whose latest protocol version consented to was 3 or higher, they 
were alive at the date of their 12 month FU visit. 
2. Patients who completed (as per point 1) were sub-categorised as having completed  
“Follow-up of 1 month” if their latest protocol consented to was version 1 or 2, or 
having completed “Follow-up of 12 months” if their latest protocol consented to was 
version 3 or a subsequent version. 
3. For the sub-categories of Number of patients discontinued from treatment: reasons of 
“Adverse Event” and “Death” are classified as Safety; any other reasons are 
classified as Non-Safety. 
4. For the sub-categories of Number of patients ongoing in study: patients categorised 
as in Follow up include the patients who have discontinued from treatment (but are 
still in the study); patients categorised as On Treatment include patients still receiving 
treatment. 
5. If the reason for Study Discontinuation is the same as the reason for Treatment 
Discontinuation then the record should be included in both sections of the display. 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
2. Patient Disposition within 24 weeks of first dose 
DST01 
Output ID: t_ds_24wkdisc_* 
● Analysis Population: Safety-Evaluable Patients 
● Column Variables:  Disease status (Locally Advanced, 
Metastatic) 
● Column Totals: Total of non-missing Disease status 
● Analysis Variables: 
             Number of Patients Completed study 
             Number of Patients discontinued from Treatment 
○ Safety 
○ Non-Safety 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
Programming Note:   
1. Only include Patients whose overall Duration of study treatment is less than or equal 
to 24 weeks i.e. less than equal to 168 days from first valid dose. 
2. Patients  are considered as completers (i.e. included in the row Number of Patients 
Completed Study) if an End of Follow-Up (EOFU) page is present, or (for patients 
whose EOFU page was missing due to issues with the system), one of the following 
conditions is met: 
a. for subjects whose latest protocol version consented to was 1 or 2, they were 
alive at the date of their 30 day FU visit. 
b. for subjects whose latest protocol version consented to was 3 or higher, they 
were alive at the date of their 12 month FU visit. 
3. For the sub-categories of Number of patients discontinued from treatment: reasons of 
“Adverse Event” and “Death” are classified as Safety; any other reasons are 
classified as Non-Safety. 
 
 
 






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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
at the informed consent (to study) date and it is derived from Informed consent date 
and Imputed Birth date (ASL.BAGE): 
            (Set to integer part of (Informed consent date – Imputed Birth Date +1)/365.25). 
             
           If Birth date of subject is partial (at least year of Birth date is present) then use the  
           following Missing Data Handling Rule: 
- 
If the day part of the birth date is missing, impute it with 15. 
- 
If the month part of the birth date is missing, impute it with June. 
            Age categories should be derived on the basis of Baseline Age. 
3. Sex, Height, Weight, and Temperature information come from the Demography and Vital 
Signs CRF page. BMI is derived using the common formula defined in the DAP M3. 
4. Race information comes from the Demography CRF page and as per SDTM controlled 
terminology 
    “Black” should be mapped as “Black or African American”.  
    Race was recorded as “Not applicable” in France. 
5. Years from First BCC Diagnosis to Dose should derived as difference between First  
    Treatment start Date and Date of First BCC Diagnosis comes from CRF page divided  
    by year i.e. 365.25 days. 
   If First BCC Diagnosis date is partial then 
   a) Impute to the first day of the month if the day is missing. 
   b) Impute to the first month of the year if the month is missing. 
6.  Baseline ECOG Performance Status, Gorlin Syndrome, Child Bearing Potential 
     information comes from CRF.  
7. Number of Target Lesion at Baseline should be calculated as total number of target 
Lesions    collected on last Tumor assessment date which is on or prior to First Dosing date 
having non missing Tumor Location and Tumor assessment date. 
 
 
 
 
 




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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Medical History: 
1. Medical History at Baseline 
MHT01 
Output ID: t_mh_* 
● Analysis Population: Safety-Evaluable Patients 
● Column Variables:Disease status (Locally Advanced, 
Metastatic) 
● Column Totals: Total of non-missing Disease status 
● Analysis Variables: MedDRA System Organ Class, MedDRA 
Preferred Term. 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
Programming Note: 
Only display General Medical History (other than BCC) collected on MEDHX CRF page . 
 
2. Medical History at Baseline for Patients with an Abnormal ECG Result 
MHT01 
Output ID: t_mh_ecgabn_* 
● Analysis Population: Safety-Evaluable Patients 
● Column Variables:  Disease status (Locally Advanced, 
Metastatic) 
● Column Totals: Total of non-missing Disease status 
● Analysis Variables: MedDRA System Organ Class, MedDRA 
Preferred Term. 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
● Optional Subsetting: Patients with abnormal ECG results at 
baseline 
 
Programming Note: 
Only include patients who had an abnormal ECG result at baseline, according to the ECG 
CRF page.                                    
Only display General Medical History (other than BCC) collected on MEDHX CRF page. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
3. Medical History Glossary 
AEL01_NOLLT 
Output ID: l_mh_gloss_SE 
● Analysis Population: Safety-Evaluable Patients 
 
● Column Variables: MedDRA System Organ Class, MedDRA 
Preferred Term, Lowest Level Term and Reported Term for the 
Medical History. 
 
● Column Totals: NA 
 
● Analysis Variables: None 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
Programming Note: 
− A glossary of all previous and current medical conditions other than BCC history will 
be provided. 
− Data will be ordered alphabetically by MedDRA System Organ Class, MedDRA 
Preferred Term, Lowest Level Term and Reported Term for the Medical History. 
 
 
 
 
 




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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
5. Disease History Glossary 
AEL01_NOLLT 
Output ID: l_ds_gloss_SE 
● Analysis Population: Safety-Evaluable Patients 
 
● Column Variables: Current Disease Status, Current Site and 
Other Specify. 
 
● Column Totals: NA 
 
● Analysis Variables: None 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
Programming Note: 
− Investigator text will be used from ‘Disease History of advanced or metastatic BCC’ 
CRF page. 
− Data will be ordered alphabetically by Current Disease Status, Current Site and 
Other Specify. 
 
 
 
 
 




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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
− Only include records where patient had Prior Medication and therapies (concomitant 
medication started and ended before actual study treatment start) collected on CRF 
page “Concomitant Medications and Therapies”.  
 
1d. Concomitant Medication and Therapies 
Output ID:  t_cm_CONMED_* 
Repeat Output t_cm_NCANRELSUR_* for Concomitant Medication and Therapies. 
Programming Note: 
− Only select records where patient had Concomitant Medication and therapies 
(ongoing medication during study treatment) collected on CRF page “Concomitant 
Medications and Therapies”.  
 
 
 
 










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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Histology:   
Output ID: t_histol_SE 
 
Programming Note: 
− N = Number of patients present in each disease status category i.e. Locally 
Advanced or Metastatic. 
− Histology confirmation comes from PDMS system - i.e. Subjects included in the 
PDMS system for a deviation of ‘Non-histologically confirmed disease’ will be 
included in the ‘No’ category. 
− Include Safety Evaluable Patients. 
 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Disease Progression prior to Study: 
Output ID: t_di_prog_IT_PV4ANY 
 
Programming Note: 
− N is Number of Patients in the Intent-to-Treat population with Protocol 4 Subset 
(consented to Protocol version 4 or higher at any time). 
− Percentages should be based upon N. 
− Documentation of Disease Progression and Newly Diagnosed mBCC information 
comes from ‘Documentation of Progression prior to Enrolment’ CRF page. 
. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Symptom Status of Metastatic Patients: 
Summary of Symptom Status of Metastatic Patients: 
STREAM 
Template 
Description 
N/A 
Output ID: t_mbcc_symp_* 
● Analysis Populations:  Safety, Excluding Patients 
with Baseline MDASI Score 
● Column Variables:  Disease Status (Metastatic) 
● Column Totals:  None 
● Analysis Variables: n, Symptomatic, Non-
Symptomatic 
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
● Numeric Precision and Formatting of Statistics:  
N/A 
● Optional Subsetting:  None.  
 
 
Programming Note: 
− Symptom status was defined via Sponsor (Clinical Science) manual review of the 
data as to whether the subject was symptomatic or not. Details of this are in the DAP 
M3. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Protocol Violations: 
 
Protocol Violations (PVs) will be taken from the PDMS (Protocol Deviation 
Management System) and reviewed by Clinical Science. All major Protocol 
Violations will be summarised and Listed. At the request of the Science team, the 
Cut-off date should not be used with Violations as the date of the Violations 
according to the system are the dates that the violation was input, not the date that 
the violation occurred. Clinical Science reviewed the file to ensure that all correct 
violations are included and reported.  
 
STREAM 
Template 
Description 
MHT01 
Output ID: t_pv* 
● Analysis Population:  Safety 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Total Patients with at least one 
Deviation, Total number of Inclusion Criteria 
Violations, Total number of Procedural Violations, 
Total number of Medication Violations, Total number 
of Exclusion Criteria Violations 
● Statistics and Calculation Methods: Use proq freq 
for individual violations or proc sql for patient counts. 
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
● Optional Subsetting:  For each Category of 
Violations,  include the counts for each individual 
Violation. 
PDL01 
Output ID: l_pv* 
● Analysis Population:  Safety 
● Column Variables:  Use Standard STREAM 
columns 
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Output Specifications:  Safety Outputs 
 
Exposure: 
Capsules are dispensed to each subject at the time of each visit and are recorded on 
the CRF. Subjects take a dose of 150 mg daily and fill in any missed dose dates on 
the Patient Diary, in case of dose missed for any reason. The investigator completes 
the number of capsules taken between visits on the basis of number of capsules 
returned by the subject at the next visit.  
It is possible for a subject to have taken all the dispensed capsules between two 
visits and still have a missed dose if there is a delay in scheduling or attending the 
next visit. Consider the total number of capsules dispensed, taken, and the missed 
dosing date for daily dose calculation (ie, consider the sum of all dispensed/taken 
doses).    
1. Overall Summary of Exposure to Study Medication (Vismodegib) 
 
EXT01 
Output ID: t_ex_SE 
● Analysis Population:  Safety-Evaluable Patients  
● Column Variables:  Disease Status (Locally Advanced, 
Metastatic)  
● Column Totals:  Totals of non-missing Disease Status 
● Analysis Variables: Summary Statistics 
o Number of days missed dose 
o Cumulative dose of Vismodegib 
o Duration on treatment (in days) 
o Dose intensity 
o Total doses 
● Numeric Precision and Formatting of Statistics:  Use 
standard display in the mockup 
 
Programming Note: 
- 
The number of days of missed dose (and so the number of missed doses) will 
be calculated as follows: The number of days between the first and last dose, 
minus the sum of the number of capsules taken according to the Dose 
Accountability CRF page. i.e. If first dose was the 1st Jan, and the last dose 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
as the 28th Feb, and the subject had taken 55 capsules (according to their 
‘taken’ records, then there would be 4 (59-55) missed doses.                                       
- 
Cumulative dose of Vismodegib will be calculated as the sum of the total 
number of capsules taken (recorded on the Dose Accountability CRF page) at 
each visit multiplied by 150 mg.                                               
- 
Duration on treatment will be calculated as time from first dose date to last 
dose date (last dose date minus first dose date + 1), measured in days.                                 
- 
Dose intensity will be calculated as the sum of the total number of capsules 
taken (recorded on the Dose Accountability CRF page) at each visit / sum of 
the total number of capsules dispensed (recorded on the Dose Accountability 
CRF page) at each visit x 100.                                
 
2. Summary of Duration of Exposure to Vismodegib as a 
Monotherapy 
 
Output ID: t_ex_dur_bymon_SE 
 
Programming Note: 
− N is number of Patients in the Safety Population. 
− Vismodegib Exposure Duration categories derived as Total duration of Exposure in 
months which is calculated using (difference between first and last administration of 
Vismodegib) divided by 30.4375 (last dose date minus first dose date + 1)/30.4375. 
− Patients with exposure of 1 month or more will be included in the summary 
frequencies (numerator). The denominator for percentages will be the subjects in the 
Safety Population. 
− Person-years should be calculated as sum of exposure duration (in days) of patients 
in each category divided by 365.25.  
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
3. Summary of Exposure to Vismodegib as a Monotherapy by Dose.   
Output ID: t_ex_bydose_SE 
 
Programming Note: 
− N is number of patients in the Safety population. 
− Vismodegib Daily Exposure is the total daily dose taken by patient. This is constant 
at 150 mg as per protocol; no daily dose variations are permitted. 
− Person-years should be calculated as sum of exposure duration in all patients in the 
safety population divided by 365.25. 
 
 
 
4. Summary of Exposure to Vismodegib as a Monotherapy by Age 
Group and Gender 
 
Output ID: t_ex_byage_bysex_SE 
 
Programming note: 
− N is number of patients in each sex category (in the safety population). 
− Age Groups derived on the basis of Baseline Age. 
− Person-years should be calculated as sum of exposure duration of Patients for each 
category of gender and age group divided by 365.25. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
5. Summary of Exposure to Vismodegib as a Monotherapy by 
Ethnicity 
Output ID: t_ex_byrace_SE 
 
Programming note: 
− N is number of patients in safety population. 
− n is number of patients with non-missing race information. 
− Race information comes from the Demography CRF page and as per SDTM 
controlled terminology  “Black” should be mapped as “Black or African American”. 
− Race was recorded as “Not applicable” in France (hence the need for this category). 
− Person-years should be calculated as sum of exposure duration of Patients in each 
race category divided by 365.25. 
 
 
 
6. Summary of Exposure to Vismodegib as a Monotherapy by Gorlin 
Status 
Output ID: t_ex_bygorlin_SE 
Programming note: 
− N is number of patients in safety population. 
− n is number of patients with non-missing Gorlin Syndrome information in each of 
disease status. 
− Gorlin Syndrome information comes from “Gorlin Syndrome” CRF page. 
− Person-years should be calculated as sum of exposure duration of patients in each 
Syndrome category and disease status category divided by 365.25. 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
7. Reason for Breaks in Treatment, Population : Safety-Evaluable 
Patients 
Output ID: l_ex_trtbrk_SE 
 
Programming note: 
− Cycle and Period Start Date will be derived based on visit windowing algorithm. 
− Information on Reason for Treatment Break and Specify if Other will come from the 
“Reason for breaks in treatment” CRF page. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Adverse Events: 
 
General AE Reporting 
 
Listings will include all AEs unless otherwise specified. A Treatment Emergent AE (TEAE) is 
defined as an AE that starts on or after the first day of study treatment and within 30 days of 
last dose (please see General Considerations for definition). Unless otherwise specified, AE 
and SAE summary tables will be restricted to TEAEs. 
In STEVIE, the data collection guidelines require that the same AE is entered multiple times 
into the database, with a separate record for each change in toxicity grade or Lower Level 
Term. AEs can be reported using this or a “collapsed” Adverse Events analysis dataset. 
The Collapsed Adverse Events dataset is derived by combining records that can be 
reasonably considered to be referring to a single AE term but with changes in toxicity grade 
(or lower level term). Records from the original AE dataset are grouped, and each group is 
represented in the collapsed dataset by a single record. The groups are built up by 
“chaining” records from the original dataset as follows: 
- 
if the Subject ID, System Organ Class and Preferred Term are the same, and 
- 
either the periods defined by the two AEs’ start and end dates overlap, or the Start 
Date of the later AE is <=2 days after the End Date of the earlier one. 
In the single record representing the “collapsed” AE: 
- 
Subject ID, System Organ Class and Preferred Term are copied across from any of 
the records in the group (these are identical so it doesn’t matter which record these 
variables come from) 
- 
Severity (i.e. toxicity grade) is taken as the most severe grade in the group 
- 
Start Date is taken as the earliest start date in the group 
- 
End Date, Lower Level Term and Outcome are taken from the record with the latest 
end date in the group 
Examples are given on the next page. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Example of derivation of “collapsed” AEs: 
Example 1: 
SUBJID 
System Organ Class 
Preferred 
Term 
Lower Level 
Term 
Severity 
Outcome 
Start 
Date 
End 
Date 
GASTROINTESTINAL 
DISORDERS 
  
DYSPEPSI 
  
DYSPEPSIA 
GRADE 2 / 
MODERATE 
  
RESOLVED 
  
GASTROINTESTINAL 
DISORDERS 
DYSPEPSI
A 
HEART BURN 
GRADE 3 / 
SEVERE 
RESOLVED 
 
Collapsed to: 
GASTROINTESTINAL 
DISORDERS 
DYSPEPSI
A 
HEART BURN 
GRADE 3 / 
SEVERE 
RESOLVED 
  
Example 2: 
SUBJID 
System Organ Class 
Preferred 
Term 
Lower Level 
Term 
Severity 
Outcome 
Start 
Date 
End 
Date 
MUSCULOSKELETAL 
  
MUSCLE 
SPASMS 
  
CRAMPS 
OF 
LOWER 
EXTREMITIES 
GRADE 2 / 
MODERATE 
  
RESOLVED 
  
MUSCULOSKELETAL 
MUSCLE 
SPASMS 
CRAMP 
IN 
HAND 
GRADE 2 / 
MODERATE 
RESOLVED 
MUSCULOSKELETAL 
MUSCLE 
SPASMS 
CRAMPS 
OF 
LOWER 
EXTREMITIES 
GRADE 1 / 
MILD 
RESOLVED 
 
Collapsed to: 
MUSCULOSKELETAL 
MUSCLE 
SPASMS 
CRAMP 
IN 
HAND 
GRADE 2 / 
MODERATE 
RESOLVED 


Study MO25616  
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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Additional Note:  
Summaries of amenorrhea are based upon the sub-population of patients who are at risk of 
this AE, including women of child-bearing potential or having menses at baseline. The 
demography CRF page captures whether patients are of child-bearing potential but there is 
nowhere to indicate whether patients have menses, and so all patients who experienced the 
AE of interest (Amenorrhea/ Irregular Menses) were also included in the denominator. 
 
 Overall summary of AEs: 
STREAM 
Template 
Description 
AET01 
Output ID: t_ae_o_* 
● Analysis Population:  Safety 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Total Patients with at least one 
AE, Total number of events, Total number of deaths, 
Total number of patients withdrawn from study due 
to an AE, Total number of patients with at least one: 
AE with Fatal outcome, Serious AE, Serious AE 
leading to treatment withdrawal, Serious AE leading 
to dose modification/interruption, AE leading to 
treatment withdrawal, AE leading to dose 
modification/interruption 
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
  
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of patients reporting AEs: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include Total number of 
patients with at least one AE, Overall total number 
of events 
      
  
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of patients reporting AEs by Sub-group: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_bysubgp_* 
● Analysis Populations:  Safety 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include sub-grouping for: 
  
o   Age (see General Considerations) i.e. <65, 
>= 65, <75, >= 75. 
o   Race where Race is taken from the CRF and 
grouped i.e. White, Non-White, Missing. 
o   Sex where sex is taken from CRF i.e. Male, 
Female. 
o   Baseline (see General Considerations) 
ECOG Score i.e. 0, 1, >=2, Missing 
      
  
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of patients reporting AEs by Severity: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_bysev_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include sub-grouping for: 
                            o   Any Grade 
o   Grades 1 through 5 
o   Missing Grade 
      
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of patients reporting AEs by Drug Relationship: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_byrel_* 
● Analysis Populations:  Safety 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include sub-grouping for: 
  
o   Related 
o   Not Related 
o   Not Applicable 
  
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of patients reporting AEs by Exposure Duration: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_byexp_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include sub-grouping for: 
  
o   < 12 months exposure 
o   >= 12 months exposure 
  
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of patients reporting AEs by Outcome: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_byout_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include sub-grouping for: 
  
o   Recovered / Resolved 
o   Not Recovered / Not Resolved 
o   Recovered / Resolved with SequelAE 
o   Fatal 
  
  
 


Study MO25616  
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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Resolution of Collapsed AEs Ongoing by Outcome: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_out_c_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include sub-grouping for: 
  
o   Resolved 
o   Resolved with SequelAE 
o   Ongoing 
o   Fatal 
o   Unknown 
o   Missing 
  


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
 Summary of Muscle Spasm AEs Ongoing at the Time of Discontinuation 
(Collapsed AEs), and Still Ongoing at Last Assessment by Preferred 
Term, Excluding Patients with Commercial Vismodegib 
 
AET02 
Output ID: t_ae_out_ongo_AEMUS_* 
● Analysis Population: Safety-Evaluable Patients, 12 
Months FU Complete Subset 
 
● Column Variables:  Disease status (Locally Advanced, 
Metastatic) 
 
● Column Totals: Total of non-missing Disease status 
 
● Analysis Variables: MedDRA System Organ Class, 
MedDRA Preferred Term. 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
● Optional Subsetting: For each System Organ Class and 
Preferred Term, include sub-grouping for: 
○ Resolved 
○ Resolved with SequelAE 
○ Ongoing 
○ Fatal 
○ Unknown 
○ Missing 
Programming Notes: 
● Only ongoing "Muscle Spasm" Adverse Events at the time of discontinuation 
are included. 
● Patients, who took commercial Vismodegib (according to the Concomitant 
Medication CRF page) between treatment discontinuation and 12 months 
after treatment and had ongoing Adverse Events at treatment discontinuation, 
have been excluded. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Summary of Alopecia AEs Ongoing at the Time of Discontinuation 
(Collapsed AEs), and Still Ongoing at Last Assessment by Preferred 
Term, Excluding Patients with Commercial Vismodegib 
Output Id : t_ae_out_ongo_AEAL_* 
Repeat output t_ae_out_ongo_AEMUS_* for “Alopecia” adverse event. 
 
Summary of Ageusia  AEs Ongoing at the Time of Discontinuation 
(Collapsed AEs), and Still Ongoing at Last Assessment by Preferred 
Term, Excluding Patients with Commercial Vismodegib 
Output Id : t_ae_out_ongo_AEAG_* 
Repeat output t_ae_out_ongo_AEMUS_* for “Ageusia” adverse event. 
 
Summary of Dysgeusia AEs Ongoing at the Time of Discontinuation 
(Collapsed AEs), and Still Ongoing at Last Assessment by Preferred 
Term, Excluding Patients with Commercial Vismodegib 
Output Id : t_ae_out_ongo_AEDY_* 
Repeat output t_ae_out_ongo_AEMUS_* for “Dysgeusia” adverse event. 
 
Summary of Weight Decreased AEs Ongoing at the Time of 
Discontinuation (Collapsed AEs), and Still Ongoing at Last Assessment 
by Preferred Term, Excluding Patients with Commercial Vismodegib 
Output Id : t_ae_out_ongo_AEWG_* 
Repeat output t_ae_out_ongo_AEMUS_* for “Weight Decreased” adverse event. 
 
 
 
 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of Patients reporting TEAEs (Enrolled Population): 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae2_* 
● Analysis Populations:  Enrolled Population 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include Total number of 
patients with at least one AE, Overall total number 
of events 
      
 
Programming Notes: 
● Table to repeated for TEAEs leading to Death, Serious TEAEs, TEAEs of 
Grades 3 to 5 and TEAEs Leading to Study Drug Discontinuation. 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
● Rate of AEs per 100 Patient Years by Exposure Duration: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_byptyrs_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Exposure Duration Categories 
(< 12 Months Exposure, >= 12 Months Exposure) 
  
● Column Totals:  None 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
   
● Numeric Precision and Formatting of Statistics:  
Use standard display in the mockup 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include Total number of 
patients with at least one AE, Overall total number 
of events 
  
  
  
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Disposition of patients with an AE ongoing at treatment discontinuation: 
STREAM 
Template 
Description 
N/A 
Output ID: t_ae_ds_persae_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: Total number of Patients with 
an Ongoing AE at discontinuation, Reason for 
Discontinuation from Treatment, Patient Died after 
Discontinuation from Treatment, Patient was Lost to 
Follow-Up After Discontinuation from Treatment, 
Latest Protocol Version Consented to 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use AET02 standard template in the mockup 
  
● Optional Subsetting:  Reason for Discontinuation 
i.e. Death, Lost To Follow-Up. Patient Died After 
Discontinuation from Treatment i.e. 0-3 months, 0-6 
months, >6 months after discontinuation.  
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
 
 
Programming Notes: 
● Only include the AEs which were ongoing at the time of treatment 
discontinuation. 
  
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Number of Patients Reporting AEs by age group: 
STREAM 
Template 
Description 
AET02 
Output ID: t_ae_byagegp_* 
● Analysis Populations:  Safety 
Output will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations 
  
● Column Variables:  Age Groups (< 65 and >= 65, 
< 75 and >= 75) 
  
● Column Totals:  None 
  
● Analysis Variables: MedDRA System Organ 
Class, MedDRA Preferred Term. 
  
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use AET02 as standard display but with above 
columns 
  
● Optional Subsetting:  For each System Organ 
Class and Preferred Term, include Total number of 
patients with at least one AE, Overall total number 
of events 
  
  
 
 
 


Study MO25616  
                                         Page 54 of 104 
Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Listing of Ongoing Adverse Events for Patients who Discontinued 
Treatment (Latest Protocol Version Consented to: 1 or 2) 
AEL02 
Output ID: l_ae_ds_PV1N2_AEPERS* 
● Analysis Population: Safety-Evaluable Patients 
 
● Column Variables:Disease status (Locally Advanced, 
Metastatic), Center/Patient ID - Age/Sex/Race, MedDRA 
Preferred Term, Date of First/ Last Study Drug Admin., Date of 
Adverse Event, Date of Treatment Disc., Date of Last Known 
Alive, Reason for Treatment Disc.,Related to Study Drug, 
Serious 
 
● Column Totals: NA 
 
● Analysis Variables: None 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
Programming notes: 
1. Listing includes patients who had an AE ongoing at time of treatment 
discontinuation, and still ongoing at the time of analysis and patients who 
latest consented to protocol version 1 and 2. 
2. Patients who died or were lost to follow-up within 6 months after treatment 
discontinuation are excluded.  
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Listing of Ongoing Adverse Events for Patients who Discontinued 
Treatment (Latest Protocol Version Consented to: 3 or Higher) 
Output ID: l_ae_ds_PV3PLUS_AEPERS* 
Repeat  l_ae_ds_PV1N2_AEPERS_* output for Patients who latest consented to 
Protocol version 3 or higher. 
 
 
 
 
 
 
 
 


Study MO25616  
                                         Page 56 of 104 
Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Listing of Adverse Events for Patients with Primary Reason of Death for 
Treatment Discontinuation 
AEL02 
Output ID: l_ae_ds_dth* 
● Analysis Population: Safety-Evaluable Patients 
 
● Column Variables:  Disease status (Locally Advanced, 
Metastatic), Center/Patient ID/Cause of Death-Other Reason,  
Date of First Study Drug Administration, 
Adverse Event MedDRA Preferred Term, Study Day of Onset, 
AE Duration in Days, Most Extreme Intensity, Caused by Study 
Drug, Treatment for SAE, Action taken with Study Drug 
 
● Column Totals: NA 
 
● Analysis Variables: None 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
Programming Note: 
Only include patients who  discontinued from Treatment due to Death. 
 
 


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Listing of All Adverse Events 
AEL02 
Output ID: l_ae_SE 
● Analysis Population: Safety-Evaluable Patients 
 
● Column Variables:  Disease status (Locally Advanced, 
Metastatic), Center/Patient ID - Age/Sex/Race,  
Date of First Study Drug Administration, 
Adverse Event MedDRA Preferred Term, Study Day of Onset, 
AE Duration in Days, Serious, Most Extreme Intensity, Caused 
by Study Drug, Outcome, , Treatment for SAE, Action taken 
with Study Drug 
 
● Column Totals: NA 
 
● Analysis Variables: None 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
 
 


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Listing of Cause of Death On Study 
AEL04 
Output ID: l_ae_dth_SE 
● Analysis Population: Safety-Evaluable Patients 
 
● Column Variables: Disease status (Locally Advanced, 
Metastatic), Center/Patient ID, Age/Sex/Race,  
Date of First Study Drug Administration, Date of Last Study 
Drug Administration, Day of Death, Cause of Death, Autopsy 
Performed? 
 
● Column Totals: NA 
 
● Analysis Variables: None 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
 
 


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       14 September 2015 
Listing of Adverse Event Glossary 
AEL01_NOLLT 
Output ID: l_ae_gloss_SE 
● Analysis Population: Safety-Evaluable Patients 
 
● Column Variables: MedDRA System Organ Class, MedDRA 
Preferred Term and Investigator-Specified Adverse Event 
Term. 
 
● Column Totals: NA 
 
● Analysis Variables: None 
 
● Numeric Precision and Formatting of Statistics: Use 
standard display in the mockup 
 
Programming Note: 
− A glossary of all Adverse Events will be provided. 
− Data will be ordered by MedDRA System Organ Class, MedDRA Preferred Term and 
Investigator-Specified Adverse Event Term. 
 
 
 
 


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       14 September 2015 
Listing of Ongoing Adverse Events Ongoing at Treatment 
Discontinuation and still Ongoing 12 Months after Treatment 
Discontinuation: 
STREAM 
Template 
Description 
N/A 
Output ID: l_ae_ongo_pt* 
● Analysis Populations:  Safety-Evaluable Patients 
with Protocol 3+ Subset, Excluding Patients who 
Discontinued Treatment within 6 months 
Output will be repeated for different AE Groups: 
Muscle Spasms, Alopecia, Ageusia, Dysgeusia and 
Weight Decreased 
  
● Column Variables:  Subject ID, Age, Sex, Disease 
Status, Treatment Discontinuation Date, Study 
Discontinuation Date and Reason, MedDRA 
Preferred Term, AE Start Date, Relativity to Treatment 
Discontinuation, AE End Date, AE Toxicity Grade and 
AE Outcome. 
   
 
Programming Note: 
− Data will be ordered by Subject ID, AE Start Date and AE End Date within each AE 
Group. 
 
 
 
 
 
 
 
 
 


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Listing of Ongoing Adverse Events Ongoing at Treatment 
Discontinuation and still Ongoing at Last Assessment (12 Months Follow 
Up): 
STREAM 
Template 
Description 
N/A 
Output ID: l_ae_ongo_pt2* 
● Analysis Populations:  Safety-Evaluable Patients 
with Protocol Version 3 or more and who completed 
the 12 Months Follow Up Visit 
Output will be repeated for different AE Groups: 
Muscle Spasms, Alopecia, Ageusia, Dysgeusia and 
Weight Decreased 
  
● Column Variables:  Subject ID, Age, Sex, Disease 
Status, Treatment Discontinuation Date, Study 
Discontinuation Date and Reason, MedDRA 
Preferred Term, AE Start Date, Relativity to Treatment 
Discontinuation, AE End Date, AE Toxicity Grade and 
AE Outcome. 
   
 
Programming Note: 
− Complete for Patients who completed the study and their 12 month Follow Up 
Assessment 
− Data will be ordered by Subject ID, AE Start Date and AE End Date within each AE 
Group. 
 
 
 
 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
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Listing of Ongoing Adverse Events Ongoing at Treatment 
Discontinuation and still Ongoing at Last Assessment (12 Months Follow 
Up), Excluding Patients with Commercial Vismodegib: 
STREAM 
Template 
Description 
N/A 
Output ID: l_ae_ongo_pt3* 
● Analysis Populations:  Safety-Evaluable Patients 
with Protocol Version 3 or more and who completed 
the 12 Months Follow Up Visit, but exclude any 
Patients who took commercial Vismodegib 
Output will be repeated for different AE Groups: 
Muscle Spasms, Alopecia, Ageusia, Dysgeusia and 
Weight Decreased 
  
● Column Variables:  Subject ID, Age, Sex, Disease 
Status, Treatment Discontinuation Date, Study 
Discontinuation Date and Reason, MedDRA 
Preferred Term, AE Start Date, Relativity to Treatment 
Discontinuation, AE End Date, AE Toxicity Grade and 
AE Outcome. 
   
 
Programming Note: 
− Exclude Patients who took commercial Vismodegib between treatment 
discontinuation and 12 months after treatment discontinuation. 
− Data will be ordered by Subject ID, AE Start Date and AE End Date within each AE 
Group. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Deaths: 
Summary of Deaths: 
STREAM 
Template 
Description 
N/A 
Output ID: t_dd_* 
● Analysis Populations:  Safety 
  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic) 
  
● Column Totals:  Totals of non-missing Disease 
Status 
  
● Analysis Variables: Number of Patients Died, 
Primary Reason for Death 
 
● Statistics and Calculation Methods: Use proq 
freq for events or proc sql for patient counts. 
  
● Numeric Precision and Formatting of Statistics:  
Use DST01 standard template in the mockup 
  
● Optional Subsetting:  Primary Reason for Death: 
Adverse Event, Disease Progression, Other. 
  
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Laboratory Assessments:  
 
Laboratory data that have been obtained using the Site’s Local Ranges will be 
converted to System International (SI) units. The vendor will supply Roche with the 
Conversion factors to convert the results and local ranges to SI Units. All local units 
should be incorporated within the Conversion Factors document. 
These Conversion Factors will then be reviewed by the Medical Review Team. The 
conversion factors will be applied directly to the raw data and reported as is; i.e. no 
adjustment for seemingly incorrect conversions will be performed. 
Grading system NCI-CTC version 4 will be used to Grade the relevant tests.  
 
Hematology and Chemistry Laboratory Data: 
Listings will be produced for the hematology and chemistry laboratory parameters 
(LBCAT=HEMATOLOGY, LBCAT=CHEMISTRY).  
Shift tables will also be presented for the laboratory parameters that have NCI CTC 
grade ranges available from baseline to worst CTC Grade on-treatment, split by High 
and Low Parameters where applicable. 
 
A Listing of Patients with a CTC Grade 3 at Baseline moving to a CTC Grade 4 will 
be created, showing the Patient’s CTC Grade 4 results. 
 
Pregnancy: 
Pregnancy results will be listed for all women of childbearing potential. 
Serum Hormone: 
Serum hormone evaluation tests and results will be listed for all women of 
childbearing potential. 
Ultrasound: 
Ultrasound results will be listed for all women of childbearing potential. 
Creatine Kinase (CPK): 
As part of the exploratory analysis, outputs will be produced with Creatine Kinase 
status (any Abnormal and No Abnormality) versus Treatment Emergent Muscle 
Spasm status (any Muscle Spasm Adverse Event and No Muscle Spasms). 
A Listing of CPK Results and Adverse Events of Muscle Spasms will be created. 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
A table of CPK Elevations by maximum CTC Grade will be created. 
A table of CPK Elevations with the maximum CTC Grade and relative to onset of first 
Treatment Emergent Muscle Spasm will be created. 
A Listing of CPK results and any Adverse Events linked to specific elevated Lab 
Tests levels which will include CPK, ALT or AST and Renal Insufficiency will be 
created. 
For Patients who consented to Protocol Version 4 and above, a shift table of 
maximum NCI CTC Grade of CPK Tests, before and after first recorded Treatment 
Emergent Muscle Spasm will be created. 
A graph of CPK Results, together with 95% Confidence Intervals will be created. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Shift from Baseline to Worst NCI CTCAE Grade During Treatment: 
STREAM 
Template 
Description 
N/A 
Output ID: t_lb_shift_wrstctc_* 
● Analysis Population:  Safety   
Output will be repeated for each Lab Category. 
● Column Variables:  Baseline CTC Grades 0 to 4  
● Column Totals:  Totals of non-missing Grades, Missing 
column 
● Analysis Variables: For each Parameter (in either 
direction) and Disease Status (Locally Advanced, 
Metastatic), Worst Post-Baseline CTC Grades 0 to 4, Total 
of non-missing Grades, Missing row. 
● Statistics and Calculation Methods: Use proc freq. 
● Numeric Precision and Formatting of 
Statistics:  Display whole numbers for patient counts and 
1 decimal point for percentages. 
  
 
 
Programming Notes: 
● Only include tests which occurred during Treatment. 
● Select Worst Post-Baseline Grade for each Parameter and NCI CTC Grade 
Direction 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Summary of CPK Abnormality Status versus Muscle Spasm Status: 
STREAM 
Template 
Description 
N/A 
Output ID: t_lb_chi_ck_* 
● Analysis Population:  Safety   
● Column Variables:  CK Abnormality,  No CK Abnormality 
● Column Totals:  None 
● Analysis Variables: Muscle Spasm status, p-value (Chi-
square). 
● Statistics and Calculation Methods: Use proc freq with 
Chi-square test. 
● Numeric Precision and Formatting of 
Statistics:  Display whole numbers for patient counts and 
1 decimal point for percentages. 
● Optional Subsetting: For Muscle Spasm status, split by 
Yes and No 
  
 
 
 
Programming Notes: 
● A Patient is considered to have a CK Abnormality if they have a CTC Grade 1 
or above any time Post-baseline 
● A Patient is considered to have a Muscle Spasm if they have a Treatment 
Emergent Adverse Event of Muscle Spasm. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
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Summary of CPK Elevations, by Maximum CTC Grade: 
STREAM 
Template 
Description 
N/A 
Output ID: t_lb_ck_* 
● Analysis Population:  Safety and consented to Protocol 
Version 4 and above   
● Column Variables:  Any time post-PV4+,  On-treatment 
only (including 30 days after treatment discontinuation) 
● Column Totals:  None 
● Analysis Variables: Patients with at least 1 CPK result, 
No Elevated CPK result, Any Elevated CPK Result. 
● Statistics and Calculation Methods: Use proc freq. 
● Numeric Precision and Formatting of 
Statistics:  Display whole numbers for patient counts and 
1 decimal point for percentages. 
● Optional Subsetting: For Any Elevated CPK result, split 
by Max CPK Grade 1-2 and Max CPK Grade 3-4 
  
 
 
 
Programming Notes: 
● Only include Patients that have consented to Protocol Version 4 and above 
● Select Worst Post-Baseline Grade for CPK tests within each Patient and 
group by Grades 1-2 and 3-4 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Summary of CPK Elevations and Muscle Spasm AEs including Relative 
Timing of CPK Elevations with onset of First Muscle Spasm: 
STREAM 
Template 
Description 
N/A 
Output ID: t_ck_ms_* 
● Analysis Population:  Safety and consented to Protocol 
Version 4 and above   
● Column Variables:  No Muscle Spasm,  With Muscle 
Spasm at any time, Prior to onset of 1st Muscle Spasm, 
After onset of 1st Muscle Spasm 
● Column Totals:  None 
● Analysis Variables: Patients with at least 1 CPK result, 
No Elevated CPK result, Any Elevated CPK Result. 
● Statistics and Calculation Methods: Use proc freq. 
● Numeric Precision and Formatting of 
Statistics:  Display whole numbers for patient counts and 
1 decimal point for percentages. 
● Optional Subsetting: For Any Elevated CPK result, split 
by Max CPK Grade 1, 2, 3 and 4 
  
 
 
 
Programming Notes: 
● Only include Patients that have consented to Protocol Version 4 and above 
● Select Worst Post-Baseline Grade for CPK tests within each Patient 
● First Muscle Spasm refers to the first occurrence of Muscle Spasm after 
Protocol Version 4 consent date 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Shift Table of Maximum CPK CTC Grade before and after onset of First 
Muscle Spasm: 
STREAM 
Template 
Description 
N/A 
Output ID: t_ck_ms_shift_* 
● Analysis Population:  Safety and consented to Protocol 
Version 4 and above   
● Column Variables:  Max CTC grade after onset of 1st 
Muscle Spasm 
● Column Totals:  None but include Missing column 
● Analysis Variables: Max CTC Grade prior to onset of 1st 
Muscle Spasm, include Missing row 
● Statistics and Calculation Methods: Use proc freq. 
● Numeric Precision and Formatting of 
Statistics:  Display whole numbers for patient counts and 
1 decimal point for percentages. 
● Optional Subsetting: For Max CTC Grade, split by Max 
CPK Grade 0, 1, 2, 3 and 4 
  
 
 
 
Programming Notes: 
● Only include Patients that have consented to Protocol Version 4 and above 
● Select Worst Post-Baseline Grade for CPK tests within each Patient 
● First Muscle Spasm refers to the first occurrence of Muscle Spasm after 
Protocol Version 4 consent date 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Plot of Mean and 95% CI of CPK over Time: 
STREAM 
Template 
Description 
MNG01 
Output ID: g_lb_ck_* 
● Analysis Population:  Safety 
● Plot:  1 Line per Disease Status (Locally Advanced and 
Metastatic)  
● Y Axis:  CPK Result 
● X Axis:  Analysis Visits (use tick-marks for each Visit) 
● Methods: Use Standard STREAM method. 
● Numeric Precision and Formatting of 
Statistics:  Display whole numbers for Y Axis and Visit 
descriptions for X Axis. 
● Optional Additions: Include N counts underneath each 
Visit for each Disease Status. Include Safety Population N 
count for each Disease Status in Legend. 
  
 
 
 
Programming Notes: 
● Include all visits from Baseline 
 
 
 




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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Listing of Creatine Kinase and Adverse Events Linked with [* (See 
below)]. 
 
Programming Notes: 
● Safety-Evaluable patients are included in the listing. 
● * would be Creatine Kinase and Adverse Events of Linked to AE with Muscle 
Spasms, Elevated Creatinine, Renal Insufficiency, Elevant Transaminase 
(ALT or AST). (ie, Listing of Creatine Kinase and Adverse Events Linked with 
Muscle Spasms). 
● Create a separate listing for Creatine Kinase and Adverse Events of Linked to 
AE with Muscle Spasms, Elevated Creatinine, Renal Insufficiency, Elevant 
Transaminase (ALT or AST). 
● Where possible, merge Lab Creatine Kinase Samples Dates with AE Start 
Date of XXX AE and display on same line.  
● Display all the records of lab Creatine Kinase which include Visit, Sample 
Date(with study Day), CPK Standard Result and CTC Grade. For Adverse 
Events include Reported Term, Start and End Date and CTC Grade. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Listing of Lab Data: 
STREAM 
Template 
Description 
N/A 
Output ID: l_lb_* 
● Analysis Population:  Safety Evaluable 
● Column Variables:  Center, Patient ID, Windowed Visit, 
relevant Lab test (within Lab Category) and results in SI 
Units. 
 
Programming Note: 
− Create Table for Lab Categories: Hematology and Biochemistry. Also repeat for all 
tests within Hematology and Biochemistry with a Shift from Grades 3 to 4. 
 
Listing of Hormone Results for Subjects with Amenorrhea or Irregular 
Menses: 
 
A subject is considered to have Amenorrhea or Irregular Menses if they have a record of 
either according the the AE CRF page. 
 
STREAM 
Template 
Description 
N/A 
Output ID: l_lb_hrm_* 
● Analysis Population:  Safety Evaluable 
● Column Variables:  Center, Patient ID, Parameter with SI 
Unit, Windowed Visit, Date of Sample Collection, Result in 
SI Units and High / Low Range indicator 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Listing of Serum Pregnancy Results for Subjects with Amenorrhea or 
Irregular Menses: 
 
A subject is considered to have Amenorrhea or Irregular Menses if they have a record of 
either according the the AE CRF page. 
 
STREAM 
Template 
Description 
N/A 
Output ID: l_lb_preg_* 
● Analysis Population:  Safety Evaluable 
● Column Variables:  Center, Patient ID, Windowed Visit, 
Date of Sample Collection, Character Result and 
Specimen Type 
 
Listing of Ultrasound Results for Subjects with Amenorrhea or Irregular 
Menses: 
 
A subject is considered to have Amenorrhea or Irregular Menses if they have a record of 
either according the the AE CRF page. 
 
STREAM 
Template 
Description 
N/A 
Output ID: l_lb_ult_* 
● Analysis Population:  Safety Evaluable 
● Column Variables:  Center, Patient ID, Windowed Visit, 
Date of Examination, Character Result, Abnormality 
Specified, Is Abnormality Significant? and Method of Test 
or Examination 
 
 
 




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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Vitals: 
Statistical Summary of Vital Signs, Population 
 
 
VST01 
Output ID: t_vs_* 
● Analysis Population:  Safety-Evaluable Patients  
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Following parameters are to be 
summarized. 
o Diastolic Blood Pressure 
o Systolic Blood Pressure 
o Heart Rate 
o Temperature 
o Weight 
● Statistics and Calculation Methods: Use proc 
means or proc univariate. 
o n, mean (SD), median, 25th-75th Percentiles 
and min-max statistics are to be included in 
the table. 
o N in the column heading is the number of 
patients in a disease status in the analysis 
population. n in the rows is the number of 
patients with available data at the visit. 
o Change from baseline at Visit X is defined as 
(Visit X value – baseline value).  Only patients 
with non-missing values at both baseline and 
Visit X are included in calculating change from 
baseline at Visit X. 
o All Visit after Windowing would be displayed in 
this table. With repeat Vital sign 
measurements in a same Visit, the last non-
missing value is reported. 
o Vital sign measurements collected 30 days 
after the last dose of study drug should be 
excluded from summaries of actual values and 
changes from baseline.  
● Numeric Precision and Formatting of 
Statistics:  Level of precision for means, SDs, and 
medians is one digit more than the level of precision 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
of the vital sign measurement (e.g. pulse reported to 
a single place after the decimal point).  Present the 
minimum and maximum to the level of precision of 
the measurement. 
 
 
 
 
 


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Output Specifications:  Questionnaires 
 
ECOG: 
Patients will be graded according to the Eastern Cooperative Oncology Group 
performance status scale and criteria as described below at each scheduled Visit 
mentioned in the Protocol: 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
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 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Shift Table from Baseline: Eastern Cooperative Oncology Group 
Performance Score 
 
Programming Note: 
- 
N is Number of Patients in each Disease Status. 
- 
Shift of ECOG Grade for each Visit from Baseline will be summarised. 
- 
Percentages will be calculated based on N in each Disease status. 
- 
If multiple records were collected during the same cycle,  then the last record within 
that cycle is used for the analysis. 
- 
Population : Intent to treat Population 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
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Skindex-16 QoL Questionnaire: 
 
Skindex-16 (Appendix 1) is a 16-question instrument that has been validated to 
accurately measure the extent patients are bothered by certain skin conditions. Each 
question asks the degree to which a patient has been concerned by their specific 
skin condition in the week prior to administration of the questionnaire.  Patients 
answer every question with a number ranging from 0 (“never bothered”) to 6 (“always 
bothered”).  In terms of scoring algorithm, responses to each item are transformed to 
a linear scale of 100, varying from 0 (“never bothered”) to 100 (“always bothered”).  
Thus, each item has a minimum score of 0 and a maximum score of 100.  With the 
exception of the 16 individual scores, three domain scores (symptom [items 1 – 4], 
emotion [items 5 – 11], and function [items 12 – 16] are grouped and calculated as 
their means ranging from 0 to 100).   
Below Table summarizes the Skindex-16 scoring algorithm.   
Table: Skindex-16 Scoring Algorithm  
 
Question   
Response Option and Score Algorithm1  
During the past week, how often have 
you been bothered by:    
 
 
If Q(i) = “never bothered,” then single 
item original score Q(i)=0  
 
if Q(i)=”always bothered,” then single 
item original score Q(i) = 6  
Question 1 - 4:   
1) Itching,   
2) Burning/stinging   
3) Hurting   
4) Being irritated   
 
Individual Skindex-16 Q1 to Q4 = 
(original item score)*100/6  
 
Symptom Domain Score = [(sum of 
original item scores of Q1 to 
Q4)*100/6]/4  
 
Question 5 - 11:   
5) Persistence/reoccurrence   
6) Worry   
7) Appearance   
8) Frustration   
9) Embarrassment   
Individual Skindex-16 Q5 to Q11 = 
(original item score)*100/6  
 
Emotion Domain Score = [(sum of 
original item scores of Q5 to 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
10) Being annoyed   
11) Feeling depressed   
Q11)*100/6]/7   
Question 12 - 16:   
12) Interaction with others,   
13) Desire to be with people,  
14) Show affection  
15) Daily activities   
16) Work or do what you enjoy  
Individual Skindex-16 Q12 to Q16 = 
(original item score)*100/6  
Function Domain Score = [(sum of 
original item scores of Q12 to 
Q16)*100/6]/5   
Note: Q = question item  
1 The “50% missing rule” which is commonly cited and used in patient-reported 
outcome analysis is used.  If more than 2 items for the symptom domain, more than 
4 items for the emotion domain, or more than 3 items for the function domain are 
missing, their respective domain values should be regarded as missing.  Otherwise, 
the sum of the nonmissing item scores should be calculated as the domain score by 
using the formula stated in the table and denominator should be total no. item with 
non-missing score. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Skindex-16 Analysis of Composite Domains Scores and 
Individual Item Scores: 
VST01 
Output ID: t_sk_* 
● Analysis Population:  Intent-to-Treat Patients with 
measurable disease at baseline.   
Outputs will be repeated for Change from Baseline 
for Composite Domains Scores and Individual Item 
Scores. 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Following parameters are to be 
summarized. 
o Composite Domain (Emotion, Function and 
Symptom) 
o Individual Item (Itching, Burning Or Stinging, 
Hurting, Being Irritated, 
Persistence/Reoccurrence, Worry, 
Appearance, Frustration, Embarrassment, 
Being Annoyed, Feeling Depressed, 
Interaction With Others, Desire To Be With 
People, Show Affection, Daily Activities, Work 
Or Do What You Enjoy) 
● Statistics and Calculation Methods: Use proc 
means or proc univariate. 
o n, mean (SD), median, and min-max statistics 
are to be included in the table. 
o N in the column heading is the number of 
patients in a disease status in the analysis 
population. n in the rows is the number of 
patients with available data at the visit. 
o Change from baseline at Visit X is defined as 
(Visit X value – baseline value).  Only patients 
with non-missing values at both baseline and 
Visit X are included in calculating change from 
baseline at Visit X. 
o All Visit after Windowing would be displayed in 
this table. With repeat Individual Item Score or 
Domain Score in a same Visit, the last non-
missing Score is reported. 
o Individual Item Score or Domain Score 
collected 30 days after the last dose of study 


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       14 September 2015 
drug should be excluded from summaries of 
actual values and changes from baseline.  
● Numeric Precision and Formatting of 
Statistics:  Display 1 decimal point for Min-Max and 
2 decimal points for Mean, SD and Median. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
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Skindex-16 Analysis of Composite Domains Scores and 
Individual Item Scores: 
VST01 
Output ID: t_sk2_* 
● Analysis Population:  Intent-to-Treat Patients with 
Excludes patients with non-histologically confirmed 
disease.   
Outputs will be repeated for Change from Baseline 
for Composite Domains Scores and Individual Item 
Scores. 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Following parameters are to be 
summarized. 
o Composite Domain (Emotion, Function and 
Symptom) 
o Individual Item (Itching, Burning Or Stinging, 
Hurting, Being Irritated, 
Persistence/Reoccurrence, Worry, 
Appearance, Frustration, Embarrassment, 
Being Annoyed, Feeling Depressed, 
Interaction With Others, Desire To Be With 
People, Show Affection, Daily Activities, Work 
Or Do What You Enjoy) 
● Statistics and Calculation Methods: Use proc 
means or proc univariate. 
o n, mean (SD), median, and min-max statistics 
are to be included in the table. 
o N in the column heading is the number of 
patients in a disease status in the analysis 
population. n in the rows is the number of 
patients with available data at the visit. 
o Change from baseline at Visit X is defined as 
(Visit X value – baseline value).  Only patients 
with non-missing values at both baseline and 
Visit X are included in calculating change from 
baseline at Visit X. 
o All Visit after Windowing would be displayed in 
this table. With repeat Individual Item Score or 
Domain Score in a same Visit, the last non-
missing Score is reported. 
o Individual Item Score or Domain Score 


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       14 September 2015 
collected 30 days after the last dose of study 
drug should be excluded from summaries of 
actual values and changes from baseline.  
● Numeric Precision and Formatting of 
Statistics:  Display 1 decimal point for Min-Max and 
2 decimal points for Mean, SD and Median. 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
M.D. Anderson Symptom Inventory (MDASI): 
 
MDASI contains 20 questions aimed to measure symptom severity.  These 
questions are split across two sections. 
The first section contains 14 questions. Each question asks the severity that patients 
feel for specific symptoms at that visit.   Patients answer every question with a 
number ranging from 0 (“Not Present”) to 10 (“As Bad As You Can Imagine”). The 14 
questions are outlined on the eCRF. 
The second section contains 6 questions. Each question asks how much specific 
symptoms affect subjects’ lives in general.  Patients answer every question with a 
number ranging from 0 (“Did Not Interfere”) to 10 (“Interfered entirely”). The 6 
questions are outlined on the eCRF. 
  
Disease Related Symptoms: 
The study has some specific items which are considered to be ‘Disease Related 
Symptoms’. These items are as follows: 
Item 1: Pain 
Item 2: Fatigue 
Item 6: Shortness of Breath 
Item 8: Lack of Appetite 
Item 10: Dry Mouth 
Item 14: Coughing 
 
 
 
 


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MDASI Individual Item Scores: 
VST01 
Output ID: t_md_* 
● Analysis Population:  Intent-to-Treat Patients with 
measurable disease at baseline.   
Outputs will be repeated for Change from Baseline 
for Individual Item Scores. 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Following parameters are to be 
summarized. 
o Individual Items 
● Statistics and Calculation Methods: Use proc 
means or proc univariate. 
o n, mean (SD), median, and min-max statistics 
are to be included in the table. 
o N in the column heading is the number of 
patients in a disease status in the analysis 
population. n in the rows is the number of 
patients with available data at the visit. 
o Change from baseline at Visit X is defined as 
(Visit X value – baseline value).  Only patients 
with non-missing values at both baseline and 
Visit X are included in calculating change from 
baseline at Visit X. 
o All Visit after Windowing would be displayed in 
this table. With repeat Individual Item Score or 
Domain Score in a same Visit, the last non-
missing Score is reported. 
o Individual Item Score collected 30 days after 
the last dose of study drug should be excluded 
from summaries of actual values and changes 
from baseline.  
● Numeric Precision and Formatting of 
Statistics:  Display 1 decimal point for Min-Max and 
2 decimal points for Mean, SD and Median. 
 
 
 


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       14 September 2015 
MDASI Reductions for Patients with Disease Related 
Symptoms: 
 
The protocol suggests that the MDASI reduction in disease related symptoms should only be 
considered for patients who had four (or more) MDASI points at baseline, in order to obtain a 
meaningful assessment of reduction in severity from baseline. It is unclear whether this 4 
points would be a patient’s average baseline score, or baseline score from any domain. The 
following output, therefore, was created for all patients with a baseline MDASI, patients with 
any score of 4 or higher at baseline, and patients with an average baseline score of 4 or 
higher. 
 
 
Programming Note: 
1. This output will be repeated for different subsets of patients. 
2. MDASI was only collected for Metastatic patients, so only display the Metastatic 
column. 
3. Percentages should be based upon the small n. 
4. 30% reductions is any 30% reduction in a given analysis variable. See titles and 
footnotes in the lopo for these different reduction criteria. 
5. N is the number of patients within the specific population. 
6. Only include the questions for Disease Related Symptoms. 
7. If a subject has had a reduction for the given criteria (see 30% reduction note) then 
they would appear in ‘yes’ and not in ‘no’. 
 
 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Output Specifications:  Efficacy Tables 
Best Response: 
1) Best Confirmed overall response. 
RSPT01 
Output ID: t_rs_best_* 
● Analysis Population: Patients with measurable disease at 
baseline, excluding patients without histologically confirmed 
BCC.   
Outputs will be repeated for different population combinations - 
please see the LoPO for details of these combinations, and the 
Efficacy Population section for details on populations. 
● Column Variables:  Disease Status (Locally Advanced, 
Metastatic)  
● Column Totals:  Totals of non-missing Disease Status 
● Analysis Variables: Response variable is the Best Overall 
Response: Complete Response, Partial Response, Stable 
Disease, Progressive Disease, Not evaluable, or Missing. 
● Statistics and Calculation Methods: Use proq freq. 
o Display Patients with histologically-confirmed measurable 
disease at baseline 
o CIs for Best Overall Response Rate presented in the 
table are displayed as percentages, i.e. the actual values 
multiplied by 100. 
o α level for CIs is 2-sided 5%. 
o Method of Clopper-Pearson is to be used to derive 95% 
CI for proportion. 
● Numeric Precision and Formatting of Statistics:  Use 
standard display in the mockup 
● Optional Subsetting:  Display Response categories i.e. 
Complete Response, Partial Response, Stable Disease, 
Progressive Disease, Missing, or Not evaluable, are displayed 
with percentage. 
 
Programming Notes: 
- 
Best Overall Response (BOR) would be Complete Response (CR) if subject 
had CR on each of two tumor assessments which are greater than or equal to 
23 days apart (with either no other tumor assessments in between or the 
tumor response between these two assessments is CR or Not Evaluable 
(NE)). 


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       14 September 2015 
- 
Best Overall Response would be Partial Response (PR) if subject’s best 
overall response is not CR and the subject had two tumor assessments 
greater than or equal to 23 days apart with the response of the first 
assessment being PR and the second being PR or CR (with either no other 
tumor assessments in between or the tumor response between these two 
assessments being CR, PR, or NE). 
- 
Best Overall Response would be Stable Disease (SD) if subject’s best overall 
response is not CR or PR, and there is at least one response assessment of 
CR, PR or SD with minimum of 51 days after First Dose Date without any 
Progressive Disease (PD) in between. 
- 
Best Overall Response would be Progression Disease (PD) if subject’s best 
overall response is not CR, PR, or SD, and if there is at least one response 
assessment of PD. 
- 
Best Overall Response would be Not Evaluable (NE) if subject’s best overall 
response is not CR, PR, SD, or PD, and there is at least one response 
assessment of NE. 
- 
BOR would be PD if PD occurred before satisfying any of the above criteria of 
Best Overall Response. 
- 
Patients who achieve best overall response of CR or PR are considered a 
responder. 
- 
Best overall response rate is defined as the number of patients with a CR or 
PR observed at two consecutive assessments >=4 weeks apart (>= 23 days) 
divided by the total number of patients with histologically confirmed 
measurable disease at baseline.   
- 
N in column headings is the number of patients with a measurable or non-
measurable disease at baseline and histologically confirmed BCC. 
Percentages are calculated based on the number of patients with a 
measurable disease at baseline and histologically confirmed BCC.   
- 
Display only Responder and 95%CI for Best Overall Response Rate. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
2) Best Confirmed Overall Response (Measurable Disease at 
Baseline) by Location of Metastatic Disease 
Output ID: t_rs_best_byloc* 
Repeat t_rs_best* output by Location of Metastatic Disease as on the “Disease 
History of advanced or metastatic BCC” CRF page. 
 
3) Best Confirmed Overall Response (Non-Measurable Disease at 
Baseline) 
Output ID: t_rs_nonm* 
Repeat t_rs_best* output for patients with non-measurable disease at baseline. 
Programming Note: 
- 
Percentages are calculated based on the number of patients with a non-
measurable disease at baseline and histologically confirmed BCC. 
- 
Only patients with non-measurable disease at baseline and histologically 
confirmed BCC should be included in the table.  
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Duration of Response: 
TTET01 
Output ID: t_tte_OBJRDR_* 
● Analysis Population: Intent-to-Treat Patients with measurable 
disease at baseline, excluding patients without histologically 
confirmed BCC.   
Outputs will be repeated for different population combinations - 
please see the LoPO for details of these combinations, and the 
Efficacy Population section for details on populations. 
● Column Variables:  Disease Status (Locally Advanced, 
Metastatic)  
● Column Totals:  Totals of non-missing Disease Status 
● Analysis Variables: Duration of response in Months 
● Statistics and Calculation Methods: Use proc freq and proc 
lifetest. 
o α level for CIs is 2-sided 5%. 
o Use proc lifetest to obtain time to event (Median, 
Percentiles) information. The 95% confidence interval for 
the median is calculated using the Brookmeyer & 
Crowley method. 
o Range, 25th and 75th Percentiles are displayed. 
● Numeric Precision and Formatting of Statistics:  Use 
standard display in the mockup 
 
Programming Note: 
- 
Duration of response will be calculated only for patients whose confirmed best 
response is CR or PR.  
- 
Duration of response is the interval between the Date of First Response and 
the Date of Progressive Disease or Death, and is calculated only for patients 
with confirmed best response of CR or PR at two consecutive assessments 
>= 23 days.   
- 
Patients without Progression of Disease or Death will be censored at the date 
of last tumour assessment and the duration of response is calculated using 
the interval between Date of First Response and the date of last tumour 
assessment. 
- 
N would be the number of patients with a measurable or non-measurable 
disease at baseline and histologically confirmed BCC.     
- 
Percentages are based on the number of patients with a measurable disease 
at baseline and histologically confirmed BCC, and who had a CR or PR.   
- 
Duration of response will be calculated in Months. 
 
 


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       14 September 2015 
Time to Response: 
TTET01 
Output ID: t_tte_TMTRS_* 
● Analysis Population: Intent-to-Treat Patients with 
measurable disease at baseline, excluding patients 
without histologically confirmed BCC.   
Outputs will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations, and the Efficacy Population 
section for details on populations. 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Time to response in patients 
with Best Overall Response (BOR) and patients 
without BOR in Months 
● Statistics and Calculation Methods: Use proq freq 
and proc lifetest. 
o α level for CIs is 2-sided 5%. 
o Use proc lifetest to obtain time to event 
(Median, Percentiles) information. The 95% 
confidence interval for the median is 
calculated using the Brookmeyer & Crowley 
method. 
o Range, 25th and 75th Percentiles are 
displayed. 
● Numeric Precision and Formatting of 
Statistics:  Use standard display in the mockup 
 
Programming Note: 
- 
Time to response is defined as the interval between the date of first treatment 
and the date of first documentation of confirmed CR or PR (whichever occurs 
first). 
- 
Patients without CR or PR will be censored at the date of last tumour 
assessment.  
- 
N would be the number of patients with a measurable or non-measurable 
disease at baseline and histologically confirmed BCC.     
- 
Percentages are based on the number of patients with a measurable disease 
at baseline and histologically confirmed BCC.   
 
 


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       14 September 2015 
Progression Free Survival:  
TTET01 
Output ID: t_tte_PFS_* 
● Analysis Population: Intent-to-Treat Patients, 
excluding patients without histologically confirmed 
BCC.   
Outputs will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations, and the Efficacy Population 
section for details on populations. 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Progression Free Survival in 
Months 
● Statistics and Calculation Methods: Use proq freq 
and proc lifetest. 
o α level for CIs is 2-sided 5%. 
o Use proc lifetest to obtain time to event 
(Median, Percentiles) information. The 95% 
confidence interval for the median is 
calculated using the Brookmeyer & Crowley 
method. 
o Range, 25th and 75th Percentiles are 
displayed. 
● Numeric Precision and Formatting of 
Statistics:  Use standard display in the mockup 
 
Programming Note: 
- 
Progression-Free Survival is defined as the interval between the date of first 
treatment and the date of Progressive Disease or Death. 
- 
Patients without disease progression or death will be censored at the date of 
last tumour assessment.  
- 
N would be the number of patients with a measurable or non-measurable 
disease at baseline and histologically confirmed BCC.     
- 
Percentages are based on N.   
- 
Patients with a measurable or non-measurable disease at baseline and 
histologically confirmed BCC are included in the analysis. 
 
 


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       14 September 2015 
Overall Survival: 
TTET01 
Output ID: t_tte_OS_* 
● Analysis Population: Intent-to-Treat Patients, 
excluding patients without histologically confirmed 
BCC.   
Outputs will be repeated for different population 
combinations - please see the LoPO for details of 
these combinations, and the Efficacy Population 
section for details on populations. 
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  Totals of non-missing Disease 
Status 
● Analysis Variables: Overall Survival in Months 
● Statistics and Calculation Methods: Use proq freq 
and proc lifetest. 
o α level for CIs is 2-sided 5%. 
o Use proc lifetest to obtain time to event 
(Median, Percentiles) information. The 95% 
confidence interval for the median is 
calculated using the Brookmeyer & Crowley 
method. 
o Range, 25th and 75th Percentiles are 
displayed. 
● Numeric Precision and Formatting of 
Statistics:  Use standard display in the mockup 
Programming Note: 
- 
Overall Survival is defined as the interval between the date of first treatment 
and the date of Death (see above for derivation of date of death). 
- 
Patients who remain alive will be censored at the last date known to be alive.  
- 
N would be the number of patients with a measurable or non-measurable 
disease at baseline and histologically confirmed BCC.     
- 
Percentages are based on N.   
- 
Patients with a measurable or non-measurable disease at baseline and 
histologically confirmed BCC are included in the analysis. 
For deriving the Date Last Known Alive, please use the standard STREAM default   
derivation, excluding lab dates.  
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Kaplan Meier Plot of Duration of Response: 
KMG01 
Output ID: g_rs_km_OBJRDR_IT 
● Analysis Population: Intent-to-Treat Patients with 
measurable disease at baseline, excluding patients 
without histologically confirmed BCC.   
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  NA 
● Analysis Variables: Plot Survival Distribution 
Function 
● Statistics and Calculation Methods: Kaplan-Meier 
using PROC LIFETEST. 
o α level is 2-sided 5%. 
o Use proc lifetest to obtain time to event 
information in months.  
● Numeric Precision and Formatting of Statistics:   
o Display censored values by flagging with 
cross “+” marks.  
o Label of X axis should be “Time” and Y axis 
should be “Survival Distribution Function”. 
Programming Note: 
- 
Duration of response will be calculated only for patients whose confirmed best 
response is CR or PR.  
- 
Duration of response is interval between the Date of First Response and the 
Date of Progressive Disease or Death, and is calculated only for patients with 
confirmed best response of CR or PR at two consecutive assessments >= 23 
days.   
- 
Patients without disease progression or death will be censored at the date of 
last tumour assessment and the duration is calculated using the interval 
between the Date of First Response and the date of last tumour assessment. 
- 
Legend should display the number of patients with measurable disease at 
baseline and histologically confirmed BCC for each Disease Status.     
- 
Patients with measurable disease at baseline and histologically confirmed 
BCC should only be included in the analysis.  
- 
Display No. of Subject at Risk for each Disease Status.  
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Kaplan Meier Plot of Progression-Free Survival: 
KMG01 
Output ID: g_rs_km_PFS_IT 
● Analysis Population: Intent-to-Treat Patients, 
excluding patients without histologically confirmed 
BCC.   
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  NA 
● Analysis Variables: Plot Survival Distribution 
Function 
● Statistics and Calculation Methods: Kaplan-Meier 
using PROC LIFETEST. 
o α level is 2-sided 5%. 
o Use proc lifetest to obtain time to event 
information in months.  
● Numeric Precision and Formatting of Statistics:   
o Display censored values by flagging with 
cross “+” marks.  
o Label of X axis should be “Time” and Y axis 
should be “Survival Distribution Function”. 
 
Programming Note: 
- 
Progression-Free Survival is defined as the interval between the date of first 
treatment and the date of Progressive Disease or Death. 
- 
Patients without disease progression or death will be censored at the date of 
last tumour assessment.  
- 
Legend should display the number of patients with a measurable or non-
measurable disease at baseline and histologically confirmed BCC for each 
Disease Status.      
- 
Patients with a measurable or non-measurable disease at baseline and 
histologically confirmed BCC are included in the analysis. 
- 
Display No. of Subject at Risk for each Disease Status. 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Kaplan Meier Plot of Overall Survival: 
KMG01 
Output ID: g_rs_km_OS_IT 
● Analysis Population: Intent-to-Treat Patients, 
excluding patients without histologically confirmed 
BCC.   
● Column Variables:  Disease Status (Locally 
Advanced, Metastatic)  
● Column Totals:  NA 
● Analysis Variables: Plot Survival Distribution 
Function 
● Statistics and Calculation Methods: Kaplan-Meier 
using PROC LIFETEST. 
o α level is 2-sided 5%. 
o Use proc lifetest to obtain time to event 
information in months.  
● Numeric Precision and Formatting of Statistics:   
o Display censored values by flagging with 
cross “+” marks.  
o Label of X axis should be “Time” and Y axis 
should be “Survival Distribution Function”. 
 
Programming Note: 
- 
Overall Survival is defined as the interval between the date of first treatment 
and the date of Death. 
- 
Patients who remain alive will be censored at the last date known to be alive.  
- 
see above output ID for t_tte_OS_* for derivation of date of death & last date 
known to be alive 
- 
Legend should display the number of patients with a measurable or non-
measurable disease at baseline and histologically confirmed BCC for each 
Disease Status.      
- 
Patients with a measurable or non-measurable disease at baseline and 
histologically confirmed BCC are included in the analysis. 
- 
Display No. of Subject at Risk for each Disease Status 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Overall Lesion Assessment: 
output ID: l_tu_lsass_IT 
 
Programming Note: 
- 
There can be multiple rows per subject: one row for each tumor assessment . 
Best overall response will be flagged (asterisk). See ‘Best Overall Response’ 
section for details on this derivation. 
- 
Patients with non-histologically confirmed disease are excluded from the 
listing. 
- 
Refer to CRF page ‘Overall Lesion Assessment’ for reporting. 
- 
Population: Intent-to-Treat Patients. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Listing of Overall Lesion Assessment: New Lesions: 
output ID: l_tu_lsass_newls_IT 
 
Programming Note: 
- 
Patients with non-histologically confirmed disease are excluded from the 
listing. 
- 
Refer to the “Overall Lesion Assessment” CRF page (‘New Lesion details 
Entry’ section) for reporting. 
- 
Population: Intent-to-Treat Patients. 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Target Lesion Assessment: 
output ID: l_tu_lsass_tgt_IT 
 
Programming Note: 
- 
Patients with non-histologically confirmed disease are excluded from the 
listing. 
- 
Refer to the “Target Lesion Assessment” CRF page for reporting. 
- 
Population: Intent-to-Treat Patients. 
 
 
 
 
 
 


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Output Specifications, Version 1.0 
 
 
 
 
 
       14 September 2015 
Non-Target Lesion Assessment: 
output ID: l_tu_lsass_ntgt_IT 
 
Programming Note: 
- 
Patients with non-histologically confirmed disease are excluded from the 
listing. 
- 
Refer to the “Non-Target Lesion Assessment” CRF page for reporting. 
- 
Population: Intent-to-Treat Patients.