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8.5.1 analysis population

The statistical analysis of efficacy will include all patients completing the initial treatment with vismodegib alone and start the concurrent vismodegib with radiation therapy. Anyone who receives any vismodegib with radiation therapy will be included in the assessment of efficacy. As the most conservative approach, any patient removed from study prior to completion of at least 75% of radiation therapy without a documented complete or partial response will be considered as a case of local-regional failure.  
Failure is defined as a lack of local-regional control within the boundaries of the treated radiation PTV area within the 12 month follow-up period.
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8.6 evaluation of safety

The analyses of safety will be performed for all patients having received at least one dose of study drug. The study will use the NCI CTCAE v4.0.
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9 study management 9.1 pre-study

This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable regulatory requirements.  
Before initiating this trial, the Investigator will have written and dated approval from the Institutional Review Board for the protocol, written informed consent form, subject recruitment materials, and any other written information to be provided to subjects before any protocol related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under the Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a letter from FDA stating that the study is exempt from IND requirements. The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory requirements.
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9.2 institutional review board approval

The protocol, the proposed informed consent form, and all forms of participant information related to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the UCSF IRB (UCSF Institutional Review Board). Prior to obtaining IRB approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol Review Committee (PRC). The initial protocol and all protocol amendments must be approved by the IRB prior to implementation.
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9.3 informed consent

All participants must be provided a consent form describing the study with sufficient information for each participant to make an informed decision regarding their participation. Participants must sign the IRB-approved informed consent form prior to participation in any study specific procedure. The participant must receive a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file.
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9.4 changes in the protocol

Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be documented in the form of an amendment. The amendment must be signed by the Investigator and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an amendment may be implemented prior to IRB approval. In this circumstance, however, the Investigator must then notify the IRB in writing within five (5) working days after implementation. The Study Chair and the UCSF study team will be responsible for updating any participating sites.
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9.5 handling and documentation of

The UCSF Principal Investigator and each participating site will maintain complete records showing the receipt, dispensation, return, or other disposition of all investigational drugs. The date, quantity and batch or code number of the drug, and the identification of patients to whom study drug has been dispensed by patient number and initials will be included. The sponsorinvestigator will maintain written records of any disposition of the study drug.  
The Principal Investigator shall not make the investigational drug available to any individuals other than to qualified study patients. Furthermore, the Principal Investigator will not allow the investigational drug to be used in any manner other than that specified in this protocol.
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9.6 case report forms (crfs)

The Principal Investigator and/or his/her designee, will prepare and maintain adequate and accurate participant case histories with observations and data pertinent to the study. Study specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion of the study visit; the Investigator will review and approve the completed CRFs. The information collected on CRFs shall be identical to that appearing in original source documents. Source documents will be found in the patient's medical records maintained by UCSF personnel. All source documentation should be kept in separate research folders for each patient.  
In accordance with federal regulations, the Investigator is responsible for the accuracy and authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all completed CRFs to attest that the information contained on the CRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the UCSF DSMC and regulatory agencies. The Principal Investigator will be responsible for ensuring the accurate capture of study data. At study completion, when the CRFs have been declared to be complete and accurate, the database will be locked. Any changes to the data entered into the CRFs after that time can only be made by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol Project Manager.  
Each participating site will complete study specific CRFs for safety monitoring and data analysis. Each site will enter the study data into OnCore® via standardized CRFs in accordance with the CTMS study calendar, using single data entry with a secure access account. The participating site's Clinical Research Coordinator (CRC) will complete the CRFs; the Investigator will review and approve the completed CRFs - this process must be completed within 3 business days of the visit. Study data from the participating site will be reported and reviewed in aggregate with data from patients enrolled at the coordinating center, UCSF. All source documentation and CTMS data will be available for review/monitoring as needed.
a phase ii study of
9.7 modality review

The Principal Investigator will perform a Quality Assurance Review of all patients in this trial. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of chemotherapy treatment data as specified in Appendix 8. The scoring mechanism is: Per Protocol/Acceptable Variation, Not Per Protocol, and Not Evaluable. A report is sent to each institution once per year to notify the institution about compliance for each case reviewed in that year.  
The Principal Investigator will perform a Quality Assurance Review after complete data for the first 4 cases enrolled has been received. The Principal Investigator will perform the next review after complete data for the next 4 cases enrolled. The final cases will be reviewed within 3 months after this study has reached the target accrual or as soon as complete data for all cases enrolled has been received, whichever occurs first.
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9.8 oversight and monitoring plan

The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity for this study. The UCSF DSMC will monitor the study in accordance with the NCIapproved Data and Safety Monitoring Plan (DSMP). The DSMC will routinely review all adverse events and suspected adverse reactions considered "serious". The DSMC will audit studyrelated activities to ensure that the study is conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). Significant results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as applicable. See Appendix 9 Data and Safety Monitoring Plan for additional information.
a phase ii study of
9.9 multicenter communication

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, quarterly conference calls with the participating sites or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:  
- Enrollment information
- Adverse events (i.e. new adverse events and updates on unresolved adverse events and new safety information)
- Protocol violations - Other issues affecting the conduct of the study
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9.10 record keeping and record

The Principal Investigator is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects, as well as written records of the disposition of the drug when the study ends.  
The Principal Investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation. Case histories include the case report forms and supporting data including, for example, signed and dated consent forms and medical records including, for example, progress notes of the physician, the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall document that informed consent was obtained prior to participation in the study. Study documentation includes all CRFs, data correction forms or queries, source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms).  
Source documents include all recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical research study.  
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years following the date a marketing application is approved for the drug for the indication for which it is being investigated; or, if no application is to be filed or if the application is not approved for such indication, until 2 years after the investigation is discontinued and FDA is notified.
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9.11 coordinating center documentation of

It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of study documents as well as their receipt (when possible). The HDFCCC recommends that the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.). Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover letters, amendment outlines (summary of changes), etc., along with distribution documentation and (when available) documentation of receipt.  
Correspondence log: should be a brief list of all documents distributed including the date sent, recipient(s), and (if available) a tracking number and date received.  
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its updates and safety information are distributed.
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9.12 regulatory documentation

Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, HIPAA authorization and any other information pertaining to participants must be approved by the UCSF Institutional Review Board (IRB). Prior to implementing this protocol at the participating sites, approval for the UCSF IRB approved protocol must be obtained from the participating site's IRB.  
The following documents must be provided to UCSF HDFCCC before the participating site can be initiated and begin enrolling participants:
- Participating Site IRB approval(s) for the protocol, appendices, informed consent form and HIPAA authorization
- Participating Site IRB approved consent form
- Participating Site IRB membership list
- Participating Site IRB's Federal Wide Assurance number and OHRP Registration number
- Curriculum vitae and medical license for each investigator and consenting professional
- Documentation of Human Subject Research Certification training for investigators and key staff members at the Participating Site
- Participating site laboratory certifications and normals Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant permission to proceed with enrollment. See Appendix 10 for submission information.
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10 protection of human subjects

Each clinical site is responsible for protecting all subjects involved in human experimentation. This is accomplished through the IRB mechanism and the process of informed consent. The IRB reviews all proposed studies involving human experimentation and ensures that the subject's rights and welfare are protected and that the potential benefits and/or the importance of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the informed consent document associated with each study in order to ensure that the consent document accurately and clearly communicates the nature of the research to be done and its associated risks and benefits.
a phase ii study of
10.2 protection of privacy

Patients will be informed of the extent to which their confidential health information generated from this study may be used for research purposes. Following this discussion, they will be asked to sign the HIPAA form and informed consent documents. The original signed document will become part of the patient's medical records, and each patient will receive a copy of the signed document. The use and disclosure of protected health information will be limited to the individuals described in the informed consent document.
a phase ii study of
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Aszterbaum M, Epstein J, Oro A, et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 1999:5;1285–91.  
Binns A, James LF, Shupe JL, Everett G. Congenital cyclopian-type malformation in lambs induced by maternal ingestion of a range plant, Veratrum californicum. Am J Vet Res 1963;24:1164–75. 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.  
Chen YJ, Lin CP, Hsu ML, et al. Sonic hedgehog signaling protects human hepatocellular carcinoma cells against ionizing radiation in an autocrine manner. Int J Radiat Oncol Biol Phys 2011;80(3):851-9.  
Cohen B, Weiss G, Yin H. Basal cell carcinoma (BCC) causing spinal cord compression. Dermatol Online J 2000;6:12. Dahmane N, Lee J, Robins P, et al. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 1997;389:876−81.  
Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, et al. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 1996;14:78−81.  
Kovarik CL, Stewart D, Barnard JJ. Lethal basal cell carcinoma secondary to cerebral invasion. J Am Acad Dermatol 2005;52:149−51. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001;15:3059−87.  
Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272:1668−71.  
Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004;431:707–12. Leonard JM, Ye H, Wetmore C, Karnitz LM. Sonic Hedgehog signaling impairs ionizing radiation-induced checkpoint activation and induces genomic instability. J Cell Biol. 2008 Nov 3;183(3):385-91.  
Lo JS, Snow SN, Reizner GT, et al. Metastatic basal cell carcinoma: report of twelve cases with a review of the literature. J Am Acad Dermatol 1991;24(5 Pt 1):715−9.  
LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR, Chang I, Darbonne WC, Graham RA, Zerivitz KL, Low JA, Von Hoff DD. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011 Apr 15;17(8):2502-11. Epub 2011 Feb 7.  
Molckovsky A, Siu LL. First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American society of clinical oncology meeting. J Hematol Oncol. 2008 Oct 29;1:20.  
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. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012 Jun 7;366(23):2171-9.  
Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366:2171-9. Supplementary Appendix.  
Sims-Mourtada J, Izzo JG, Apisarnthanarax S, et al. Hedgehog: An attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res 2006;12:6565-72. Snow SN, Sahl W, Lo JS, et al. Metastatic basal cell carcinoma. Report of five cases. Cancer 1994;73:328−35.  
Spates ST, Mellette JR Jr, Fitzpatrick J. Metastatic basal cell carcinoma. Dermatol Surg 2003;29:650−2.  
Thayer SP, Pasca di Magliano M, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425:851–6. Unden AB, Zaphiropoulos PG, Bruce K, et al. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res 1997;57:2336–40.  
von Domarus H, Stevens PJ. Metastatic basal cell carcinoma: report of five cases and review of 170 cases in the literature. J Am Acad Dermatol 1984; 10:1043−60.  
Wadhera A, Fazio M, Bricca G, et al. Metastatic basal cell carcinoma: a case report and literature review. How accurate is our incidence data? Dermatol Online J 2006;12:7. Williams JA, Guicherit OM, Zaharian BI, et al. Identification of a small molecule inhibitor of the Hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci USA 2003;100:4616−21.  
Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008;455(7211):406-10. Zeng J, Aziz K, Chettiar ST, et al. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers. Int J Radiat Oncol Biol Phys. 2012 Nov 20. doi:pii: S0360-3016(12)03664-4.
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appendices appendix 1 performance status

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

TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor 2 cm or less in greatest dimension with less than two high risk features** T2 Tumor greater than 2 cm in greatest dimension or Tumor any size with two or more high risk features** T3 Tumor with invasion of maxilla, orbit, or temporal bone T4 Tumor with invasion of skeleton (axial or appendicular) or perineural invasion of skull base
* Excludes cutaneous carcinoma of the eyelid. **High Risk Features for the Primary Tumor (T) Staging : Depth/Invasion: >2 mm thickness, Clark level Ñ IV, Perineural invasion Anatomic Location: Primary site ear, Primary site hair-bearing lip Differentiation: Poorly differentiated or undifferentiated
a phase ii study of
regional lymph nodes (n)

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2 Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3 Metastasis in a lymph node, more than 6 cm in greatest dimension
a phase ii study of
distant metastasis (m)

M0 No distant metastasis (no pathologic M0; use clinical M to complete stage group)
M1 Distant metastasis ANATOMIC STAGE/PROGNOSTIC GROUPS Group T N M 0 Tis N0 M0 I T1 N0 M0 II T2 N0 M0 III T3 N0 M0 T1 N1 M0 T2 N1 M0 T3 N1 M0 IV T1 N2 M0 T2 N2 M0 T3 N2 M0 T Any N3 M0 T4 N Any M0 T Any N Any M1
a phase ii study of
appendix 3 rtog/eortc late radiation

| RTOG/EORTC Late Radiation Morbidity Scoring Scheme 0 GRADE 1 GRADE 2   | GRADE 3                                                                                           | GRADE 4                                                                        | 5                                                                                                                 |                                                                           |                     |
|------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|---------------------|
| ORGAN TISSUE SKIN                                                      | None                                                                                              | Slight atrophy;  Pigmentation  change; Some hair  loss                         | Patch atrophy; Moderate  telangiectasia; Total hair  loss                                                         | Marked atrophy;                                                           | Ulceration          |
| Gross telangiectasia                                                   |                                                                                                   |                                                                                |                                                                                                                   |                                                                           |                     |
| SUBCUTANEOUS                                                           | None                                                                                              | Slight induration  (fibrosis) and loss  of subcutaneous fat                    | Moderate fibrosis but                                                                                             |                                                                           |                     |
| asymptomatic; Slight field  contracture; <10% linear  reduction        | Severe induration and  loss of subcutaneous  tissue; Field  contracture > 10%  linear measurement | Necrosis                                                                       | D                                                                                                                 |                                                                           |                     |
| TISSUE                                                                 | E                                                                                                 |                                                                                |                                                                                                                   |                                                                           |                     |
| MUCOUS                                                                 | None                                                                                              | Slight atrophy and                                                             | Moderate atrophy and                                                                                              |                                                                           |                     |
| dryness                                                                | telangiectasia; Little  mucous                                                                    | Marked atrophy with  complete dryness;  Severe telangiectasia                  | Ulceration                                                                                                        | A  T                                                                      |                     |
| MEMBRANE SALIVARY                                                      | None                                                                                              | Slight dryness of  mouth; Good  response on  stimulation                       | Moderate dryness of                                                                                               |                                                                           |                     |
| mouth; Poor response on  stimulation                                   | Complete dryness of  mouth; No response  on stimulation                                           | Fibrosis                                                                       | H                                                                                                                 |                                                                           |                     |
| GLANDS                                                                 | D                                                                                                 |                                                                                |                                                                                                                   |                                                                           |                     |
| SPINAL                                                                 | None                                                                                              | Mild L'Hermitte's                                                              | Severe L'Hermitte's                                                                                               | Objective                                                                 |                     |
| syndrome                                                               | syndrome                                                                                          | neurological findings  at or below cord level  treated                         | Mono, para  quadriplegia                                                                                          | I                                                                         |                     |
| CORD                                                                   | R                                                                                                 |                                                                                |                                                                                                                   |                                                                           |                     |
| BRAIN                                                                  | None                                                                                              | Mild headache;                                                                 | Moderate headache; Great                                                                                          | Severe headaches;                                                         |                     |
| Slight lethargy                                                        | lethargy                                                                                          | Severe CNS                                                                     |                                                                                                                   |                                                                           |                     |
| dysfunction (partial  loss of power or  dyskinesia)                    | Seizures or                                                                                       |                                                                                |                                                                                                                   |                                                                           |                     |
| paralysis; Coma                                                        | E  C                                                                                              |                                                                                |                                                                                                                   |                                                                           |                     |
| EYE                                                                    | None                                                                                              | Asymptomatic  cataract; Minor  corneal ulceration  or keratitis                | Symptomatic cataract;  Moderate corneal  ulceration; Minor  retinopathy or glaucoma                               | Severe keratitis;                                                         |                     |
| Severe retinopathy or  detachment Severe  glaucoma                     | Panopthalmitis/ Blindness                                                                         | E T                                                                            |                                                                                                                   |                                                                           |                     |
| LARYNX                                                                 | None                                                                                              | Hoarseness; Slight                                                             | Moderate arytenoid                                                                                                | Severe edema; Severe                                                      | Necrosis            |
| arytenoid edema                                                        | edema; Chondritis                                                                                 | chondritis                                                                     | L Y                                                                                                               |                                                                           |                     |
| LUNG                                                                   | None                                                                                              | Asymptomatic or  mild symptoms  (dry cough); Slight  radiographic  appearances | Moderate symptomatic  fibrosis or pneumonitis  (severe cough); Low grade  fever; Patchy radiographic  appearances | Severe symptomatic  fibrosis or  pneumonitis; Dense  radiographic changes | Severe  respiratory |
| insufficiency/co ntinuous  O2/Assisted  ventilation                    | R                                                                                                 |                                                                                |                                                                                                                   |                                                                           |                     |
| HEART                                                                  | None                                                                                              | Asymptomatic or  mild symptoms;  Transient T wave  inversion & ST              | Moderate angina on effort;  Mild pericarditis; Normal  heart size; Persistent  abnormal T wave and ST             | Severe angina;                                                            |                     |
| Pericardial effusion;  Constrictive  pericarditis; Moderate            | Tamponade/Sev ere heart  failure/Severe  constrictive                                             | E                                                                              |                                                                                                                   |                                                                           |                     |  
Version date: 11-07-2016 Protocol CC#:122011  
| Changes; Sinus  tachycardia >110                                                                                                           | changes ; Low ORS                                                                                                                             | heart failure; Cardiac  enlargement; EKG  abnormalities                                                      | pericarditis                                       | L A     |
|--------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|----------------------------------------------------|---------|
| (at rest)                                                                                                                                  | T                                                                                                                                             |                                                                                                              |                                                    |         |
| ESOPHAGUS                                                                                                                                  | None                                                                                                                                          | Mild fibrosis;                                                                                               |                                                    |         |
| Slight difficulty in  swallowing solids;  No pain on  swallowing                                                                           | Unable to take solid food  normally; Swallowing  semi-solid food; Dilation  may be indicated                                                  | Severe fibrosis; Able  to swallow only  liquids; May have  pain on swallowing                                | Necrosis/Perfor ation Fistula                      | E  D    |
| Dilation required                                                                                                                          |                                                                                                                                               |                                                                                                              |                                                    |         |
| SMALL/LARGE                                                                                                                                | None                                                                                                                                          | Mild diarrhea;  Mild cramping;  Bowel movement 5  times daily Slight  rectal discharge or  bleeding          | Moderate diarrhea and                              |         |
| colic; Bowel movement >5  times daily; Excessive  rectal mucus or  intermittent bleeding                                                   | Obstruction or                                                                                                                                |                                                                                                              |                                                    |         |
| bleeding, requiring  surgery                                                                                                               | Necrosis/Perfor ation Fistula                                                                                                                 | T                                                                                                            |                                                    |         |
| INTESTINE                                                                                                                                  | O                                                                                                                                             |                                                                                                              |                                                    |         |
| LIVER                                                                                                                                      | None                                                                                                                                          | Mild lassitude;                                                                                              |                                                    |         |
| Nausea, dyspepsia;  Slightly abnormal  liver function                                                                                      | Moderate symptoms;  Some abnormal liver;  function tests; Serum  albumin normal                                                               | Disabling hepatitic  insufficiency; Liver  function tests grossly  abnormal; Low  albumin; Edema or  ascites | Necrosis/Hepati c coma or  encephalopathy          | R  A  D |
| KIDNEY                                                                                                                                     | None                                                                                                                                          | Transient                                                                                                    |                                                    |         |
| albuminuria; No  hypertension; Mild  impairment of  renal function;  Urea 25-35  mg%;Creatinine  1.5-2.0 mg%;  Creatinine  clearance > 75% | Persistent moderate                                                                                                                           | Severe albuminuria;  Severe hypertension                                                                     | Malignant  hypotension;  Uremic  coma/Urea >  100% |         |
| albuminuria (2+); Mild                                                                                                                     | I                                                                                                                                             |                                                                                                              |                                                    |         |
| Persistent anemia (<  10%); Severe renal  failure; Urea >60  mg% Creatinine >4.0  mg% Creatinine  clearance < 50%                          | A                                                                                                                                             |                                                                                                              |                                                    |         |
| hypertension; No related anemia; Moderate  impairment of renal  function; Urea > 36- 60mg% Creatinine  clearance (50-74%)                  | T  I  O                                                                                                                                       |                                                                                                              |                                                    |         |
| BLADDER                                                                                                                                    | None                                                                                                                                          | Slight epithelial  atrophy; Minor  telangiectasia  (microscopic  hematuria)                                  | Moderate frequency;                                |         |
| Generalized telangiectasia;  Intermittent macroscopic  hematuria                                                                           | Severe frequency &  dysuria Severe  generalized  Telangiectasia (often  with petechiae);  Frequent hematuria;  Reduction in bladder  capacity | Necrosis/Contra cted bladder  (capacity < 100  cc); Severe  hemorrhagic  cystitis                            | N                                                  |         |
|                                                                                                                                            | E                                                                                                                                             |                                                                                                              |                                                    |         |
| (< 150 cc)                                                                                                                                 | F                                                                                                                                             |                                                                                                              |                                                    |         |
| BONE                                                                                                                                       | None                                                                                                                                          | Asymptomatic; No  growth retardation;  Reduced bone  Density                                                 | Moderate pain or  tenderness; Growth               |         |
| retardation; Irregular bone                                                                                                                | Severe pain or                                                                                                                                |                                                                                                              |                                                    |         |
| tenderness; Complete  arrest of bone growth;  Dense bone sclerosis                                                                         | Necrosis/Sponta neous fracture                                                                                                                | F  E                                                                                                         |                                                    |         |
| sclerosis                                                                                                                                  | C                                                                                                                                             |                                                                                                              |                                                    |         |
| JOINT                                                                                                                                      | None                                                                                                                                          | Mild joint stiffness;  Slight limitation of  movement                                                        | Moderate stiffness;                                |         |
| Intermittent or moderate  joint pain; Moderate  limitation of movement                                                                     | Severe joint stiffness;  Pain with severe  limitation of  movement                                                                            | Necrosis/Compl ete fixation                                                                                  | T  S                                               |         |  
Version date: 11-07-2016 Protocol CC\#:122011
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appendix 4 management of dental

Dental Care for Irradiated Patients Goals for a dental care program include:
1. To reduce incidence of bone necrosis.  
2. To reduce incidence of irradiation caries.  
3. To allow proper fitting of dentures following treatment.
Pre-irradiation Care and Procedures The patients may be grouped into four groups in accordance with the problems they present prior to irradiation.
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group 1

Includes edentulous patients. They may require surgical removal of any symptomatic cysts, infected retained root tips, or alveolar hyperplasia. These patients require hygiene instruction and precautionary instruction about trauma with premature use of a prosthesis.
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group 2

Includes those with poor dental hygiene, including those patients whose teeth are beyond repair by ordinary dental procedure, those with generalized oral sepsis, those with generalized periodontal disease, and those with chronic periapical abscesses or granulomas.  
Procedures performed on this group include removal of all remaining teeth prior to irradiation with primary closure and surgical preparation of the alveolar ridges to laterally support a prosthesis. There should be antibiotic coverage during the healing stage and adequate time prior to the start of radiation therapy. These patients need complete hygiene instruction and precautionary instruction about premature use of a prosthesis.
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group 3

Includes those in whom dental condition is fair, including those patients whose teeth are restored, ordinary dental procedures, periodontal pockets are less than 3 mm deep, carious lesions are not in proximity to the pulp, and no more than 20 restorable carious lesions are present. X-ray examinations show at least 1/2 of the bone still present around root surfaces. These patients require removal of any teeth that are non-salvageable in accordance with the above and restorations of the remaining teeth as required. The patients are instructed for dental prophylaxis and the patients utilize custom-made fluoride carriers.
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group 4

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

Vismodegib inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro at clinically relevant concentrations. Caution should be exercised and dose reduction of the concomitant substrate drug should be considered when dosing vismodegib concurrently with medications with narrow therapeutic windows that are substrates of CYP2C8, CYP2C9, and CYP2C19, because their concentrations may become elevated and their effects increased or prolonged.  
Vismodegib did not significantly inhibit CYP3A4 at clinically relevant concentrations in vitro; however, the clinical impact of vismodegib on substrates of CYP3A4 is unknown. Vismodegib is a substrate of CYP3A4; however, the in vitro metabolic conversion of vismodegib is low. Effects of CYP inducers (i.e., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St John's wort, and troglitazone) on clinical concentrations of vismodegib are unknown; it is possible that these drugs could reduce concentrations of vismodegib. Likewise, the effects of strong inhibitors of CYP3A4 (i.e., clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, telithromycin) on vismodegib clinical concentrations are unknown; it is possible that these drugs could increase the concentrations of vismodegib.  
Use of these drugs with vismodegib should be documented. The table below lists substrate drugs in columns under the designation of specific cytochrome P450 isoforms. A drug appears in a column if there is published evidence that it is metabolized, to a clinically relevant degree by that isoform (Flockhart) or in the FDA table of in vivo substrates for study. This is not necessarily a complete list; other medications may also interact with vismodegib.  
| 2C8                                                                                                                                        | 2C9                                                                                      | 2C19                                                            |
|--------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|-----------------------------------------------------------------|
| Miscellaneous:                                                                                                                             | NSAIDs:                                                                                  | Proton Pump Inhibitors:                                         |
| repaglinide                                                                                                                                | Diclofenac                                                                               |                                                                 |
| rosiglitazone                                                                                                                              | Ibuprofen  piroxicam  naproxen  celecoxib                                                | omeprazole  lansoprazole  pantoprazole  rabeprazole  esoprazole |
| Oral Hypoglycemic Agents:                                                                                                                  | Anti-epileptics:  diazepam  phenytoin  phenobarbitone                                    |                                                                 |
| glipizide  tolbutamide Angiotensin II Blockers:                                                                                            | Miscellaneous:  amitriptyline  clomipramine  clopidogrel  cyclophosphamide  progesterone |                                                                 |
| irbesartan  losartan NOT candesartan NOT valsartan  Miscellaneous:  fluvastatin  phenytoin  sulfamethoxazole  tamoxifen torsemide warfarin |                                                                                          |                                                                 |
| Reference: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction; Table. Indiana University School of Medicine                 |                                                                                          |                                                                 |  
Reference: Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction; Table. Indiana University School of Medicine (2007); http://medicine.iupui.edu/flockhart/clinlist.htm FDA Drug Development and Drug Interactions: Table of Substrates; Inhibitors and Inducers (May 2006). http://www.fda.gov/cder/drug/drugInteractions/tableSubstrates.htm\#classSub
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appendix 6 skindex-16 survey

Skindex16 cMMChren 1997  
  
Skindex16 ©MMChren, 1997 SKINDEX 16 SCORING  
  
Item scores transformed to 0 - 100 scale.  
Scale Score:
Average of items in given scale
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appendix 7 digital photographic procedures

Views  
- Close-up view with millimeter scale of the target area of the basal cell carcinoma(BCC):
two each
- Global view of the target BCC area: two each
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procedures

In these clinical photographs for the duration of the study, the only variable allowed to change is the skin condition itself. Therefore, anything extraneous to the condition (furniture, etc.) is to be eliminated from the photographic field, starting at the entry visit through the final visit. The necessity of good end-of-study photographs should be stressed to patients to ensure their cooperation. Lighting, framing, exposure, and reproduction ratios must be held constant. In the end, the images should read like a time-lapse movie. Any doubt as to the correctness of the photographic technique should result in an immediate re-shoot.  
Each photographic session includes an exposure series of:  
a. Patient ID, which will include the following legible information in black indelible ink (two exposures):
Date Center name Patient's study ID number Photographer's initials  
b. Close-up view of patient's target BCC area(s), consisting of one individual BCC lesion
(two exposures)
c. Global view of patient's target BCC area(s), consisting of up to two individual BCC
lesions (two exposures)
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appendix 8 data submission

Participating sites must submit the following data components.  
- Within 2 weeks of study entry, the following documents must be submitted to the coordinating center  
o Demographic Form (A5)
o Initial Evaluation Form (I1)
o Pathology Report (P1)
- At the completion of preradiotherapy component and at the completion of concurrent therapy component: Treatment Form (TF) and Pill Diary (DP) 3 months from the start of treatment, after restaging imaging and before starting post-radiation therapy: Initial Follow-up Form (F0)
- After the F0, q 12 weeks for 1 year, all subsequent follow up with patient will be done by UCSF per section 6.1.5
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dosimetry data submission

Hard copy isodose distributions for total dose plan DVH printouts showing doses to critical structures Summary printout of entire plan, including summary table of contour names, with contour (region) volume, and the Min, Mean and Max dose to the regions of interest.
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data should be submitted to

Appendix 9 Data And Safety Monitoring Plan* For A Multicenter **Institutional Study**  
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for all HDFCCC institutional clinical studies. A summary of DSMC activities for this study includes:  
- Review of subject data
- Review of suspected adverse reactions considered "serious" - Monthly monitoring (depending on study accrual)
- Minimum of a yearly regulatory audit
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monitoring and reporting guidelines

All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk assessment. The data is monitored every six months, with twenty percent of the subjects monitored (or at least three subjects if the calculated value is less than three).  
The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate quarterly conference calls with the participating sites to communicate the review of adverse events, safety data, and other study matters. The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites. The Study Chair will conduct continuous review of data and subject safety and discuss each subject's treatment at monthly UCSF Site Committee meetings. The discussions are documented in the UCSF Site Committee meeting minutes.
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multicenter communication

The UCSF Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, monthly conference calls with the participating sites at the completion of each cohort or more frequently as needed to discuss risk assessment. The following issues will be discussed as appropriate:
- Enrollment information
- Adverse events (i.e. new adverse events and updates on unresolved adverse events and new safety information)
- Protocol violations
- Other issues affecting the conduct of the study Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, as well as the participating sites. The DSMC will be responsible for monitoring all data entered in OnCore® at the UCSF Coordinating Center and the participating sites. The data (i.e. copies of source documents) from the participating sites will be sent electronically or faxed over to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor the participating site's compliance with the protocol, patient safety, and to verify data entry.
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adverse event review and monitoring

All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered to be associated with the use of study drug, will be entered into OnCore®, UCSF's Clinical Trial Management System.  
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the UCSF Site Committee meetings. All clinically significant adverse events must be reported to the UCSF Coordinating Center by the participating sites within 10 business days of becoming aware of the event or during the next scheduled quarterly conference call, whichever is sooner. The UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of the adverse event to the administration of the study drug(s) from the UCSF Coordinating Center and the participating sites.  
In addition, all suspected adverse reactions considered "serious" must be entered in OnCore® and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse reactions considered "serious" will be reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take place every six (6) weeks. If a death occurs during the treatment phase of the study or within 30 days after the last administration of the study drug(s) and is determined to be related either to the investigational drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the assigned designee must be notified within 1 business day from the participating site(s) and the Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of this notification. The contact may be by phone or e-mail.
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increase in adverse event rates

If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is responsible for notifying the DSMC at the time the increased rate is identified. The report will indicate if the incidence of adverse events observed in the study is above the range stated in the Investigator Brochure or package insert.  
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC must receive a formal letter within 10 business days and the IRB must be notified.  
  
  
Data and Safety Monitoring Committee Contacts:
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appendix 10 ucsf policy/procedure for

This policy defines the required Regulatory Documents for Single Site and Multicenter Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer Center (HDFCCC) where the Principal Investigator (PI) holds the IND.
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background

The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines define Essential Regulatory Documents as those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of data produced. These documents serve to demonstrate compliance with standards of GCP and with all applicable regulatory requirements. Filing essential documents in a timely manner can greatly assist in the successful reconscilimanagement of a clinical trial.  
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials.
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procedures 1. hdfccc essential regulatory

- IRB approvals for initial submission of application, all modifications, and continuing annual renewals
- Current and prior approved protocol versions with signed protocol signature page(s) - Institutional Review Board (IRB) approval letters and Informed Consent Form(s) (ICF)
- Current and prior versions of the Investigator Brochure (IB).  
- Serious Adverse Event Reporting - Protocol Violations and Single Patient Exception (SPE) Reports to IRB with supporting fax documentation
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documents filed in oncore

- Package Insert (if the study drug is commercial) or Investigator Brochure
- Protocol Review Committee (PRC) approved protocols, protocol amendments and Summary of Changes (SOC)
- Patient handouts
- Screening/enrollment log
- Data and Safety Monitoring Committee (DSMC) monitoring reports
- DSMC dose escalation approvals with study status summary forms
- OnCore® Case Report Form (CRF) completion manual
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documents filed in regulatory binder

- Completed Food and Drug Administration (FDA) 1572 document with Principal Investigator's signature
- For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA)
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative
(CITI), etc.)
- Site Initiation Visit (SIV) minutes and correspondence with participating site(s).  
- As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center
- Serious Adverse Event (SAE) reports to IRB and sponsor. - MedWatch reporting to FDA and sponsor
- Delegation of Authority Form
- Drug Destruction Standard Operating Procedure (SOP) - For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges
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2. additional essential documents for

- Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form
(ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form for the Participating Site(s)
- For all Principal Investigators and Sub-Investigators listed on the 1572 at the Participating Site(s) - Financial Disclosure Forms, CVs, MD Licenses, and Staff Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational New Drug Application
- Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s).  
- As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion Center for the Participating Site(s)
- Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting fax documentation for Participating Site(s)
- Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s) - Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating Site(s)
- For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating Site(s)
- Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan
(if an outside CRO is used for the study)
- Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the Participating Site(s)
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3 required regulatory documents for

Directions:
1) Fax the documents listed below to the UCSF Coordinating center or 2) Scan the documents and upload to OnCore® and create a Note to File for the on-site Regulatory binder to indicate where these documents may be found
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1572

PI and Sub investigators:
CV and Medical license Financial disclosure form NIH or CITI human subject protection training certification Laboratories CLIA and CAP CV of Lab Director and Lab Licenses Laboratory reference ranges
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local institutional review board

IRB Approval letter Reviewed/Approved documents
- Protocol version date: ___________ - Informed consent version date: ___________
- Investigator Brochure version date: ___________
- HIPAA
Current IRB Roster
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other

Delegation of Authority Log
- Include NIH or CITI human subject protection training certificates or GCP training certification Pharmacy
- Drug destruction SOP and Policy Protocol signature page Executed sub contract 27.apr.2012
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genentech a member of the

SAFETY REPORTING FAX COVER SHEET
Genentech Supported Research AE / SAE FAX No:  
  
| Alternate Fax No:                                            |                     |
|--------------------------------------------------------------|---------------------|
| Genentech Study Number                                       |                     |
| Principal Investigator                                       |                     |
| Site Name                                                    |                     |
| Reporter name                                                |                     |
| Reporter Telephone #                                         |                     |
| Reporter Fax #                                               |                     |
| Initial Report Date                                          | [DD] / [MON] / [YY] |
| Follow-up Report Date                                        | [DD] / [MON] / [YY] |
| Subject Initials                                             | []-[.]-[.]          |
| (Enter a dash if patient has no                              |                     |
| middle name)                                                 |                     |
| SAE or Safety Reporting questions, contact Genentech Safety: |                     |  
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS
COVER SHEET.  
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Vismodegib—F. Hoffmann-La Roche Ltd Protocol MO28295, Final Version 1, 29 October 2012