Conditions: Metastatic Pancreatic Cancer
Keywords: Adenocarcinoma Hedgehog Neoplasms Digestive System Diseases Neoplasms by Site Digestive System Neoplasms Neoplasms by Histologic Type Pancreatic Neoplasms Pancreatic Diseases Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 98
Healthy volunteers: no

Brief summary:
This is an open-label, single arm, multi-center, Phase II trial to evaluate the progression free survival in patients with metastatic adenocarcinoma of the pancreas treated with a hedgehog inhibitor (GDC-0449) in combination with chemotherapy (gemcitabine and nab-Paclitaxel).

Detailed description:
The emergence of new small molecules with capacity of blocking the Hedgehog signaling pathway provides a novel therapeutic approach in pancreatic adenocarcinoma treating the primary tumor, stroma, systemic metastases and pancreatic cancer stem cells by hedgehog pathway inhibition. This phase 2 clinical trial will evaluate the progression free survival (PFS) in patients with previously untreated metastatic pancreatic adenocarcinoma. We hypothesize that the combination of cytotoxic agents (gemcitabine and nab-paclitaxel) with the Hedgehog inhibitor GDC-0449 may increase PFS.

This study includes correlative studies to attempt to understand the stem cell biology and mechanism for any observed clinical benefits with the use of Hedgehog inhibitor GDC-0449. These include changes in the hedgehog pathway and changes in pancreatic cancer stem cell markers with pre and post treatment biopsies. The safety of GDC-0449 when combined with chemotherapy gemcitabine and nab-paclitaxel will also be assessed by evaluating adverse event rate.

Following the determination of eligibility patients will receive the following treatment:

1. One cycle of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 (28 days cycle) then
2. Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days cycle in combination with oral GDC-0449 150 mg daily

Patients may continue on treatment regimen until they experience progressive disease or unacceptable toxicity, require palliative radiotherapy, withdraw consent or the physician feels it is not longer in their best interest to continue on treatment.

Arms:
arm 1: Gemcitabine and nab-Paclitaxel in combination with GDC-0449 (Vismodegib)

Interventions: intervention 1: Gemcitabine, nab-Paclitaxel, GDC-0449
Intervention descriptions: intervention 1: 1. One cycle of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 (28 days cycle) then
2. Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days cycle in combination with oral GDC-0449 150 mg daily

Protocol document:
Prot_SAP_000.pdf: 
Protocol Amendment 12, date December 4, 2014 
1
 
 
SCHEMA 
(STUDY SYNOPSIS) 
 
 
A Phase II Study of Gemcitabine and nab-Paclitaxel in Combination with 
Vismodegib (GDC-0449; Hedgehog Pathway Inhibitor) in Patients with 
Previously Untreated Metastatic Adenocarcinoma of the Pancreas 
 
 
 
Johns Hopkins Protocol Number: J1013, NA_00036883 
 
 
IND Number: 108819 
 
 
Sponsor: Stand Up to Cancer (SU2C) 
 
 
 
 
 
 
 
 
Key Principal Investigator: 
Daniel Laheru, M.D. 


Protocol Amendment 12, date December 4, 2014 
2
    (Johns Hopkins)                     The Sidney Kimmel Comprehensive Cancer Center  
                                                      at Johns  Hopkins 
 
Bunting Blaustein Cancer Research Building 
 
1650 Orleans Street, 4M09 
 
Baltimore MD 21231-1000 
 
(410) 955-8974 
 
laherda@jhmi.edu  
 
Co-Principal Investigator: 
Ana De Jesus-Acosta MD 
       (Johns Hopkins)                   The Sidney Kimmel Comprehensive Cancer Center  
                                                      at Johns  Hopkins 
 
Bunting Blaustein Cancer Research Building 
 
1650 Orleans Street, 4M08 
 
Baltimore MD 21231-1000 
 
 
 
 
      adejesu1@jhmi.edu 
 
 Principal Investigators:   
     Ramesh K. Ramanathan, MD                                                  
                                                     Peter O’Dwyer MD 
                                                
 
Co-Investigators:                     Anirban Maitra, MD     
  (Johns Hopkins)                    Ross Donehower, MD 
                                                  Luis Diaz, MD 
                                                  Dung Thi Le, MD 
                                                  David Cosgrove, MBBCh  
                                                  Nilofer S Azad, MD 
                                                  Lei Zheng, MD PhD 
                                                  Marcia Irene Canto, MD 
                                                  Eun Shin, MD 
                                                  Zeshaan Rasheed, MD   
  Pamela Johnson, MD 
  Emily Petito, CRNP 
  Keith McIntyre, CRNP 
  Atif Zaheer, MD 
  Ilene Browner, MD 
                                             
                                                   
Study Coordinating Center:  Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
 
Study Center (s):      Translational Genomics Research Institute, Scottsdale AZ 
University of Pennsylvania, PA  
 
         
 
              
       


Protocol Amendment 12, date December 4, 2014 
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Statistician: 
                          Study Coordinator: 
 
 
Elizabeth Sugar 
Yvette Cetasaan, CCRP 
 
615 North Wolfe St, W5010 
550 North Broadway, Suite 415 
 
Baltimore, MD 21205 
Baltimore, MD 21205 
 
410-502-3913 
410-955-4035 
 
Fax: 410-502-4621 
Fax: 443-287-6566 
 
esugar@ jhsph.edu 
freemyv@jhmi.edu 
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Rosalind Walker 
Yvette Cetasaan, CCRP 
 
550 North Broadway, Suite 415 
550 North Broadway, Suite 415 
 
Baltimore, MD 21205 
Baltimore, MD 21205 
 
410-955-9628 
410-955-4035 
 
Fax: 443-287-6566 
Fax: 443-287-6566 
 
Rwalker3@jhmi.edu 
freemyv@jhmi.edu 
 
 
 
Summary of the protocol versions:  
 
Protocol Version 
Date of Protocol 
IRB Approved Date 
Initial Protocol 
May 3, 2010 
July 6, 2010 
Amendment 1 
June 8, 2010 
N/A 
Amendment 2 
June 11, 2010 
N/A 
Amendment 3 
July 6, 2010 
July 23, 2010 
Amendment 4 
August 16, 2010 
Oct 19, 2010 
Amendment 5 
February 1, 2011  
March 8, 2011 
Amendment 6 
August 3, 2011 
Aug 30, 2011 
Amendment 7 
January 11, 2012 
February 7, 2012 
Amendment 8 
February 15, 2012 
March 6, 2012 
Amendment 9 
February 22, 2013 
February 26, 2013 
Amendment 10 
April 16, 2013 
May 15, 2013 
Amendment 11 
August 16, 2013 
September 11, 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Amendment 12, date December 4, 2014 
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Study Phase: Phase II                   
 
Patient Population:  Patients with untreated metastatic pancreatic adenocarcinoma  
                                               
Concept and Rationale 
 
Pancreatic cancer is one of the most dismal malignancies in the gastrointestinal tract and remains the 
fourth leading cause of cancer related mortality.   The majority of patients with pancreatic 
adenocarcinoma have evidence of metastatic disease at presentation with a median survival of 6 months.  
New therapies are urgently needed. 
The Hedgehog (Hh) signaling pathway is persistently activated in several malignancies including 
pancreatic cancer leading to activation and nuclear localization of GLI1 transcription factors, with 
subsequent induction of Hh target genes, many of which are involved in proliferation, survival and 
angiogenesis. The Hh signaling pathway also plays a role in maintaining subpopulations of cancer stem 
cells (CSC) in pancreatic cancer. Based on previous preclinical studies, pancreatic CSC comprise 0.2-
0.8% of all pancreatic cancer cells, are highly tumorigenic and possessed the ability of self-renew and 
produce a differentiated progeny. These CSC can elicit tumor progression and metastases and confer 
potential resistance to available therapeutic approaches including chemotherapy and radiation.  
 
In preclinical studies pharmacologic blockade of the Hh signaling pathway using Hh inhibitors 
decreased tumor proliferation, increased survival in animal models and decreased CSC markers in 
primary and metastatic tumors. Inhibition of the Hh signaling pathway in pancreatic cancer may provide 
a therapeutic strategy by treating the primary tumor, systemic metastases and targeting CSC by Hh 
pathway inhibition. Other postulated mechanisms for clinical benefit using Hh inhibitors in pancreatic 
cancer include modulation of surrounding stroma and increased drug delivery of cytotoxic agents into 
tumor tissue. 
 
In a phase I study in patients with advance solid tumors GDC-0449 was well tolerated with no dose 
limiting-toxicities. We hypothesize that the combination of GDC-0449 with chemotherapy (gemcitabine 
and nab-paclitaxel) will provide clinical benefit as measured by progression free survival in patients 
with metastatic previously untreated pancreatic adenocarcinoma. 
 
 
Primary Objective (s) 
 To evaluate whether the addition of a vismodegib (GDC-0449; Hedgehog Pathway Inhibitor) to 
cytotoxic chemotherapy (Gemcitabine and nab-paclitaxel) in patients with metastatic 
adenocarcinoma of the pancreas increases progression free survival (PFS).   
 
Secondary Objectives (s) 
 To evaluate overall survival 
 To evaluate for tumor response (complete response, partial response), stable disease and 
progressive disease  
 To evaluate the safety of the combination gemcitabine + nab-paclitaxel with GDC-0449 in 
patients with metastatic adenocarcinoma of the pancreas 


Protocol Amendment 12, date December 4, 2014 
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 To evaluate the presence of pancreatic CSC in tissue and peripheral blood and its changes with 
therapy using above combination 
 To evaluate changes of Hh signaling pathway using GDC-0449 
 To evaluate if serum and/ or tumor biomarkers predict clinical benefit with GDC-0449 
 
Primary Endpoints(s)  
 PFS as defined by the time from first therapy received to the earlier documented disease 
progression or death from any cause. PFS will be determined by the investigator. Imaging studies 
to assess response will be evaluated by expert radiologists using RECIST 1.1 criteria. 
 
Secondary Endpoint(s) 
 
Efficacy endpoints 
 Overall survival from the time of cycle 1, day 1 until death from any cause 
 Objective tumor response (partial response, complete response) or stable disease based on CT 
scans (or MRI scans if patient is allergic to contrast agent or has some other contraindication to a 
CT scan). These will be evaluated according to RECIST 1.1 criteria. 
 
Safety endpoints 
 Number of grade 3 and 4 toxicities according to National Cancer Institute Common Toxicity 
Criteria for Adverse Events (NCI CTCAE; Version 4.0) that occur after Cycle 1, day 1 
 Incidence, nature and severity of all adverse events that occur on or after Cycle 1, Day 1 
 
Correlative studies endpoints 
 Quantitative pancreatic CSC identification using functional assays and phenotypic assays. 
Functional assays include immunohistochemistry or RT-PCR for ALDH bright cells. Phenotypic 
assays include immunohistochemistry, quantitative RT-PCR or flow cytometry for pancreatic 
cancer stem cell markers (CD24+/CD44+/ESA+ and CD133+) in tissue biopsy and peripheral 
blood.  
 Semi-quantitative measurement of Hh ligand expressions in pre-post treatment biopsies and Hh 
signaling pathway downregulation as measured by Gli 1 and Patch 
 Biomarker changes as measured by serum CA19-9 and plasma and tumor SPARC  
 
 
 
 


Protocol Amendment 12, date December 4, 2014 
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Study Design: 
 
This is an open-label, single arm, multi-center, Phase II trial to evaluate progression free  
survival in patients with metastatic adenocarcinoma of the pancreas treated with a Hh inhibitor and 
chemotherapy. This trial will also assess for objective tumor response and evaluate changes in 
pancreatic CSC markers and Hh signaling pathway inhibition using the Vismodegib (GDC-0449; 
hedgehog pathway inhibitor) in combination with chemotherapy (gemcitabine and nab-paclitaxel). 
Following the determination of eligibility patients will receive the following treatment:  
1.  One cycle of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 (28 
days cycle) then 
2.  Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days cycle 
in combination with oral GDC-0449 150 mg daily 
 
Number of Patients: 72 patients 
 
 
Duration of Intervention and Evaluation 
 
Patients may continue on treatment regimen until they experience progressive disease or unacceptable 
toxicity, require palliative radiotherapy, withdraw consent or the physician feels it is no longer in their 
best interest to continue on treatment. If a patient is removed from treatment he/she will be followed to 
gather information of overall survival.  If an individual is lost to follow-up, then they will be censored at 
the time of the last contact. 
 
Statistical Methods 
 
The patient demographics will be described using summary statistics (mean, S.D., median, range, count, 
percentage).  Kaplan-Meier techniques will be used to summarize time to event outcomes (progression 
free survival and overall survival) graphically and to estimate the median and one-year survival 
outcomes with 80% confidence intervals.   The percent change from the pre to the post-treatment 
biopsies will be calculated for the correlative outcomes.  The outcomes will be summarized using 
means, standard deviations, medians and ranges.   
 
The study is power to determine whether the addition of GDC-0449 provides benefit over chemotherapy 
alone (gemcitabine and nab-paclitaxel).  The primary outcome is progression free survival.  In previous 
trial using chemotherapy with gemcitabine and nab-paclitaxel, the median progression free survival was 
5.5 months. We have powered our study with the assumption of 24 months accrual. Based upon these 
assumptions, a sample size of 72 patients will have an 80% power to detect an increase in the median 
progression free survival to 7.15 months from the null rate of 5.5 months using a one sided type 1 error 
of 0.10.  Up to an additional 10% will be accrued in order to control for loss to follow-up.  The expected 
accrual rate is between 4-5 patients per month. 
 
 
 


Protocol Amendment 12, date December 4, 2014 
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Funding, Regulatory, and Feasibility Issues: Genentech will provide GDC-0449. Abraxis will provide 
nab-paclitaxel. Gemcitabine will be obtained by commercial means.  
 
Patient Acceptability/Ethics and Concepts Issues: None 
 
 
 
Contents 
SCHEMA ........................................................................................................................................ 1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................. 10 
1. 
OBJECTIVES ....................................................................................................................... 12 
1.1. 
Primary Objectives ......................................................................................................... 12 
1.2. 
Secondary Objectives ..................................................................................................... 12 
2. 
BACKGROUND .................................................................................................................. 12 
2.1 
 Study Disease ................................................................................................................ 12 
2.2    Rationale for this study .................................................................................................... 15 
2.3    Correlative Studies ........................................................................................................... 16 
2.4 
 Study Drugs ................................................................................................................... 16 
2.4.1 
GDC-0449 ............................................................................................................... 16 
2.4.2 
nab-paclitaxel .......................................................................................................... 20 
2.4.3 Gemcitabine: ................................................................................................................ 22 
3. 
PATIENT SELECTION ....................................................................................................... 23 
3.1 
 Eligibility Criteria ......................................................................................................... 23 
3.2 
 Exclusion Criteria .......................................................................................................... 25 
3.3 
 Inclusion of Women and Minorities .............................................................................. 27 
4. REGISTRATION PROCEDURES .......................................................................................... 27 
4.1 General Guidelines .............................................................................................................. 27 
4.2 Data Submission Procedures............................................................................................... 27 
5. 
TREATMENT PLAN ........................................................................................................... 29 
5.1 Time and Events Schedule .................................................................................................. 29 
5.1.1 Screening and Pre-study Assessments ......................................................................... 30 
5.1.2 Assessments during the study period ........................................................................... 31 
5.1.3 Beginning of each cycle ............................................................................................... 32 


Protocol Amendment 12, date December 4, 2014 
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5.1.4 Follow up assessments ................................................................................................. 33 
5.2 
 Agent Administration .................................................................................................... 36 
5.2.1 GDC-0449 .................................................................................................................... 36 
5.2.2 nab-paclitaxel ............................................................................................................... 37 
5.2.3 Gemcitabine ................................................................................................................. 37 
5.2.4      
Other Modality (ies) or Procedures ..................................................................... 38 
5.3 General Concomitant Medication and Supportive Care Guidelines ................................... 38 
5.3.1 GDC-0449 .................................................................................................................... 38 
5.3.2 Other Considerations ................................................................................................... 41 
5.4 
Duration of Therapy ....................................................................................................... 42 
5.5 
Duration of Follow Up ................................................................................................... 42 
5.6 
Criteria for removal from Study ..................................................................................... 42 
6. 
DOSING DELAYS/DOSE MODIFICATIONS/DOSE OMISSIONS ................................ 42 
6.1 GDC-0449 ........................................................................................................................... 43 
6.2 Gemcitabine and nab-Paclitaxel ......................................................................................... 43 
7. 
ADVERSE EVENTS ............................................................................................................ 48 
7.1 Adverse Events (AE) definition .......................................................................................... 48 
7.2 Serious Adverse Events (SAE) Definition .......................................................................... 49 
7.3 Grading and Assessing Causality ........................................................................................ 50 
7.4 Potential Risks for Study Drugs .......................................................................................... 53 
7.5 Reporting Adverse Events .................................................................................................. 58 
7.6  Safety Reporting Requirements for IND Holders .............................................................. 62 
7.7 Data and Safety Monitoring Plan ........................................................................................ 63 
8. PHARMACEUTICAL INFORMATION ................................................................................. 64 
8.1 
GDC-0449 ...................................................................................................................... 65 
8.2 
nab-Paclitaxel ................................................................................................................. 66 
8.3 
 Gemcitabine .................................................................................................................. 69 
8.3 
 Study Medication Accountability and Destruction ....................................................... 71 
(GDC-0449 and nab-Paclitaxel) ............................................................................................... 71 
9. 
CORRELATIVE/SPECIAL STUDIES ................................................................................ 71 
10. 
STUDY CALENDAR ....................................................................................................... 78 
11. 
MEASUREMENT OF EFFECT........................................................................................ 79 


Protocol Amendment 12, date December 4, 2014 
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12. 
STATISTICAL CONSIDERATIONS............................................................................... 87 
REFERENCES ............................................................................................................................. 92 
APPENDICES .............................................................................................................................. 94 
APPENDIX A ........................................................................................................................... 94 
APPENDIX B ........................................................................................................................... 95 
APPENDIX C ............................................................................................................................. 1 
APPENDIX D ............................................................................................................................. 2 
APPENDIX E ............................................................................................................................. 3 
APPENDIX F.............................................................................................................................. 7 
APPENDIX G: PROTOCOL SIGNATURE PAGE .................................................................. 8 
APPENDIX H: MEDICAL MONITOR SIGNATURE PAGE .................................................. 9 
APPENDIX I: AMENDMENTS SUMMARIES ..................................................................... 10 
       Amendment # 1, June 8, 2010 ............................................................................................... 10 
       Amendment 2, June 11, 2010 ................................................................................................ 10 
       Amendment 3, July 6, 2010 ................................................................................................... 10 
       Amendment 4, August 16, 2010 ............................................................................................ 11 
       Amendment 5, February 1, 2011 ........................................................................................... 13 
       Amendment 6, August 3, 2011 .............................................................................................. 13 
       Amendment 7, January 11, 2012……………………………………………………………15 
       Amendment 8, February 7, 2012…………………………………………………………....15 
       Amendment 9, February 22, 2013…………………………………………………………..16 
       Amendment 10, April 16, 2013……………………………………………………………..16 
       Amendment 11, August 16, 2013…………………………………………………………...16 
       Amendment 12, December 4, 2014…………………………………………………………16 
 
APPENDIX J: Genentech SAE Fax Cover Sheet…………………………………………..17&18 
       
APPENDIX K: TASTE AND SMELL QUESTIONNAIRES…………...………………….19-26 
 
 
 
 
 
 
 
 
 
 
 


Protocol Amendment 12, date December 4, 2014 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
ADR   
Adverse Drug Reaction 
AE          
Adverse Event 
ALDH 
Aldehyde dehydrogenase 
ALT (SGPT)        
Alanine Aminotransferase (SGPT) 
ANC   
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT)       
Aspartate Aminotransferase (SGOT) 
β-hCG                 
                    
Beta subunit of human chorionic gonadotropin 
(hCG) 
BSA 
Body Surface Area 
BUN      
Blood Urea Nitrogen 
CA19-9               
Carbohydrate Antigen 19-9 
CBC 
Complete Blood Count 
CI   
Confidence Interval 
CrEL 
Cremophor-EL 
CRAB 
Cancer Research and Biostatistics 
CR     
Complete Response 
CRO 
Clinical Research Organization 
CSC 
Cancer Stem Cells 
CT    
Computed Tomography 
CTC 
Circulating Tumor Cells 
CTCAE             
                
Common Terminology Criteria for Adverse 
Events 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
FDA   
Food and Drug Administration 
G-CSF              
Granulocyte Colony-Stimulating Factor 
Hh 
Hedgehog 
Hgb   
Hemoglobin 
IB   
Investigator Brochure 
ICF                   
Informed Consent Form 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
MRI                   
Magnetic Resonance Imaging 


Protocol Amendment 12, date December 4, 2014 
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MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NCI CTCAE 
National 
Cancer 
Institute 
Common 
Terminology Criteria of Adverse Effects 
PD 
Progressive Disease 
PE   
Paraffin Embedded 
PFS   
Progression-free Survival 
PK     
Pharmacokinetics 
PR 
Partial Response 
PT 
Prothrombin Time 
PTCH 
Patched 
PTT 
Partial Thromboplastin Time 
RECIST              
Response Evaluation Criteria in Solid Tumors 
SAE   
Serious Adverse Event 
SD     
Stable Disease 
S.D.                  
Standard Deviation 
SGOT   
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SKCCC 
Sidney Kimmel Comprehensive Cancer Center 
SMO 
Smoothened 
SPARC             
                 
Secreted Protein Acidic and Rich in Cysteine (a 
glycoprotein) 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell 
 
 
 
 


Protocol Amendment 12, date December 4, 2014 
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1. 
OBJECTIVES 
 
1.1. 
Primary Objectives 
 
 To evaluate whether the addition of a Vismodegib (GDC-0449; Hedgehog Pathway 
Inhibitor)to cytotoxic chemotherapy (Gemcitabine and nab-paclitaxel) in patients with  
metastatic adenocarcinoma of the pancreas increases progression free survival (PFS).   
 
1.2. 
Secondary Objectives 
 
 To evaluate overall survival 
 To evaluate for tumor response (complete response, partial response), stable disease and 
progressive disease  
 To evaluate the safety of the combination gemcitabine + nab-paclitaxel with GDC-0449 in 
patients with metastatic adenocarcinoma of the pancreas 
 To evaluate the presence of pancreatic cancer stem cells in tissue and peripheral blood and its 
changes with therapy with above combination 
 To evaluate changes of hedgehog signaling pathway with therapy with GDC-0449 
 To evaluate if serum and/ or tumor biomarkers predict clinical benefit with GDC-0449 
 
 
2. 
BACKGROUND 
 
2.1  
Study Disease 
 
Pancreatic cancer continues to be one of the most dismal malignancies in the gastrointestinal tract 
and remains the fourth leading cause of cancer related mortality. In the United States an estimated 
total of 42,470 pancreatic cancers are expected in the year 2009 with 35, 240 estimated deaths 
among these patients[1].  The majority of patients with pancreatic adenocarcinoma have evidence of 
metastatic disease at presentation with a median survival of 6 months [2].  More recent strategies 
have focused on improving the efficacy of Gemcitabine by either improving the method of delivery 
or by combining Gemcitabine with other non-cross resistant agents. However, the clinical benefits, 
response rates, and the duration of responses have been modest.  
 
The most recent advance for the management of this disease was achieved with the combination of 
gemcitabine and nab-paclitaxel. The phase I/ II study with this combination was presented at the 
American Society of Clinical Oncology (ASCO) 2009 annual meeting and demonstrated promising 
results with improvement of response rate and overall survival [3].  Given these findings a phase III 
trial with that particular combination is under way. Novel therapeutic approaches and a better 
understanding of disease’s biology for tumor driven disease progression are needed. 
 
 
 


Protocol Amendment 12, date December 4, 2014 
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Hedgehog Signaling pathway in pancreatic cancer  
 
The Hedgehog (Hh) signaling pathway regulates epithelial and mesenchymal interactions in a 
variety of tissues during mammalian embryogenesis[4]. The Hh ligand in the extracellular space 
binds to Patched (PTCH), a 12 pass transmembrane receptor on the surface of cells. Hh binding 
relieves the inhibitory effect of PTCH on Smoothened (SMO), a 7 pass transmembrane domain 
protein and a member of the G-protein coupled receptor superfamily. Signal transduction by SMO 
then leads to the activation and nuclear localization of GLI1 transcription factors and induction of 
Hh target genes, many of which are involved in proliferation, survival and angiogenesis in different 
malignancies. 
 
Investigations suggest that the Hh signaling pathway is persistently activated in several malignancies 
including pancreatic adenocarcinoma [5], [6].  Berman and colleagues demonstrated that upper 
gastrointestinal malignancies derived from the esophagus, biliary tract, stomach, and pancreas 
display increased Hh pathway activity. Cell growth was mediated by endogenous expression of Hh 
ligands through demonstration of the growth inhibitory activity of Hh-neutralizing antibody and the 
growth stimulatory activity of exogenously added Hh ligand [6]. Hh pathway activation is mediated 
either through aberrant ligand overexpression by pancreatic cancer cells [5], aberrant activation of 
Hh signaling pathway in the surrounding stromal compartment through a paracrine model [7-9] or  
alternative proposed mechanism through silencing of the pathway inhibitor human Hh interacting 
protein by  promoter hypermethylation [10]. The Hh signaling promotes epithelial-mesenchymal 
transition and increases motility and invasiveness of pancreatic cancer cells. Several genes have been 
identified as potential hedgehog downstream targets in the setting of pancreatic cancer including 
BIRC3, TGM2, PLAU, and BMP2 and these genes have been previously found to be 
mechanistically involved in tumor cell proliferation, invasion/migration, and metastatic tumor spread 
[11].  
 
Relation with pancreatic cancer stem cells 
 
More recent interest has emerged with the identification of cancer stem cells (CSC) and it is believed 
that these cells can elicit tumor progression and metastases. In pancreatic cancer two different subset 
of CSC have been identified. First Li et al identified CD24+/CD44+/ESA+ cells [12]. These cells 
composed 0.2-0.8% of all pancreatic cancer cells, were highly tumorigenic and possessed the ability 
of self-renew and produce a differentiated progeny. More recently, Hermann and colleagues 
identified a subset of CD133+ cells and found that this marker also discriminates for cells in 
pancreatic cancer and pancreatic cell lines with enhanced proliferative capacity [13].  
 
The clinical significance of pancreatic CSC is related to resistance to available therapeutic 
approaches. In other malignancies including chronic myeloid leukemia, brain tumors, and colon 
cancer, stem cells have been found to be resistant to conventional chemotherapy and radiation. In 
pancreatic cancer some evidence suggests resistance of pancreatic CSC to chemotherapy and 
radiation in cell lines. Hermann and colleagues found that CD133+ populations in the L3.6 
pancreatic cancer cell line were enriched after exposure to gemcitabine. Treatment with ionizing 
radiation and the chemotherapeutic agent gemcitabine resulted in enrichment of the 
CD44+CD24+ESA+ population in human pancreatic cancer xenografts. These findings indicate that 
novel therapies that target CSC may be crucial for successful anti-cancer therapy. One approach to 


Protocol Amendment 12, date December 4, 2014 
14
do so is by identifying signaling pathways that may sustain such stem cells and developing targeted 
therapies against it. 
 
The hedgehog signaling pathway plays a role in maintaining subpopulations of cancer cells with 
increased tumorogenic potential [12, 14].  Several points suggest an element of hedgehog 
dependence in a subset of pancreatic cancer cells with tumor-initiating properties. First Sonic 
Hedgehog ligand (SHH) might be specifically overexpressed in a subpopulation of 
CD24+/CD44+/ESA+ pancreatic cancer cells with increased tumorigenic potential and other stem 
cell-like properties [12]. Second, overexpression of Gli1, the major activating hedgehog transcription 
factor, is observed at the mRNA level in a subset of SSC-low /aldehyde dehydrogenase (ALDH)-
“bright” cells with increased clonogenic potential [12]. 
 
Pharmacologic blockade of Hh in pancreatic cancer 
 
Several small molecules with capacity of Hh pathway inhibition have been studied in  
the preclinical setting.  
 
Studies with Cyclopamine: Cyclopamine is a steroidal alkaloid that inhibits Hh signaling through 
direct interaction with SMOH. In vitro Hh blockade with cyclopamine in pancreatic cancer cell lines 
led to tumor growth inhibition [11]. In vivo, cyclopamine retarded the growth of s.c. pancreatic 
cancer xenografts [5, 6], prolonged the median survival of transgenic mouse models, [11], and 
prevented metastatic tumor spread using murine orthotopic xenograft models of human pancreatic 
cancer [14].  Cyclopamine caused downregulation of the Hh target genes Gli1 and Ptch in 
genetically engineered mouse models of pancreatic cancer [11]. 
 
Studies with IPI-269609: Feldman and colleagues tested IPI-269609, another inhibitor of the Hh 
pathway, using in vitro and in vivo model systems. Single agent IPI inhibited systemic metastases in 
orthotopic xenografts established from human pancreatic cell lines. Hh blockade had minimal effect 
on primary tumor volume, but the phenotype observed within the treated primary tumor showed a 
reduction in the population of aldehyde dehydrogenase-bright cells (which has been previously 
identified as clonogenic tumor-initiating population in pancreatic cancer). Selective ex-vivo 
depletion of aldehyde dehydrogenase-bright cells with IPI-269609 was accompanied by significant 
reduction in tumor engraftment rates in athymic mice. Their data suggested that pharmacologic 
blockade of aberrant Hh signaling might be an effective strategy for inhibition of systemic 
metastases in pancreatic cancer by targeting subsets of cancer cells with tumor-initiating, or CSC 
properties[15].  
 
Studies with GDC-0449: GDC-0449 is a small-molecule antagonist of the Hh signaling pathway 
that binds to and inhibits SMO, blocking Hh signal transduction. In vitro and in vivo preclinical 
studies have demonstrated inhibition of Hh signaling following GDC-0449 administration.  GDC-
0449 has demonstrated anti-tumor activity against a variety of primary human tumor xenografts and 
tumor cell line xenograft models (Investigator Brochure). These include CRC, in which activity was 
seen both as a single agent and in combination with cytotoxic agents, as well as in primary xenograft 
models of pancreatic carcinoma. In murine models, the anti-tumor effect of GDC-0449 correlates 
with blockade of the Hh pathway measured by reduction in the expression of stromal Gli1 mRNA, 
which is itself a transcriptional target of Hh signaling. Specifically, sustained reduction of Gli1 


Protocol Amendment 12, date December 4, 2014 
15
expression is associated with inhibition of tumor growth. Nonclinical efficacy studies suggest that 
sustained inhibition of Hh signaling is necessary to achieve an anti-tumor effect. For this reason, 
regimens of continuous dosing over 28 days are being examined. In a phase I studies, in patients 
with advance solid tumors, GDC-0449 was well tolerated with no dose limiting-toxicities.  The 
recommended Phase II dose is 150 mg by oral administration on a continuous daily schedule[16] 
[17]. Phase II studies using GDC-0449 150 mg orally once daily on a continuous schedule are 
ongoing in first-line metastatic CRC, recurrent ovarian cancer, and advanced BCC. 
 
Pharmacologic blockade of Cancer Stem Cells: Jimeno et al used a direct pancreatic cancer 
xenograft model as a platform for CSC therapeutic development. Tumors from a gemcitabine-
sensitive xenograft were treated with gemcitabine induction first, and randomized, after tumor 
regression to continuing treatment with gemcitabine, a Hh inhibitor alone (cyclopamine) or in 
combination with gemcitabine. They tested markers described in association with CSC such as 
CD24, CD44, ALDH, nestin and the hedgehog pathway. After induction with gemcitabine, treated 
tumor showed enrichment in CSC markers such as ALDH and CD24. Subsequently, combined 
treatment with gemcitabine and Hh inhibitor (cyclopamine) induced further tumor regression, 
decreased CSC markers and Hh signaling. Hh inhibitors as part of a dual compartment therapeutic 
approach were able to further reduce tumor growth and decreased both static and dynamic markers 
of CSC[18]. 
 
Other proposed mechanisms for Hh inhibitors in pancreatic cancer 
 
In addition to the CSC theory, other mechanisms for potential clinical benefit using Hh inhibitors in 
the setting of pancreatic cancer have been described. The Hh signaling pathway is active in a 
paracrine model in which the tumor cells secrete Hh ligand to induce tumor-promoting Hh target 
genes in adjacent stroma [7-9]. Olive and colleagues found that IPI-926, a small molecule inhibitor 
of SMO, can be a strategy to enhance drug delivery and overcome the well-known chemoresistance 
of pancreatic cancer if combined with gemcitabine in genetically engineered models of pancreatic 
cancer. IPI-926 targets the Hh pathway in the stroma of malignant tumors reducing the fibrotic 
reaction that occurs with pancreatic cancer. IPI-926 was able to increase the intratumoral vascular 
density and increase intratumoral concentration of gemcitabine [19].  
 
2.2    Rationale for this study 
 
The emergence of new small molecules with capacity of blocking the Hh signaling pathway provides 
a novel therapeutic approach in pancreatic adenocarcinoma treating the primary tumor, stroma, 
systemic metastases and CSC by Hh pathway inhibition. These preclinical findings and the lack of 
significant effective therapies in patients with metastatic pancreatic cancer resulted in our interest to 
do this clinical trial.  We propose an open label phase 2 clinical trial evaluating the progression free 
survival (PFS) in patients with previously untreated metastatic pancreatic adenocarcinoma. Given 
the promising survival advantage on recent clinical trial with the combination of gemcitabine and 
nab-paclitaxel both agents will be included in this study and will be considered our historical 
control[20]. The combination of gemcitabine with our without nab-Paclitaxel is currently been 
evaluated in a multi-institutional phase III clinical trial.  
 
We hypothesize that the combination of cytotoxic agents (gemcitabine and nab-paclitaxel) with the 


Protocol Amendment 12, date December 4, 2014 
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Hh inhibitor GDC-0449 may increase PFS in patients with previously untreated metastatic 
adenocarcinoma of the pancreas. We will include correlative studies to attempt to understand the 
stem cell biology and mechanism for any observed clinical benefits with the use of Hh inhibitor 
GDC-0449. We will evaluate the changes in Hh pathway downregulation and changes in pancreatic 
CSC markers with pre and post treatment biopsies. Finally this study will also evaluate the incidence 
of detectable Hh expression in pancreatic adenocarcinoma to assess whether Hh expression might be 
used as a predictive factor for GDC-0449 clinical benefit, which may be necessary for appropriate 
patient selection in future trials. Given the lack of prior experience with the combination of the three 
drugs, the he safety of GDC-0449 when combined with chemotherapy gemcitabine and nab-
paclitaxel will also be monitored continuously during the study by evaluating adverse event rate.  
 
 
2.3    Correlative Studies 
 
We will evaluate the changes in the pre- and post-treatment Hh signaling pathway down regulation 
and the presence of pancreatic CSC. The biopsies will be obtained by core biopsy or fine needle 
aspiration (FNA) both pre and post treatment. The findings will be correlated with clinical response 
to GDC-0449. 
 
1. To identify presence of pancreatic cancer stem cells in biopsy samples 
 By functional assay with Aldehyde dehydrogenase (ALDH) bright cells  
by immunohistochemistry if core biopsy is obtained or RT-PCR for ALDH if fine needle 
aspiration is obtained. 
 By phenotypic assays CD24+/ CD44+/ESA+ and CD133+ by immunohistochemistry if core 
biopsy is obtained or by quantitative RT-PCR if FNA is obtained.     
 
2. To evaluate for hedgehog signaling pathway downregulation 
 
 Evaluate for the Hh target genes Gli1 and Ptch at the mRNA level in primary tumor 
 
3. Circulating pancreatic cancer stem cells in peripheral blood by flow cytometry 
 
 
 
 
 
 
 
2.4  
Study Drugs 
 
2.4.1 
GDC-0449 
 
GDC-0449 is a small-molecule inhibitor of the Hh signal pathway with a molecular 
weight of 421.30 g/mol. The International Union of Pure and Applied Chemistry name 
for 
GDC-0449 
is 
2-chloro-N-(4-chloro-3-pyridin-2-yl-phenyl)-4-methanesulfonyl-
benzamide. Its structure is shown in Figure 1. GDC-0449 binds to and inhibits SMO that 


Protocol Amendment 12, date December 4, 2014 
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results in blocking of the Hh signal. GDC-0449 has proven to be efficacious in 
nonclinical tumor models of both mutated and ligand-overexpressing tumors. 
 
Figure 1: Clinical Structure of GDC-0449 
 
 
GDC-0449 is a small-molecule antagonist of the Hh signal pathway. Specifically GDC-
0449 has demonstrated anti-tumor activity against a variety of primary human tumor 
xenografts and tumor cell line xenograft models (Investigator Brochure). These include 
CRC, in which activity was seen both as a single agent and in combination with cytotoxic 
agents, as well as in primary xenograft models of pancreatic carcinoma (Investigator 
Brochure). In murine models, the anti-tumor effect of GDC-0449 correlates with 
blockade of the Hh pathway measured by reduction in the expression of stromal Gli1 
mRNA, which is itself a transcriptional target of Hh signaling. Specifically, sustained 
reduction of Gli1 expression is associated with inhibition of tumor growth. 
 
 
Preclinical studies with GDC-0449: A range of preclinical studies in the appropriate 
species have been completed with GDC-0449 including single and repeat-dose toxicity 
studies and toxicity studies.  A thorough discussion of these is included in the 
Investigator’s Brochure (IB). Preclinical studies had combined GDC-0449 with 
gemcitabine in a pancreatic model without any evidence of antagonism or unexpected 
toxicity. 
 
 
Clinical Experience 
 
GDC-0449 was studied in Phase I and is currently undergoing Phase II studies 
(Investigator Brochure, Edition 3).  
 
Phase 1 study with GDC-0449 


Protocol Amendment 12, date December 4, 2014 
18
 
In the Phase I study (SHH3925g), GDC-0449 was given orally on a continuous daily 
schedule to patients with advanced solid malignancies that were refractory to standard 
therapy or for whom no standard therapy exists. Enrollment in this study occurred in two 
stages. Stage 1 was the dose-escalation portion of the study, with a “3+3” design and 
modified dose-doubling. The objectives for Stage 1 were to assess safety, tolerability, and 
pharmacokinetics/pharmacodynamics of GDC-0449 and to determine the MTD. In Stage 
1, GDC-0449 is administered orally as a single dose on Day 1, followed by a 7-day PK 
observation period, and then continues on Day 8 as a once-daily regimen on a continuous 
28-day schedule (Cycle 1 = 35 days). Patients who withdraw without DLT in the first 
cycle are replaced. Stage 2 had three cohorts to collect additional safety data, preliminary 
efficacy in advanced BCC, and safety/PK data with the new Phase II drug product (150 
mg). Patients treated in Stage 2 received GDC-0449 orally once daily on a continuous, 
uninterrupted 28-day schedule.  
 
The phase 1 study SHH3925g enrolled a total of 68 patients by December 2008 and has 
been completed to date. The recommended Phase II dose is 150 mg GDC-0449 given 
orally on a continuous daily schedule. Dose-limiting toxicities (DLTs) were not seen with 
GDC-0449; however, reversible Grade 3 fatigue and asymptomatic hyponatremia have 
been reported beyond the DLT window. 
 
Study SHH4318g was conducted with a single refractory medulloblastoma pediatric 
patient and has also been completed. Study SHH4433g was a healthy volunteer 
pharmacokinetic (PK) study to further characterize and understand the unique plasma PK 
profile observed during the Phase I dose-escalation trial, in which GDC-0449 displayed 
an unusual pharmacokinetic profile with high sustained micromolar plasma 
concentrations and a long terminal half-life. 
 
Potential Risks 
 
GDC-0449 has been given to 68 patients in the Phase I study SHH3925g. The following 
side effects were observed in a small number of patients and may be related to GDC-
0449: changes in or lack of taste sensation for food; loss of appetite; heartburn and 
stomach upset; nausea; vomiting; weight loss; decrease in sodium and magnesium levels 
in the blood; severe fatigue; loss of hair on the scalp, body, eyelashes, and face; joint 
pain; acne-like skin rash; skin peeling; numbness; and muscle spasms (cramps). There 
may be risks that have not yet been identified and that were not predicted by nonclinical 
testing.  
 
In this Phase I clinical study, Grade 3 adverse events attributable to study drug have been 
reversible and minimal in number. No Grade 4 or 5 events related to study drug have 
been reported. The safety profile of GDC-0449 supports single-agent studies of this drug 
in the Phase II setting.  
 
Notable findings in the nonclinical toxicity studies included tremors, alopecia, follicular 
cysts and pilomatricoma, effects on male and female reproductive parameters, and 


Protocol Amendment 12, date December 4, 2014 
19
alterations of epiphyses and incisors in rats, as well as decreased platelet count and red 
cell mass, increased serum cholesterol, alopecia, localized skin inflammation, and paw 
swelling in dogs. Because of the relatively slow clearance of GDC-0449 in humans, the 
exposures achieved at the highest doses that were tolerated in the repeat-dose toxicity 
studies were comparable to those that are typically observed in patients. However, with 
the exception of pharmacologically mediated alopecia, the toxicities evident in the 
nonclinical studies were not clearly correlated with drug-related adverse events in the 
Phase I clinical trial. 
 
In general, the results of the nonclinical toxicity studies conducted with GDC-0449 
demonstrate a favorable safety profile to support the proposed clinical trials. The finding 
of pilomatricoma (a benign, cutaneous neoplasm that is readily excisable in humans) at a 
low incidence at the high dose level in the chronic rat toxicity study is not considered to 
substantially impact the risk/benefit profile for clinical trials in patients with late-stage or 
advanced cancers. 
 
As of 14 July 2009, there has been one IND safety report from this study.  This Grade 3 
atrial fibrillation AE was assessed as serious, unexpected, and related to study drug. 
 
As of January 2011 the following list of IND safety reports have been submitted as 
related to GDC-0449: atrial fibrillation, convulsion, dyspnea, lung infiltration, pulmonary 
embolism, diarrhea, renal failure, dehydration, abdominal pain, paranoia, gastroenteritis, 
cholestasis, elevated hepatic enzymes, pneumonia, cholestasis, cardiac failure, syncope. 
One episode of sudden death assessed due to myocardial infart was reported as non-
related by investigator and assessed as related by Genentech. 
 
The toxicities possibly related to GDC-0449 reported in previous phase 1 clinical trial 
included:  
 
• Constitutional: Fatigue, weight loss 
 
• Cardiovascular: atrial fibrillation 
 
• Gastrointestinal: anorexia, dyspepsia (heartburn or stomach upset), nausea, vomiting 
 
• Metabolic: hyponatremia, hypomagnesemia 
 
• Neurologic: hypoesthesia (sensory neuropathy), dysgeusia (taste alteration), numbness 
 
• Musculoskeletal: arthralgia, muscle spasms 
 
• Skin and subcutaneous tissue disorders: skin exfoliation, alopecia (scalp, body, 
eyelashes and face), dermatitis acneiform 
 
Reproductive and developmental Toxicity 
 


Protocol Amendment 12, date December 4, 2014 
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Studies to assess the reproductive and developmental toxicity of GDC-0449 have not 
been conducted to date. However, based on the central role of the Hh signaling  pathway 
in embryogenesis and published studies with other small-molecule Hh pathway 
inhibitors, GDC-0449 is expected to be teratogenic to humans, and pregnant women 
should avoid exposure to the compound. The teratogenic potential of Hh pathway 
inhibitors has been well established with observational and experimental studies in 
animals. A description of all these observational studies is included in the investigator 
brochure. 
 
Women who are pregnant, plan to become pregnant, or are lactating (during the study or 
for up to 7 months after the last dose) are excluded from all clinical studies with GDC-
0449. Pregnancy prevention measures will be undertaken in this study. 
 
Proposed dose for GDC-0449 
 
Based on the PK parameters and the lack of AEs observed, the proposed starting dose for 
oral administration of GDC-0449 to cancer patients is 150 mg/day (92.5 mg/m2/day) 
 
Other ongoing phase II studies with GDC-0449 
 
Study SHH4429g is an ongoing randomized, placebo-controlled, double-blind Phase II 
trial of GDC-0449 added to biochemotherapy standard of care regimens (FOLFOX or 
FOLFIRI chemotherapy with bevacizumab) for first-line metastatic colorectal cancer 
(CRC). The primary goal of this study is to determine if adding GDC-0449 to the 
standard of care therapy increases antitumor efficacy as measured by PFS when 
compared with the standard of care therapy alone.  
 
2.4.2 
nab-paclitaxel  
 
Nab- paclitaxel is a Cremophor EL-free, albumin-bound paclitaxel particle with a mean 
size of approximately 130 nm.  Each 50 mL vial contains 100 mg of paclitaxel, and 
approximately 900 mg of human albumin, as a white to yellow sterile lyophilized powder 
for reconstitution with 20 mL of 0.9% Sodium Chloride Injection.  
 
Nab- paclitaxel is a unique protein formulation of a non-crystalline, amorphous form of 
paclitaxel in an insoluble particle state.  It has been developed to reduce the toxicities 
associated with Taxol (paclitaxel) Injection (in which paclitaxel - from the native 
crystalline form - is in solution with Cremophor EL/ethanol as the solvent) while 
maintaining or improving its chemotherapeutic effect.  Nab- paclitaxel has been approved 
in the US, Canada, India, the EU, Korea and China (and is under review in a number of 
other countries) for the treatment of women with metastatic breast cancer (MBC).  Nab- 
paclitaxel alone and in combination is being evaluated in a number of cancers including: 
metastatic melanoma, pancreatic cancer, cervical cancer and other solid tumors. 
Conditions which are responsive to paclitaxel such as non-hematological solid tumor 
malignancies are good clinical candidates for treatment with nab- paclitaxel.  
 


Protocol Amendment 12, date December 4, 2014 
21
Preclinical studies with nab- paclitaxel: A range of preclinical studies in the 
appropriate species have been completed with nab- paclitaxel including single and repeat-
dose toxicity studies, carcinogenicity evaluations, reproductive toxicity assessments, and 
mutagenicity and toxicity studies.  A thorough discussion of these is included in the 
Investigator’s Brochure (IB). 
 
Preclinical studies comparing nab-paclitaxel to Taxol demonstrated lower toxicities, with 
a MTD approximately 50% higher for nab-paclitaxel compared to Taxol. At equitotoxic 
doses of paclitaxel, nab-paclitaxel was found to be markedly more efficacious in animal 
models than Taxol. 
 
In an on-going study of nab- paclitaxel in combination with gemcitabine administered 
weekly (Abraxis Protocol CA040; updated results as of October 2008), a total of 41 
patients with advanced metastatic pancreatic cancer were treated with doses ranging from 
100 to 150 mg/m
2
. Though results are preliminary and follow-up is on-going, 27 patients 
(66%) experienced at least 1 treatment-related AE and 11 (27%) patients experienced at 
least one treatment-emergent SAE.  With the exception of the “Gastrointestinal: 
Dehydration”, “not classified” and “pain: other” categories (2 (5%) events each), no 
treatment-emergent SAE categories had more than a single event. 
 
Dose delays were mainly due to blood/bone marrow treatment-related AEs (mostly 
neutrophils). There were no nab- paclitaxel dose interruptions due to treatment-related 
AEs, and 2 instances of dose interruptions for gemcitabine (dermatology/skin: injection 
site reaction).  Also, 2 patients had a total of 3 treatment-related AEs involving 
blood/bone marrow (neutrophils and platelets) resulting in dose reductions and 2 
treatment-related AE resulted in dose discontinuation (gastrointestinal: diarrhea and 
infection: systemic).  There were 3 treatment-emergent AEs resulting in death (lung 
infection, systemic infection, and gastrointestinal obstruction), but only systemic 
infection was considered treatment-related.  Patients treated with nab- paclitaxel in 
combination with gemcitabine had levels of myelosuppression consistent with those 
expected following treatment with taxanes.    
 
Potential Risks for nab- paclitaxel based on previous clinical studies 
 
Nab- paclitaxel is not formulated in Cremophor and thus the risk of hypersensitivity 
reactions is much less than that of Taxol. The major risks of nab- paclitaxel have been 
assessed in clinical trials in patients with a variety of malignances and reflect the known 
toxicities of paclitaxel.  See the IB for a complete description of all toxicities reported in 
conjunction with nab- paclitaxel administration. 
 
The most common toxicities reported in previous clinical trials included:  
 
•  
Myelosuppression, predominantly neutropenia. Grade 4 neutropenia was reported 
and typically resolved in < 7 days and did not require colony stimulating factor support.  
 
•  
Peripheral neuropathy, predominantly sensory. Grade 3 peripheral neuropathy 


Protocol Amendment 12, date December 4, 2014 
22
was reported and typically improved to Grade 1 or 2 within 21 days of interrupting the 
nab-paclitaxel dose. Following resolution of the peripheral neuropathy to acceptable 
levels, clinicians were able to restart nab-paclitaxel dosing at a lower dose levels.  
 
•  
Nausea and vomiting. Nausea and vomiting were seen, typically at Grade 1 or 2 
levels. This AE responded well to standard anti-emetic regimens.  
 
•  
Myalgias and arthralgias. Myalgias and arthralgias were reported and typically 
were Grade 1 or 2; these were responsive to standard acetaminophen-containing 
medication. 
 
•  
Mucositis. Mucositis was reported typically Grade 1 or 2. It was not dose limiting 
 
•  
Alopecia. Alopecia was reported by most patients and was similar to that seen 
with Taxol. 
 
2.4.3 Gemcitabine:  
 
Gemcitabine is approved for the treatment of metastatic pancreatic cancer. For more 
information please refer to package insert. The most common toxicities reported with 
gemcitabine are: 
 
• 
Hematological- In studies in pancreatic cancer, myelosuppression is the dose-
limiting toxicity with Gemzar®, but <1% of patients discontinued therapy for anemia, 
leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of 
patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss 
(hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients 
required platelet transfusions. Patients should be monitored for myelosuppression during 
Gemzar therapy and dosage modified or suspended according to the degree of 
hematologic toxicity. 
   
• 
Gastrointestinal - Nausea and vomiting were commonly reported (69%) but were 
usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) 
occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis 
by 11% of patients.   
 
 
• 
Hepatic - In clinical trials, Gemzar was associated with transient elevations of one 
or both serum transaminases in approximately 70% of patients, but there was no evidence 
of increasing hepatic toxicity with either longer duration of exposure to Gemzar or with 
greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, 
has been reported very rarely in patients receiving Gemzar.   
• 
Renal - In clinical trials, mild proteinuria and hematuria were commonly reported. 
Hemolytic Uremic Syndrome (HUS) has been reported rarely (0.25%) with the use of 
Gemzar. Renal failure may not be reversible even with discontinuation of therapy and 
dialysis may be required.  
 


Protocol Amendment 12, date December 4, 2014 
23
• 
Fever - The overall incidence of fever was 41%. This is in contrast to the 
incidence of infection (16%) and indicates that Gemzar may cause fever in the absence of 
clinical infection. Fever was frequently associated with other flu-like symptoms and was 
usually mild and clinically manageable.   
 
 
• 
Rash - Rash was reported in 30% of patients. The rash was typically a macular or 
finely granular maculopapular pruritic eruption of mild to moderate severity involving 
the trunk and extremities. Pruritus was reported for 13% of patients.   
 
• 
Pulmonary- In clinical trials, dyspnea, unrelated to underlying disease, has been 
reported in association with Gemzar therapy. Dyspnea was occasionally accompanied by 
bronchospasm. Pulmonary toxicity has been reported with the use of Gemzar. The 
etiology of these effects is unknown. If such effects develop, Gemzar should be 
discontinued. Early use of supportive care measures may help ameliorate these 
conditions. 
 
• 
Edema: Edema (13%), peripheral edema (20%) %), and generalized edema (<1%) 
were reported. Less than 1% of patients discontinued due to edema. 
 
 
• 
Neurotoxicity - There was a 10% incidence of mild paresthesias and a <1% rate of 
severe paresthesias 
 
• 
Flu-like Symptoms - “Flu syndrome” was reported for 19% of patients. Individual 
symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly 
reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, 
rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients 
discontinued due to flu-like symptoms.   
 
• 
Infection - Infections were reported for 16% of patients. Sepsis was rarely reported.   
• 
Alopecia- Hair loss, usually minimal, was reported by 15% of patients 
 
 
Please see gemcitabine prescribing information for more details on the known 
precautions, warnings, and adverse reactions of gemcitabine (current version of 
Prescribing Information is provided in the Study Manual).  
 
 
3. 
PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 Patients must have histologically or cytologically confirmed metastatic 
adenocarcinoma of the pancreas. Patients with islet cells tumors are excluded. Biopsy 
is required within 14 days before starting treatment. 
 


Protocol Amendment 12, date December 4, 2014 
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3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm with conventional techniques or as >10 mm with spiral CT scan.  See 
Section 11 for the evaluation of measurable disease. 
 
3.1.3 Patient must have received no previous radiotherapy, surgery or chemotherapy or 
investigational drug therapy for the treatment of metastatic disease. Radiotherapy, 
chemotherapy or investigational therapy in the adjuvant setting should be completed 
3 weeks prior to enrollment. Prior therapy with 5FU, gemcitabine or other agents in 
the adjuvant setting is allowed. If a patient received gemcitabine in the adjuvant 
setting, tumor recurrence must have occurred at least six months after completing the 
last dose of gemcitabine 
 
3.1.4 Age >18 years.  Because no dosing or adverse event data are currently available on 
the use of   GDC-0449 in combination with nab-paclitaxel and gemcitabine in 
patients <18 years of age, children are excluded from this study but will be eligible 
for future pediatric phase 2 combination trials. 
 
3.1.5 Life expectancy of greater than 1 month. 
 
3.1.6 ECOG performance status <1 (Karnofsky >70%; see Appendix A). 
 
3.1.7 Patients must have adequate organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/mcL 
- 
absolute neutrophil count  
>1,500/mcL 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
total bilirubin  
 
 
 
< 1.5 ULN 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal, unless 
liver metastases are clearly present, then < 5X ULN 
is allowed 
- 
creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
creatinine clearance  
 
Creatinine clearance >50 mL/min/1.73 m2 for 
patients. Serum creatinine < 2 mg/mL 
 
3.1.8   Patients should be asymptomatic for jaundice and ascites prior to Day 1. Pain                     
           symptoms should be stable. 
 
 
3.1.9 The effects of GDC-0449 on the developing human fetus at the recommended 
therapeutic dose are unknown.  For this reason and because Hh signal pathway 
inhibitors are known to be teratogenic, women of child-bearing potential and men 
must use two forms of contraception (i.e., barrier contraception and one other method 
of contraception) at least 4 weeks prior to study entry, for the duration of study 
participation, and for at least 7 months post-treatment. For appropriate methods of 


Protocol Amendment 12, date December 4, 2014 
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contraception considered acceptable see Appendix B.  Should a woman become 
pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
 
 
 
Pregnancy Testing.  Women of childbearing potential are required to have a negative 
serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days 
and within 24 hours prior to the first dose of GDC-0449 (serum or urine).  A 
pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual 
cycles are regular or every 2 weeks if their cycles are irregular while on study within 
the 24-hour period prior to the administration of GDC-0449.  A positive urine test 
must be confirmed by a serum pregnancy test.  Prior to dispensing GDC-0449, the 
investigator must confirm and document the patient’s use of two contraceptive 
methods, dates of negative pregnancy test, and confirm the patient’s understanding of 
the teratogenic potential of GDC-0449. 
 
Women of childbearing potential are defined as follows: 
• 
Patients with regular menses 
• 
Patients with amenorrhea, irregular cycles, or using a contraceptive method that 
precludes withdrawal bleeding 
• 
Women who have had a tubal ligation 
 
Women are considered not to be of childbearing potential for the following reasons: 
• 
The patient has undergone hysterectomy and/or bilateral oophorectomy. 
• 
The patient is post-menopausal defined by amenorrhea for at least 1 year in a 
woman > 45 years old. 
 
3.1.10 For sexually active males, use of barrier form of contraception, even if they have had 
a vasectomy, during the study and for 2 months after stopping GDC-0449 is required. 
Males should not donate sperm during treatment or up to three months after last dose. 
 
3.1.11 All patients should agree not to donate blood products for 7 months after stopping 
GDC-0449 
 
3.1.12 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2  
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy for metastatic disease 
 
3.2.2 Patients may not be receiving any other investigational agents. 
 
3.2.3   Patient has known brain metastases, unless previously treated and well              
           controlled for at least three months (defined as clinically stable, no edema, no                    
           steroids and stable in 2 scans at least 4 weeks apart) 
 


Protocol Amendment 12, date December 4, 2014 
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3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to GDC-0449 or other agents used in the study. 
 
3.2.5 Patients taking medications with narrow therapeutic indices that are metabolized by 
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible. 
 
3.2.6 GDC-0449 inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in 
vitro at concentrations that may be clinically relevant.  Therefore, caution should be 
exercised when dosing GDC-0449 concurrently with medications that are substrates 
of CYP2C8, CYP2C9, and CYP2C19 and have narrow therapeutic windows. 
 
In addition, GDC-0449 is a substrate of CYP3A4; however, the in vitro metabolic 
conversion of GDC-0449 is low.  Effects of CYP inducers (e.g., carbamezepine, 
phenobarbital, phenytoin, rifabutin, rifampin, St. John’s wort, and troglitazone) on 
clinical concentrations of GDC-0449 are unknown.  Likewise, the effects of strong 
inhibitors of CYP3A4 (e.g., clarithromycin, erythromycin, itroconazole, 
ketoconazole, nefazodone, and telithromycin) on GDC-0449 clinical concentrations 
are unknown, and caution should be exercised when dosing GDC-0449 concurrently 
with inhibitors of CYP3A4 (refer to Appendix C for a list of drugs that may 
potentially interact with CYP3A4).   
 
3.2.7 Uncontrolled illness including, but not limited to, ongoing or active infection 
requiring IV antibiotics, symptomatic congestive heart failure not controlled with 
medication, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
3.2.8 Pregnant and nursing women are excluded from this study because GDC-0449 is a 
Hh pathway inhibiting agent with the potential for teratogenic or abortifacient effects. 
Women planning to become pregnant during treatment and for 7 months after last 
dose of treatment are excluded from this study. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with GDC-0449, breastfeeding should be discontinued if the mother is treated 
with GDC-0449.  These potential risks may also apply to other agents used in this 
study.  
 
                  3.2.9   Patient has undergone a major surgery, other than diagnostic surgery (i.e.    
                             surgery done to obtain a biopsy for diagnosis without removal of an organ) 
                             within four weeks prior to Day 1 of treatment on this study. 
                     
                 3.2.10 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 render the patient at high risk 
                            from treatment complications 
 


Protocol Amendment 12, date December 4, 2014 
27
3.3  
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 General Guidelines 
 
 
All sites should call the Study Coordinator Yvette Cetasaan, CCRP at 410-955-4035 (or 
Rosalind Walker at 410-955-9628) to verify agent availability.  A signed informed consent 
document must be obtained prior to entry onto the study.   This study uses a web based data 
entry system for data submission through Cancer Research and Biostatistics (CRAB).  
Patient enrollment materials may be accessed online through the study website at:  
www.crab.org/SU2C.  
 
Eligibility criteria must be verified according to the eligibility checklist located in Appendix 
F and stored in the patient chart.  The Principal investigator of each site is responsible to 
verify that all the eligibility criteria are met. Following completion of the eligibility checklist, 
subjects must be registered on the CRAB study website to be considered on study.  Each 
patient will be automatically assigned a patient identification number following enrollment.   
 
Signed and completed informed consent forms should be faxed to Yvette Cetasaan at 443-
287-6566.  
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the 
study may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible. 
 
Agents may be ordered by a participating site only after the initial IRB approval for the site 
has been forwarded by the Coordinating Center. 
 
 
4.2 Data Submission Procedures 
 
Data will be completed and submitted electronically using the study web based system 
provided by CRAB.  Electronic case report forms (eCRFs) can be accessed on-line through 
the study website at:  www.crab.org/SU2C.  This website is used to register patients and 
submit data using eCRFs.  In addition, study resource information (SAE submission forms, 
protocol documents and other study guidelines) can be found on the website. 
 
 


Protocol Amendment 12, date December 4, 2014 
28
 
 
 
 
4.3 Coordinating Center Guidelines 
 
        Responsibility of the Protocol Chair  
        The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
        The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements are the responsibility 
of the Protocol Chair.  
        The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
        The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center (SKCCC)  
 
       The Coordinating Center will maintain documentation of AE reports.  The Coordinating 
Center will submit AE reports to the Protocol Chair for timely review. 
      The Coordinating Center is responsible for overseeing and approving the distribution of the 
investigational study medication, GDC-0449, to each participating site. 
Responsibilities of the CRO: Cancer Research And Biostatistics (CRAB): 
 
Each participating institution will have an appropriate assurance on file with the Office for Human 
Research Protection (OHRP), NIH.  CRAB is responsible for assuring that each participating 
institution has an OHRP assurance and must maintain copies of IRB approvals from each 
participating site. 
 
CRAB is responsible for providing an electronic data capture (EDC) system and maintaining the 
study web based system that is used for registration and data submission.  CRAB is responsible for 
assuring IRB approval has been obtained at each participating site prior to the first patient registration 
from that site.  During the registration process, CRAB will collect the date each patient signs the 
informed consent form and HIPAA authorization form. 
 
CRAB is responsible for the preparation of all submitted data for review by the Protocol Chair. 
 
CRAB is responsible for conducting on-site monitoring as described in Section 7.7 – Data and Safety 
Monitoring Plan. 
 
Due to budget constraints CRO QA will conduct on-site monitoring as described in Section 7.7 – 
Data and Safety Monitoring Plan however CRAB will continue to monitor the CRAB database. 
 
 


Protocol Amendment 12, date December 4, 2014 
29
 
 
 
 
 
5. 
TREATMENT PLAN 
 
Following the determination of eligibility patients will receive the following treatment:  
1.  One cycle of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15  (28 
days cycle) then 
2.  Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days cycle 
in combination with oral GDC-0449 150 mg daily 
 
Table 1. Drug Schedule 
 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
Gemcitabine + nab- paclitaxel 
Cycle 1 
Cycle 2 onward 
 
X 
X 
X 
 
X 
X 
X 
 
GDC-0449 
 
 
 
 
Daily Dose Administration 
 
 
5.1 Time and Events Schedule 
 
An overview of the schedule of study assessments is provided in the Study Calendar in section 10. 
 
Informed consent will be obtained prior to any study procedures being performed. Each participant 
will be given a copy of the signed informed consent form (ICF). The ICF must be approved by an 
Institutional Review Board (IRB)/Ethics Committee (EC). 
 
A complete medical history and physical examination will be conducted on each patient for a review 
of systems and determination of any concurrent symptoms or conditions prior to the first dose of 
study drug. Routine study evaluations will be conducted to monitor for existing adverse events and 
the development of new adverse events.  
 
Patients are to be encouraged to call the site to report any unexpected symptoms or problems they 
encounter between study visits. Medical symptoms or conditions present at or before study drug 
administration that manifest with the same intensity or frequency subsequent to study drug 
administration do not need to be recorded as adverse events in the CRF. However, any pre-existing 
condition that presents with increased intensity or increased frequency following study drug 
administration, or any exacerbation of an event that is present at the time of study drug 
administration, should be considered an adverse event. All adverse events occurring from initial 
dosing through study end, inclusive, should be followed as outlined in section 7.  All adverse events 
must be completely and promptly recorded in the patient's source document (e.g., patient hospital 
records, patient clinic charts, and laboratory reports) and on the CRF. Note that individual 
signs/symptoms should not be recorded in the CRF as adverse events. If a unifying diagnosis is 


Protocol Amendment 12, date December 4, 2014 
30
known, it is the diagnosis that should be recorded as the adverse event. 
 
Clinically significant laboratory abnormalities present at the pre-study (baseline) visit will be 
recorded as pretreatment signs and symptoms. After study treatment administration, laboratory 
abnormalities will not be recorded as adverse events unless considered clinically significant by the 
Investigator, and clinically significant laboratory abnormalities will not be recorded as serious 
adverse events unless the event meets the definition of serious. 
 
Each Investigator is responsible for assessing the clinical significance of all abnormal laboratory 
values using the NCI CTCAE Scale version 4.0 (see http://ctep.cancer.gov/reporting/ctc.html), 
where applicable. It is also the responsibility of the Investigator to assess the clinical significance of 
all abnormal laboratory values as defined by the list of normal values provided by the local 
laboratory. All abnormal laboratory tests that are judged to be at least possibly drug related, or 
clinically relevant abnormal laboratory tests of uncertain causality, must be repeated. Any abnormal 
values that persist should be followed at the discretion of the Investigator. In some cases, significant 
changes within the range of normal values will require similar judgment. 
 
5.1.1 Screening and Pre-study Assessments 
                      
The following evaluations and procedures will be performed within 28 days prior to Day 
1: 
 
• Signed informed consent 
 
• Clinical evaluations 
 
• Medical and surgical history (including demographics and prior cancer therapy history) 
 
• Complete physical examination       
 
 • Vital Signs: Height, weight, pulse, blood pressure, respiratory rate, and temperature 
 
•ECOG performance status (see Appendix A) 
 
• Concurrent medications: Record all concurrent medications administered within the 28 
days preceding Day 1 
 
• Laboratory assessments 
 
Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, 
white blood cell (WBC) count, and percent and absolute differential count 
(neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells) 
 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, magnesium, 
bicarbonate, calcium, total protein, albumin, serum total bilirubin, alkaline 
phosphatase, LDH, phosphorus, Chloride, AST, AST, and ALT ) 


Protocol Amendment 12, date December 4, 2014 
31
 
Complete Urinalysis 
 
Coagulation: PT, PTT, INR 
 
Pregnancy Testing.  Women of childbearing potential are required to have a negative 
serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days 
and within 24 hours prior to the first dose of GDC-0449 (serum or urine).  A 
pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual 
cycles are regular or every 2 weeks if their cycles are irregular while on study within 
the 24-hour period prior to the administration of GDC-0449.  A positive urine test 
must be confirmed by a serum pregnancy test.  Prior to dispensing GDC-0449, the 
investigator must confirm and document the patient’s use of two contraceptive 
methods, dates of negative pregnancy test, and confirm the patient’s understanding of 
the teratogenic potential of GDC-0449. 
 
• 12-lead ECG 
 
• Tumor assessment (per RECIST 1.1; see section 11). The method used for a patient 
must be the same throughout the study.  CT scan of chest, abdomen and pelvis (or MRI if 
patient allergic to contrast agent).  
 
• Consent to obtain tissue biopsy by ultrasound or ct guided biopsy  
 
• Pretreatment biopsy for correlative studies, must be obtained within 14 days before 
cycle 1, day 1 
 
5.1.2 Assessments during the study period 
 
The study period begins on Day 1 of Cycle 1 and continues until documented disease 
progression. A window of ± 3 days will be allowed for all visits and radiographic 
assessments performed during the study period. All assessments and procedures should 
be performed prior to study treatment on the scheduled treatment day, unless otherwise 
specified. 
 
• Response assessments: Response assessment CT scans should be performed at Baseline, 
Cycle 1 Day 1 (only if Baseline CT scan not done within 14 days prior to Cycle 1 Day 1), 
every 8 weeks (at any time during that week), and EOS (if required per the defined study 
imaging schedule). The same mode of imaging for target lesions must be used at Baseline 
and throughout the study. CT image preparation will follow the specifications provided in 
the RECIST 1.1 response guidelines. CT imaging should include contrast unless 
medically contraindicated and conventional CT should be performed with contiguous 
cuts of 10 mm or less in slice thickness. If spiral CT is used, it should be performed by 
use of a 5 mm contiguous reconstruction algorithm. 
 
• Drug related toxicities: If the investigator suspects a drug-related toxicity, an extra-


Protocol Amendment 12, date December 4, 2014 
32
unscheduled visit with additional laboratory tests may be performed. 
 
• GDC-0449, nab paclitaxel and gemcitabine should be administered as specified in 5.2 
and study calendar in section 10.  
 
5.1.3 Beginning of each cycle 
 
The following assessments will be performed on Day 1 of each treatment cycle: 
 
• GDC-0449 drug accountability. The first dose of GDC-0449 will be taken on Day 1 of 
Cycle 2 while the patient is at the site. Drug will be dispensed to the patient on this day. 
GDC-0449 drug accountability and review of the Medication Diary will occur at the 
beginning of each subsequent visit. GDC-0449 will be dispensed every 4 weeks. Unused 
medication should not be re-dispensed. 
 
• Clinical evaluations: Weight, pulse, blood pressure, respiratory rate, and temperature 
 
• BSA calculations (Day 1 of cycle 1, and then subsequently if there is a weight change 
of more than 10%) 
 
• Concurrent procedures 
 
• Adverse event evaluation 
 
• Peripheral neuropathy assessment 
 
• Cycle 1, Day 1 CT scan (only if baseline CT not done within 14 days prior to Cycle 1, 
Day 1) 
 
• Serum CA19-9 (Day 1 of Cycle 1, Cycle 2, Cycle 4 and every even cycle onward) 
 
• Plasma SPARC (Day 1 of Cycle 1, Cycle 2, Cycle 4 and every even cycle onward) 
 
• Local laboratory assessments 
 
• Day 1 evaluations may be omitted if Baseline evaluations are performed within 72 
hours of Cycle 1, Day 1. 
 
Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, 
white blood cell (WBC) count, and percent and absolute differential count 
(neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells) 
 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, magnesium, 
bicarbonate, calcium, total protein, albumin, serum total bilirubin, alkaline 
phosphatase, AST, and ALT ) 
 


Protocol Amendment 12, date December 4, 2014 
33
Serum or urine pregnancy test (for women of childbearing potential). If a urine test is 
positive should be confirmed with serum pregnancy test. For all other women, 
documentation must be present in their medical histories confirming that the patient 
is not of childbearing potential (see Appendix B). 
 
• Record concurrent medications. 
 
• Record cancer-related medical or surgical procedures. 
 
• Record adverse events. 
 
 
5.1.4 Follow up assessments 
 
Efficacy Response Assessments 
 
The following efficacy response assessments will be performed: 
 
• CT scan (or MRI if patient is allergic to contrast agent) every 8 weeks at any time 
during that week, starting from Cycle 1 Day 1. In order to confirm objective response, an 
unscheduled CT scan will be allowed 4 weeks (a minimum of 28 days) from the initial 
documented complete or partial response. For such patients, all subsequent CT scans 
should return to the original schedule performed every 8 weeks starting from the date of 
first dose of study therapy. An unscheduled CT scan for suspected progression may be 
performed at any time; 
 
Per Cycle Evaluations 
 
On Days 8 and 15 of each cycle, the following assessments will be performed: 
 
• Concomitant medication evaluation 
 
• Vital signs (prior to dosing) 
 
• CBC, differential and platelet count 
 
• Adverse event evaluation. 
 
At the beginning of each cycle 
 
Note: The following procedures should be performed during the entire study period.  
 
• Brief physical examination 
 
• Clinical evaluations (performed at beginning of each chemotherapy cycle or, if 
chemotherapy has been stopped, every 3-4 weeks): Weight, pulse, blood pressure, 


Protocol Amendment 12, date December 4, 2014 
34
respiratory rate, and temperature 
 
• Local laboratory assessments (performed at beginning of each chemotherapy cycle or, if 
chemotherapy has been stopped, every 3-4 weeks) 
 
Hematology: hemoglobin, hematocrit, platelet count, RBC count, WBC count, and 
percent and absolute 
differential 
count (neutrophils, bands, eosinophils, 
lymphocytes, monocytes, basophils, other cells) 
 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, magnesium, 
bicarbonate, calcium, total protein, albumin, serum total bilirubin, alkaline 
phosphatase, AST, and ALT) 
 
• ECOG performance status (see Appendix A) 
 
• Serum or urine pregnancy test every 4 weeks (for women of childbearing potential) 
 
• Record concurrent medications. 
 
• Record cancer-related medical or surgical procedures. 
 
• Record adverse events. 
 
Every 8 weeks 
Note: The following procedures should be performed during the entire study period. If 
chemotherapy has been stopped every 8 weeks 
 
• Tumor assessment (per RECIST 1.1; see section 11). The method used for a patient 
must be the same throughout the study 
 
• Record concurrent medications. 
 
• Record cancer-related medical or surgical procedures. 
 
• Record adverse events. 
 
End-of-Study (EOS) Evaluations 
 
An EOS evaluation should be performed for all patients who end treatment. The 
following procedures will be completed at the EOS Visit: 
 
• Physical examination 
 
• Weight assessment 
 
• Concomitant medication evaluation 


Protocol Amendment 12, date December 4, 2014 
35
 
• Concurrent procedures 
 
• Vital signs 
 
• ECOG performance status scale 
 
• Clinical chemistry panel 
 
• CBC, differential and platelet count 
 
• CT scan (or MRI if patient is allergic to contrast agent) only if required per the defined 
study imaging schedule; 
 
• Adverse event evaluation. 
 
The Investigator must follow all SAEs observed during the study until these events have 
resolved or stabilized, the patient is lost to follow-up, or the events are otherwise 
explained. The Investigator should report these SAEs in accordance with the procedures 
described in Section 7. Clinical laboratory tests may be repeated during the post-
treatment period if clinically indicated. 
 
Follow-up for Adverse Events 
 
Any AE or SAE whose onset occurred between the first administration of study drug to 
30 days after the last dose of study drug or EOS (whichever is later) will be collected. 
The Investigator should report SAEs in accordance with the procedure described in 
Section 7. Adverse event follow-up will be conducted as follows: 
 
• Non-serious adverse events, other than neuropathy, will be followed for 30 days after 
the patient’s last dose of study drug. 
 
• Neuropathy will be followed until improvement to Grade 1 occurs, or at least 3 months 
have elapsed without improvement or worsening, or the patient initiates any other 
anticancer therapy during follow-up. 
 
• All serious adverse events (regardless of relationship to study drug) will be followed 
until resolution. Clinical laboratory tests may be repeated during follow-up if clinically 
indicated. Follow-up evaluations include studies necessary to document the resolution or 
persistence of any unresolved AEs and could include: 
 
• Physical examination, weight; 
• Concomitant medication evaluation; 
• Concurrent procedures; 
• Vital signs; 


Protocol Amendment 12, date December 4, 2014 
36
• ECOG Performance Status scale; 
• CBC, differential, platelet count, and clinical chemistries; 
• Peripheral neuropathy assessment. 
 
Follow-up for Disease Progression 
 
Patients who are discontinued from treatment in the absence of disease progression (e.g., 
patients removed for unacceptable toxicity or patient/investigator discretion) should 
undergo repeat imaging and tumor response assessments until disease progression is 
documented. Imaging studies (CT scans) should be continually performed into follow-up 
every 8 weeks (at any time during that week), regardless of regimen. It is recommended 
that subsequent therapy not be instituted until disease progression is documented. Ideally 
this repeat imaging should be done at the treating institution.  
 
Follow-up for Overall Survival 
 
Post-study, overall survival status will be monitored on a monthly basis for 6 months and 
then every 3 months thereafter for 12 months. Patients will be followed for a total of 18 
months. This evaluation may be by record review and/or telephone contact.  
 
 
5.2  
Agent Administration 
 
Patients will be treated on an outpatient basis. Patients receiving nab-Paclitaxel +gemcitabine will 
receive 125 mg/m2 nab-Paclitaxel as a 30-minute infusion followed by 1000 mg/m2 gemcitabine as 
a 30-minute infusion for 3 weeks followed by a week of rest. Supportive care per the institution’s 
normal standard of care can be provided at the Investigator’s discretion. 
 
 
 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Gemcitabine 
Dexamethasone 
12 mg PO or IV 
30-60 min prior 
to Gemcitabine 
 
1000 mg/m2 
IV  
Days 1, 8 
and 15 
4 weeks 
(28 days) 
 
Nab-
paclitaxel 
Not required 
125 mg/m2 
IV  
Days 1, 8 
and 15 
GDC-0449 
Morning or PM.  
150 mg tablet 
PO in the a.m.  
Daily 
starting on 
cycle 2 
 
5.2.1 GDC-0449 
 


Protocol Amendment 12, date December 4, 2014 
37
Administration  
 
GDC-0449 150 mg will be administered beginning on Cycle 2, Day 1 once daily by oral dosing, in 
combination with gemcitabine and nab-paclitaxel as described in section 5.1. Therapy should 
continue until one of the conditions specified in section 5.4 occurs. 
 
Drug should be taken at approximately the same time each day, with or without food. If a patient 
misses a dose (e.g., due to emesis), he or she should be instructed not to take or make up that dose 
and to resume dosing with the next scheduled dose. Missed doses will not be made up. Patients will 
be instructed to bring all unused capsules and their medication diary to each study visit for 
assessment of compliance. 
 
The terminal half-life of GDC-0449 is currently unknown, but is expected to be longer than 1 week, 
and may be as high as 2 to 3 weeks. If plasma levels of GDC-0449 need to be lowered emergently, 
animal studies suggest that oral administration of activated charcoal may lower drug plasma levels 
more quickly than dose cessation alone. 
 
5.2.2 nab-paclitaxel 
 
nab-Paclitaxel Premedication 
 
Patients do not require premedication prior to nab-Paclitaxel administration,  
as hypersensitivity reactions are not expected, though initial antiemetic prophylaxis  
is recommended due to administration of gemcitabine following nab-Paclitaxel treatment. 
 
Hypersensitivity reactions are not expected with either nab-paclitaxel or gemcitabine. If they do 
occur, minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia may 
require temporary interruption of the infusion. However, severe reactions, such as hypotension 
requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require 
immediate discontinuation of study drug administration and aggressive symptomatic therapy. 
Patients who develop a severe hypersensitivity reaction to nab-paclitaxel should not be re-
challenged. 
 
If a hypersensitivity reaction occurs, the infusion should be stopped and not restarted. If felt to be in 
the patient’s best interests, at the investigator’s discretion, treatment may continue on subsequent 
cycles using the premedication regimen the institution typically uses for Taxol. 
 
Chemotherapy Dose 
 
The cycle length is 4 weeks (28 days). Treatment with protocol therapy will continue until one or 
more of the criteria listed in Section 5.4 are met. 
 
5.2.3 Gemcitabine 
 
Gemcitabine Premedication 
 


Protocol Amendment 12, date December 4, 2014 
38
Please see gemcitabine prescribing information for recommended premedication strategies. 
 
 
5.2.4      
Other Modality (ies) or Procedures 
 
Administration of other chemotherapy, immunotherapy, or anti-tumor hormonal therapy during the 
study is not allowed. All concomitant treatments, including blood and blood products, must be 
reported on the case report form (CRF). Erythropoietin may be administered at the discretion of the 
Investigator, consistent with institutional guidelines. Guidelines for administration of GCSF are 
described in Table 5 but will be to the discretion of the investigator and according to institutional 
guidelines. 
 
      Planned Surgical Procedures 
 
If, during the course of therapy, a planned surgical procedure is anticipated, chemotherapy, GDC-
0449 may be stopped 4 weeks prior to minimize surgical complications. Patients may restart 
chemotherapy as appropriate. GDC-0449 must be restarted within 8 weeks of stopping in order to 
continue treatment with GDC-0449. 
 
 
5.3 General Concomitant Medication and Supportive Care Guidelines 
 
 
5.3.1 GDC-0449 
 
 
 GDC-0449 inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes 
in vitro at clinically relevant concentrations. There is a potential for GDC-0449 to 
also inhibit CYP1A2 and 2D6. Caution should be exercised and dose reduction of 
the concomitant substrate drug should be considered when dosing GDC-0449 
concurrently with medications with narrow therapeutic windows that are 
substrates of CYP2C8, CYP2C9, CYP2C19, CYP1A2 and 2D6  because their 
concentrations may become elevated and their effects increased or prolonged. 
 
 GDC-0449 did not significantly inhibit CYP3A4 at clinically relevant 
concentrations in vitro; however, the clinical impact of GDC-0449 on substrates 
of CYP3A4 is unknown. GDC-0449 is a substrate of CYP3A4; however, the in 
vitro metabolic conversion of GDC-0449 is low. Effects of CYP inducers (i.e., 
carbamezepine, phenobarbital, phenytoin, rifabutin, rifampin, St John’s wort, and 
troglitazone) on clinical concentrations of GDC-0449 are unknown, it is possible 
that these drugs could reduce concentrations of GDC-0449. Likewise, the effects 
of strong inhibitors of CYP3A4 (i.e., clarithromycin, erythromycin, itroconazole, 
ketoconazole, 
nefazodone, 
and 
telithromycin) 
on 
GDC-0449 
clinical 
concentrations are unknown; it is possible that these drugs could increase the 
concentrations of GDC-0449. Use of these drugs with GDC-0449 should be 
documented in the eCRFs.  


Protocol Amendment 12, date December 4, 2014 
39
 
 The following table lists clinically significant substrates of CYP2C8, CYP2C9, 
CYP2C19, CYP1A2 and 2D6.  This is not necessarily a complete list; other 
medications may also interact with GDC-0449. 
 
2C8 
2C9 
2C19 
Miscellaneous 
 
Repaglinide 
 
Rosiglitazone 
       Paclitaxel 
       Torsemide 
       Cerivastatin 
       Amiodaquine 
NSAIDs 
 
Diclofenac 
 
Ibuprofen 
 
Piroxicam 
 
Naproxen 
 
Celecoxib 
 
Oral hypoglycemic agents 
 
Glipizide 
 
Tolbutamide 
 
Angiotensin II blockers 
 
Irbesartan 
 
Iosartan 
 
NOT candesartan 
 
NOT valsartan 
 
Miscellaneous 
 
Fluvastatin 
 
Phenytoin 
 
Sulfamethoxazole 
 
Tamoxifen 
 
Torsemide 
 
Warfarin 
Proton-pump inhibitors 
 
Omeprazole 
 
Lansoprazole 
 
Pantoprazole 
 
Rabeprazole 
 
Esoprazole 
 
Anti-epileptics 
 
Diazepam 
 
Phenytoin 
 
Phenobarbitone 
 
Miscellaneous 
 
Amitriptyline 
 
Clomipramine 
 
Clopidogrel 
 
Cyclophosphamide 
 
NSAIDs = Non-steroidal anti-inflammatory drugs 
 
 
 
1A2 
2D6 
 
Amitriptyline 
Clomipramine 
Clozapine 
Cyclobenzaprine 
Estradiol 
Fluvoxamine 
Haloperidol 
Imipramine  
Mexiletine 
Naproxen 
Olanzapine 
Ondansetron 
Phenacetin 
AcetaminophenNAPQI
Propanolol 
Tamoxifen 
 
BBlockers 
  Carvedilol 
  S-metoprolol 
  Propafenone 
  Timilol 
 
Antidepressants   
  Amitriptyline 
  Clomipramine 
  Desipramine 
  Fluoxetine 
  Imipramine 
  Paroxetine 
Atomoxetine 
Bufuralol 
Chlorpheniramine 
Chlorpromazine 
Codeine 
Debrisoquine 
Dexfenfluramine 
Dextromethorphan 
Donepezil 
Duloxetine 
Encainide 
Flecainide 
Fluvoxamine 
Lidocaine 
Metoclopramide 


Protocol Amendment 12, date December 4, 2014 
40
Riluzole 
Ropivicaine 
Tacrine 
Theophylline 
Tizanidine 
Verapamil  
Warfarin 
Zileuton 
Zolmitriptan 
 
 
 
Antipsychotics 
  Haloperidol 
  Perphenazine 
  Risperidone 
  Thioridazine 
  Zuclopenthixol 
 
Alprenolol 
Amphetamine 
Aripiprazole 
 
 
Methoxyamphetamine 
Mexiletine 
Minaprine 
Nebivolol 
Nortriptyline 
Ondansetron 
Oxycodone 
Perhexiline 
Phenacetin 
 
 
Because there is a potential for interaction of GDC-0449 with other 
concomitantly-administered drugs through the cytochrome P450 system, the case 
report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted 
if the patient is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes (refer to Appendix C for a list of drugs that may 
potentially interact with CYP3A4).  
 
 Use of medications or food that may interfere with the metabolism of GDC-0449 
is prohibited, including ketoconazole and fresh-squeezed grapefruit juice. 
 
 If plasma levels need to be lowered emergently, animal studies have suggested 
that oral administration of activated charcoal may lower drug plasma levels more 
quickly than drug cessation alone. 
 
 Women of childbearing potential (defined in Appendix B) are required to have a 
negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 
10-14 days and within 24 hours prior to the first dose of GDC-0449 (serum or 
urine).  A pregnancy test (serum or urine) will be administered every 4 weeks if 
their menstrual cycles are regular or every 2 weeks if their cycles are irregular 
while on study within the 24-hour period prior to the administration of GDC-
0449.  Prior to dispensing GDC-0449, the investigator must confirm and 
document the patient’s use of two contraceptive methods, dates of negative 
pregnancy test, and confirm the patient’s understanding of the teratogenic 
potential of GDC-0449. 
 
Female patients are required to use two forms of acceptable contraception (refer 
to Appendix B), including one barrier method during participation in the study 
and for the 7 months following the last dose.  Women of childbearing potential 
are also advised to have monthly pregnancy tests for 12 months after 
discontinuation of GDC-0449.  All patients should receive contraceptive 
counseling either by the investigator, or by an obstetrician(OB)/gynecologist or 


Protocol Amendment 12, date December 4, 2014 
41
other physician who is qualified in this area of expertise.  If a woman of 
childbearing potential believes that her contraceptive method has failed, 
emergency contraception should be considered. 
 
If a patient is suspected to be pregnant, GDC-0449 should be immediately 
discontinued.  In addition, a positive urine test must be confirmed by a serum 
pregnancy test.  If it is confirmed that the patients is not pregnant, the patient may 
resume dosing with GDC-0449.   
 
If a female patient becomes pregnant during therapy or within 7 months 
after the last dose of GDC-0449, or if the female partner of a male patient 
exposed to the drug becomes pregnant while the male patient is receiving 
GDC-0449 or within 7 months after the last dose of GDC-0449, the 
investigator must be notified in order to facilitate outcome follow-up. 
 
Abortion, whether accidental, therapeutic, or spontaneous, should always be 
classified as serious.  Any congenital anomaly/birth defect in a child conceived 
during the study or within 7 months after the last dose of GDC-0449 to a female 
patient or to a female partner of a male patient exposed to the agent during 
treatment or within 7 months after the last dose of GDC-0449 should be recorded 
and reported as an SAE. 
 
 Female patients should not breastfeed a baby while on this study.   
 
 Female patients must NEVER donate ova while being treated with GDC-0449. 
 
 All sexually active male subjects (including those who have undergone 
vasectomy) should utilize a barrier form of contraception during study 
treatment and for 7 months after the last dose as it is not known whether 
GDC-0449 that may be present in seminal fluid would cause teratogenic effects in 
a fetus born to the female partner of a male subject.  Males should also not donate 
sperm during treatment or up to 3 months after the last dose. 
 
 All patients are prohibited from donating blood for 7 months after the last dose of 
GDC-0449. 
 
 
5.3.2 Other Considerations 
 
5.3.2.1  
Concomitant and Excluded Therapies 
 
For information regarding other drugs that may interact with either nab-paclitaxel or 
gemcitabine and affect their metabolism, pharmacokinetics, or excretion, please see the 
gemcitabine and nab-paclitaxel package inserts. 
 
5.3.2.2  
Supportive Care and administration of additional therapies 


Protocol Amendment 12, date December 4, 2014 
42
 
Over the course of this trial, additional medications may be required to manage aspects of the 
disease state of the patients; including side effects from trial treatments or disease 
progression Supportive care not otherwise specified in this protocol may be administered per 
institutional standard of care. Supportive care, including but not limited to anti-emetic 
medications, may be administered at the discretion of the Investigator. Irradiation is not 
allowed during the study. 
 
Colony stimulating factors may be given according to institutional guidelines for the 
treatment of neutropenic fever or infections associated with neutropenia. References on use 
of granulocyte colony-stimulating factors can be used as recommended by the American 
Society of Clinical Oncology (ASCO) guidelines. 
 
 
5.4 Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for   
indefinitely or until one of the following criteria applies: 
 
• Disease progression 
• Intolerable (Grade 3 or 4) toxicity most probably attributable to GDC-0449 or other agents 
• Intercurrent illness that prevents further administration of treatment 
• Require palliative radiotherapy 
• Withdrawal from the study 
• Initiation of other anticancer therapy. 
• The physician feels it is not longer in their best interest to continue on treatment 
• If the patient becomes pregnant 
• Noncompliance (e.g., missed doses, visits) 
 
 
5.5 Duration of Follow Up 
 
Patients will be followed for 18 months after removal from study or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. 
 
 
5.6 
Criteria for removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  
The reason for study removal and the date the patient was removed must be documented in 
the Case Report Form. 
 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS/DOSE OMISSIONS 
 


Protocol Amendment 12, date December 4, 2014 
43
      6.1 GDC-0449 
 
Dose modifications of GDC-0449 are not planned. Treatment with GDC-0449 may be interrupted 
for up to 4 weeks for evaluation of a toxicity finding or up to 8 weeks for a planned surgical 
procedure. If a treatment interruption occurs and it is determined that GDC-0449 will be restarted, 
the original dose will be maintained. There are no planned dose reductions of GDC-0449. 
 
     6.2 Gemcitabine and nab-Paclitaxel 
 
Rules for Dose Omissions and Modified Schedules 
 
Day 1 dose missed: 
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle will not be 
considered to start until the day the first dose is actually administered to the patient (i.e., 1-2-3-Rest, 
X-1-2-3-Rest, etc.) 
 
Day 8 dose is missed: 
Cycle continues per protocol, with one dose not given (i.e., 1-2-3-Rest, 1-X-3-Rest, 1-2-3- Rest, 
etc.). Day 15 is administered as per cycle calendar if counts and chemistries permit. 
 
Day 15 dose missed: 
That week becomes the week of rest. Next dose (if counts and chemistries permit) becomes Day 1 of 
a new cycle, and the patient is considered to have had a x2q3 (21-day) cycle (i.e., 1-2-3-Rest, 1-2-X, 
1-2-3-Rest, etc). 
 
Doses will be reduced for hematologic and other non-hematologic toxicities. Dose adjustments are to 
be made according to the system showing the greatest degree of toxicity. Toxicities will be graded 
using the NCI CTCAE Version 4.0. Two dose modifications are permitted according to the criteria 
below. If a toxicity requiring dose modification occurs following the second dose reduction, further 
treatment should be discontinued. 
 
 
Dose Level 
 
nab- Paclitaxel 
(mg/m2) 
 
Gemcitabine 
(mg/m2)a 
 
 
 
 
 
Study Dose 
125 
 
1000 
-1 
100 
 
800 
- 2b 
75 
 
600 
aDose reductions may or may not be concomitant. Please refer to Tables 4-6 for specific 
recommendations regarding dose reductions 
 
bAdditional 25% dose modifications are permissible to establish the tolerable dose for an individual 
patient 
 
 
If patients experience study drug-related toxicities that require a delay in scheduled nab-paclitaxel 
and gemcitabine dosing for ≥ 28 days will be discontinued from further participation in this study. 


Protocol Amendment 12, date December 4, 2014 
44
When a dose reduction is required for Day 1 of any cycle, no dose re-escalation will be permitted for 
the duration of study treatment. 
 
DOSE MODIFICATIONS AT DAY 1 
In the event dose modifications are required at the beginning of a cycle due to AEs or hematologic 
toxicities, doses of nab-paclitaxel and gemcitabine may be adjusted as detailed in Table 3 and Table 
4 below: 
 
 
Table 3. Dose Modifications for Hematologic Toxicities (Day 1 of Each Cycle) 
 
Absolute Granulocytes 
 
Platelets 
Timing 
≥ 1.5 x 109/L  
AND 
≥ 100 x 109/L  
Treat on time 
< 1.5 x 109/L  
OR 
<100 x 109/L  
Delay by one week 
intervals until 
recovery 
 
 
 
 
 
 
Table 4. Dose Modifications for Non-Hematologic Toxicity (Day 1 of Each Cycle) 
 
 
Non Hematologic Toxicity and/ or Dose Hold with Previous Cycle 
 
Toxicity/ dose held 
 
Gemcitabine/ Gemcitabine + nab-paclitaxel 
dose this cycle 
Grade 0, 1 or 2 
Same as day 1 previous cycle 
Grade 3 toxicity 
Decrease gemcitabine and nab-Paclitaxel to next 
lower dose levela  
Grade 4 toxicity 
Off protocol treatmentb 
Dose held in 2 previous consecutive cycles 
Decrease gemcitabine to next lower dose level 
and continue throughout the rest of treatment 
a  If the toxicity only affects neuropathy, then only nab-Paclitaxel should be reduced 
b  Pulmonary embolism (a Grade 4 toxicity in CTCAE tables) if mild or asymptomatic, will be 
exempt from this requirement. 
 
 
DOSE ADJUSTMENTS WITHIN A TREATMENT CYCLE 
In the event that patients must have treatment delayed within a treatment cycle due to toxicities, 
those doses held during a cycle will not be made up. Dose modifications due to hematologic toxicity 
(as represented by the blood counts and toxicities, below) within a treatment cycle should be 
adjusted as outlined in Table 5. 
 


Protocol Amendment 12, date December 4, 2014 
45
 
Table 5. Dose Modifications for Hematologic Toxicity within a Cycle 
 
     Day 8 
BloodCount 
        Day 8      
Nab-
Paclitaxel 
     Day 8 
Gemcitabine 
  Day 15        
Blood Count 
    Day 15         
Nab-
Paclitaxel 
     Day 15 
Gemcitabine 
ANC > 1000     
and             
Platelets           
≥ 75,000          
100% 
100% 
ANC > 1000    
and           
Platelets        
≥ 75,000        
100% 
100% 
ANC 500-1000   
or              
Platelets       
50,000-74,999 
Full 
Dose(treat on 
time) 
+GCSF* 
Full 
Dose(treat on 
time) 
+GCSF* 
ANC < 500      
or             
Platelets        
< 50,000 
Hold+GCSF* 
Hold+GCSF* 
ANC 500-1000a    
or                
Platelets        
50,000-74,999 
Decrease 
dose by 1 
level (treat 
on time) 
Decrease 
dose by 1 
level (treat 
on time) 
ANC > 1000    
and           
Platelets        
≥ 75,000        
Return to Full 
Dose(treat on 
time) + 
GCSF* 
Return to Full 
Dose(treat on 
time) + 
GCSF* 
ANC 500-1000   
or              
Platelets       
50,000-74,999 
Same 
Dose(as Day 
8, treat on 
time) 
+GCSF*††† 
Same 
Dose(as Day 
8, treat on 
time) 
+GCSF*††† 
ANC < 500      
or              
Platelets        
< 50,000 
Hold+GCSF* 
Hold+GCSF* 
ANC < 500a        
or                
Platelets           
< 50,000 
Hold 
Hold 
ANC > 1000    
and           
Platelets        
≥ 75,000        
Decrease Day 
8 dose by 1 
level (treat on 
time)+GCSF* 
Decrease Day 
8 dose by 1 
level (treat on 
time)+GCSF* 
ANC 500-1000   
or              
Platelets       
50,000-74,999 
Decrease Day 
8 dose by 1 
level (treat on 
time)+GCSF* 
Decrease Day 
8 dose by 1 
level (treat on 
time)+GCSF* 
ANC < 500      
or              
Platelets        
< 50,000 
Hold+GCSF* 
Hold+GCSF* 
 
 
 
 
 


Protocol Amendment 12, date December 4, 2014 
46
 
Febrile 
Neutropenia 
(Grade 3 or 4)b 
Hold. Upon 
resuming 
dosing, 
decrease to 
next lower 
level and do 
not re-
escalate 
throughout 
the rest of 
treatment 
Hold. Upon 
resuming 
dosing, 
decrease to 
next lower 
level and do 
not re-
escalate 
throughout 
the rest of 
treatment 
  
Hold. Upon 
resuming 
dosing, 
decrease to 
next lower 
level and do 
not re-
escalate 
throughout 
the rest of 
treatment 
Hold. Upon 
resuming 
dosing, 
decrease to 
next lower 
level and do 
not re-
escalate 
throughout 
the rest of 
treatment 
Recurrent Febrile 
neutropenia 
(Grade 3 or 4) b  
Decrease to 
next lower 
dose level 
and do not  
re- escalate 
throughout 
the rest of 
treatment 
Decrease two 
dose levels 
(to 600 
mg/m2) and 
do not re-
escalate  
throughout 
the rest of 
treatment 
  
Decrease to 
next lower 
dose level 
and do not  
re- escalate 
throughout 
the rest of 
treatment 
Decrease two 
dose levels 
(to 600 
mg/m2) and 
do not re-
escalate  
throughout 
the rest of 
treatment 
a  If patient do not experience resolution of neutropenia within 21 days, despite  uninterrupted  
   G-CSF treatment, study treatment will be discontinued 
 
b Febrile patient (regardless of neutrophil count) should have their chemotherapy treatment interrupted.  
  A full sepsis diagnostic work-up should be performed while continuing  broad spectrum antibiotics. 
  If cultures are positive, the antibiotic may or may not be changed, depending on the sensitivity profile 
  of the isolated organism. Patients with persisting fever after 3 weeks, despite uninterrupted antibiotic 
  treatment, will discontinue study treatment. Febrile neutropenic patients can also receive G-CSF, in  
  addition to antibiotic treatment, to hasten the resolution of their febrile neutropenia (following current 
   institutional guidelines). In all cases, blood counts must have returned to baseline levels before resuming  
  chemotherapy treatment. 
 
 
* G-CSF to the investigator discretion. It is optional if 
descent only affects platelets  
††† If episode of myelosuppression 
occurred starting day 15 of this cycle 
decrease day 8 dose by 1 level 
 
 
 
 
Dose modifications may also be made for non-hematological toxicity within a cycle as specified in 
Table 6. 
 
 


Protocol Amendment 12, date December 4, 2014 
47
 
Table 6. Dose Modifications for Non-Hematological Toxicity within a Cycle 
CTC Grade 
 
 
CTC Grade 
 
Percent of Day 1  
 
0-2   (and Grade 3 nausea/ vomiting and alopecia) 
100% 
3      (except nausea/vomiting and alopecia) 
50% or Holda 
4 
Holda 
a  This decision as to which drug should be modified will depend upon the type of non-hematologic toxicity seen and 
which course is medically most sound in the judgment of the physician/investigator. Treatment may be reinstated on 
Day 1 of the next cycle. 
 
 
 
Peripheral Neuropathy 
 
Nab-Paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 peripheral 
neuropathy. Gemcitabine administration can continue during this period at the discretion of the 
investigator.  Nab-Paclitaxel treatment may be resumed at the next lower dose level in subsequent 
cycles after the peripheral neuropathy improves to ≤ Grade 1, regardless of suspected cause. Patients 
experiencing peripheral neuropathy that requires a delay in scheduled nab-Paclitaxel dosing for  28 
days will be discontinued from further participation in this study. Additionally patients receiving a 
reduced dose of nab-Paclitaxel who experience ≥ Grade 3 peripheral neuropathy at that dose level 
requiring a dose delay  28 days without resolving to < Grade 1 will be discontinued from further 
participation in this study. 
 
Similarly, GDC-0449 should be held in the event that patients experience ≥ Grade 3 peripheral 
neuropathy. GDC-0449 may be resumed at the same dose of 150 mg daily after the peripheral 
neuropathy improves to ≤ Grade 1. 
 
As observed in other clinical trials, ≥ Grade 3 neuropathy related to nab-Paclitaxel is usually seen in 
later phases of the treatment (cycle 6 and beyond). If ≥ Grade 3 neuropathy occurs in early treatment 
cycles, other factors predisposing the patient to neuropathy might be present (eg. diabetes, alcohol 
consumption, concomitant medications). To maintain dose intensity during the first 6 treatment 
cycles, careful consideration should be exercised when these predisposing factors are present.  
 
 
 
 
Cutaneous Toxicity 
 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the next 
lower dose level of both drugs. If the patient continues to experience these reactions, nab-paclitaxel 
despite dose reduction, treatment should be discontinued. Patients who develop Grade 4 cutaneous 


Protocol Amendment 12, date December 4, 2014 
48
toxicity should have treatment discontinued.  
 
Gastrointestinal Toxicity 
 
If Grade 3 mucositis or diarrhea occurs, study drug should be withheld until resolution to ≤ Grade 1, 
then reinstituted at the next lower dose level of both drugs. Patients who develop Grade 4 mucositis 
or diarrhea should have treatment discontinued. 
 
7. 
ADVERSE EVENTS 
 
These adverse event management guidelines are intended to ensure the safety of each patient while 
attempting to characterize the safety and tolerability of the test products. In agreeing to the provisions 
of this protocol, the Investigator accepts all legal responsibilities for prompt notification of SAEs 
to the Coordinating Center (Johns Hopkins), Genentech, Cancer Research and Biostatistics 
(CRAB) and IRB.  
 
7.1 Adverse Events (AE) definition 
 
An adverse event is any untoward medical occurrence in a patient receiving a marketed 
pharmaceutical product or in a patient who is participating on a clinical trial who is receiving an 
investigational or non-investigational pharmaceutical agent. The AE does not necessarily have a 
causal relationship with the patient’s treatment. Therefore, an adverse event can be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered to be related to the medicinal product. In cancer 
clinical trials, many AEs are in fact related to progression of the patient’s underlying malignancy. 
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with pancreatic cancer that were not 
present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged by the investigator to 
have worsened in severity or frequency or changed in character during the protocol-specified AE 
reporting period. 
 
An adverse event includes: 
• an exacerbation of a pre-existing illness; 
 
• an increase in frequency or intensity of a pre-existing episodic event or condition; 
 
• a condition detected or diagnosed after study drug administration even though it may 


Protocol Amendment 12, date December 4, 2014 
49
have been present prior to the start of the study 
 
• continuously persistent disease or symptoms that were present at Baseline and worsen following 
the start of the study. 
An adverse event does not include: 
• medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, or transfusion); 
however, the condition that leads to the procedure is an adverse event.  
 
• pre-existing diseases, conditions, or laboratory abnormalities present or detected at the 
start of the study that do not worsen; 
 
• hospitalizations or procedures that are done for elective purposes not related to an 
untoward medical occurrence (e.g., hospitalizations for cosmetic or elective surgery or 
social/convenience admissions); 
 
• the disease being studied or signs/symptoms associated with the disease unless more 
severe than expected for the patient's condition; 
 
• overdose of study drug without any clinical signs or symptoms. 
 
7.2 Serious Adverse Events (SAE) Definition  
 
A serious adverse event (SAE) is defined as any untoward medical occurrence at any dose 
that: 
 
• is fatal; 
• is life-threatening (defined as an immediate risk of death from the event as it occurred);  
• results in persistent or significant disability or incapacity; 
• requires in-patient hospitalization or prolongs an existing hospitalization. (Exception: 
Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study 
is not considered an adverse event. NOTE: Complications that occur during hospitalization are 
adverse events and if a complication prolongs hospitalization, then the event is serious); 
• is a congenital anomaly/birth defect in the offspring of a patient who received medication; 
• conditions not included in the above definitions that may jeopardize the patient or may 
require intervention to prevent one of the outcomes listed above unless clearly related to 
the patient’s underlying disease. 
 
The Investigator should exercise medical and scientific judgment when deciding whether expedited 
reporting is appropriate in other situations not strictly meeting the criteria outlined above. Examples 
of important medical events which may also meet the definition of a SAE include: intensive 
treatment in an emergency room or at home for a reversible condition that did not result in 
hospitalization (e.g., allergic bronchospasm or convulsions), certain laboratory abnormalities (e.g., 
blood dyscrasias), or development of drug dependency or drug abuse. If there is any question, please 
consult the relevant Medical Monitor. 
 


Protocol Amendment 12, date December 4, 2014 
50
7.3 Grading and Assessing Causality 
 
Adverse events occurring during the study will be graded according to the NCI CTCAE Scale 
version 4.0 (see http://ctep.cancer.gov/reporting/ctc.html), where applicable. Adverse events that are 
not included on the toxicity scale will be designated as Grade 1 = mild, Grade 2 = moderate, Grade 3 
= severe, Grade 4 = life-threatening, and Grade 5 = death.  
 
The Investigator should evaluate all adverse events and should make an immediate effort to 
determine their etiology. Adverse events that are determined not to be possibly, probably, or 
definitely related to study drug may not require further evaluation but will need to be recorded on the 
CRAB eCRFs. Study medications may be interrupted for an adverse event at the discretion of the 
Investigator. Patients requiring toxicity management should be assessed and evaluated at least 
weekly as indicated by the severity of the event. 
 
 
Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be reported 
appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end dates), 
regulatory seriousness criteria if applicable, suspected relationship to the {study drug} (see following 
guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the  
following general guideline: 
 
Yes 
 
There is a plausible temporal relationship between the onset of the AE and administration of the  
{study drug}, and the AE cannot be readily explained by the subject’s clinical state, intercurrent  
illness, or concomitant therapies; and/or the AE follows a known pattern of response to the  
{study drug}; and/or the AE abates or resolves upon discontinuation of the {study drug} or dose  
reduction and, if applicable, reappears upon re-challenge. 
 
No 
 
Evidence exists that the AE has an etiology other than the {study drug} (e.g., preexisting medical  
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has  
no plausible temporal relationship to {study drug} administration (e.g., cancer diagnosed 2 days  
after first dose of study drug). 


Protocol Amendment 12, date December 4, 2014 
51
 
Expected adverse events are those adverse events that are listed or characterized in the Package  
Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or current Investigator  
Brochure (I.B.) or not identified. This includes adverse events for which the specificity or  
severity is not consistent with the description in the P.I. or I.B. For example, under this  
definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated  
hepatic enzymes or hepatitis. 
 
[Insert additional unexpected adverse events applicable to this disease state] 
 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE  
EVENTS 
 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points should be  
adopted. Examples of non-directive questions include:  
• “How have you felt since your last clinical visit?” 
• “Have you had any new or changed health problems since you were last here?”  
 
Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  
Avoid colloquialisms and abbreviations. 
 
a.  
Diagnosis vs. Signs and Symptoms 
 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and  
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated  
transaminases). However, if a constellation of signs and/or symptoms cannot be medically  
characterized as a single diagnosis or syndrome at the time of reporting, it is ok to report the  
information that is currently available. If a diagnosis is subsequently established, it should be  
reported as follow-up information. 
 
b.  
Deaths 
 
All deaths that occur during the protocol-specified AE reporting period (see Section 5.1.2),  
regardless of attribution, will be reported to the appropriate parties. When recording a death, the  
event or condition that caused or contributed to the fatal outcome should be reported as the single  
medical concept. If the cause of death is unknown and cannot be ascertained at the time of  
reporting, report “Unexplained Death”. 
 
c.  
Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present at the start of the study. Such conditions  


Protocol Amendment 12, date December 4, 2014 
52
should be reported as medical and surgical history. A preexisting medical condition should be re- 
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or  
character of the condition worsens during the study. When reporting such events, it is important  
to convey the concept that the preexisting condition has changed by including applicable  
descriptors (e.g., “more frequent headaches”). 
 
d.  
Hospitalizations for Medical or Surgical Procedures 
 
Any AE that results in hospitalization or prolonged hospitalization should be documented and  
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a  
result of an AE, the event responsible for the procedure, not the procedure itself, should be  
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass  
surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for  
 
preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the  
 
study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the study. 
 
 
 


Protocol Amendment 12, date December 4, 2014 
53
e.  
Pregnancy 
 
If a female subject becomes pregnant while receiving investigational therapy or within [insert  
time period (e.g., 90 days)] after the last dose of study drug, a report should be completed and  
expeditiously submitted to the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy  
should also occur. Abortion, whether accidental, therapeutic, or spontaneous, should always be  
classified as serious, and expeditiously reported as an SAE. Similarly, any congenital  
anomaly/birth defect in a child born to a female subject exposed to the {study drug} should be  
reported as an SAE. 
 
 
f. 
Post-Study Adverse Events 
 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior {study drug} exposure. If the investigator should 
become aware of the development of cancer or a congenital anomaly in a subsequently conceived 
offspring of a female subject who participated in the study, this should be reported as an SAE.  
 
g. 
Reconciliation 
 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will agree to 
the reconciliation periodicity and format, but agree at minimum to exchange monthly line listings of 
cases received by the other party. If discrepancies are identified, the Sponsor and Genentech will 
cooperate in resolving the discrepancies. The responsible individuals for each party shall handle the 
matter on a case-by-case basis until satisfactory resolution. 
 
h. AEs of Special Interest (AESIs) 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product  
  
The [study drug] Events of Special Interest are: [List of Events of Special Interest HERE] 
 
7.4 Potential Risks for Study Drugs  
 
The following adverse events has been reported in previous clinical trials with the drugs that 
are used in the current study (GDC-0449, nab-Paclitaxel and Gemcitabine) and can be  
expected during the study. 
 
7.4.1 Adverse Event List(s) for GDC-0449 
 
The toxicities possibly related to GDC-0449 reported in previous phase 1 clinical trial 
included:  
 
• Constitutional: Fatigue, weight loss 
 


Protocol Amendment 12, date December 4, 2014 
54
• Cardiovascular: atrial fibrillation 
 
• Gastrointestinal: anorexia, dyspepsia (heartburn or stomach upset), nausea, vomiting 
 
• Metabolic: hyponatremia, hypomagnesemia 
 
• Neurologic: hypoesthesia (sensory neuropathy), dysgeusia (taste alteration), hypogeusia 
(decrease taste), ageusia (loss of taste), numbness 
 
• Musculoskeletal: arthralgia, muscle spasms 
 
• Skin and subcutaneous tissue disorders: skin exfoliation, alopecia (scalp, body, 
eyelashes and face), dermatitis acneiform 
 
GDC-0449 has been administered in a limited number of clinical studies. The following 
adverse events had been observed in animal studies. The adverse events of GDC-0449 
with other combinations chemotherapy are not known. Several studies in humans 
combining GDC-0449 with other chemotherapy agents are currently underway. 
 
 
Dogs: 
Decreased platelets; prolonged QTc; increased salivation; increased cholesterol; 
proteinuria; weight loss; weight gain; foamy vomitus; orange mucoid feces; alopecia, 
increased male germ cell degeneration in seminiferous tubules and epididymides, 
decreased sperm motility and decreased number of corpora lutea. 
 
Rats: 
Hunched appearance; increased stomach weight; weight gain; weight loss; rough 
haircoat; dehydration; few feces; increased incidence of malocclusion; microscopic 
lesions on incisors; hyperalbuminemia; increased cholesterol; decreased alkaline 
phosphatase; decreased grip strength; decreased motor activity; reversible mild body 
tremors (male), twitching, ataxia.  
 
Note: GDC-0449 in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
Teratogenic Effects of GDC-0449 
Studies have demonstrated that inhibition of the Hh pathway in embryos results in brain, 
facial, and other midline defects, including holoprosencephaly or microencephaly, 
cyclopia, absent nose, cleft palate, tooth abnormalities, and bone development 
abnormalities.  While the effects of GDC-0449 on the developing human fetus at the 
recommended therapeutic dose are unknown, women of childbearing potential and men 
must agree to use two methods of contraception (i.e., barrier contraception and another 
method of contraception) prior to study entry, for the duration of study participation, and 
for 7 months following treatment. 


Protocol Amendment 12, date December 4, 2014 
55
 
Women of childbearing potential are defined as follows: 
 Patients with regular menses 
 Patients with amenorrhea, irregular cycles, or using a contraceptive method that 
precludes withdrawal bleeding 
 Women who have had a tubal ligation 
 
Women are considered not to be of childbearing potential for the following reasons: 
 The patient has undergone hysterectomy and/or bilateral oophorectomy. 
 The patient is post-menopausal defined by amenorrhea for at least 1 year in a woman > 
45 years old. 
 
Women of childbearing potential are required to use two forms of acceptable 
contraception (refer to Appendix B), including one barrier method during participation in 
the study and for the 12 months following the last dose.  Women of childbearing potential 
are also advised to have monthly pregnancy tests for 7 months after discontinuation of 
GDC-0449.  All patients should receive contraceptive counseling either by the 
investigator or by an OB/gynecologist or other physician who is qualified in this area of 
expertise.  If a woman of childbearing potential believes that her contraceptive method 
has failed, emergency contraception should be considered. 
 
If a patient is suspected to be pregnant, GDC-0449 should be IMMEDIATELY 
discontinued and the study physician contacted.  A positive urine test must be confirmed 
by a serum pregnancy test.  If it is confirmed that the patients is not pregnant, the patient 
may resume dosing with GDC-0449.   
 
If a female patient becomes pregnant during therapy or within 7 months after the 
last dose of GDC-0449, or if the female partner of a male patient exposed to the 
drug becomes pregnant while the male patient is receiving GDC-0449 or within 7 
months after the last dose of GDC-0449, the investigator must be notified in order to 
facilitate outcome follow-up. 
 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious.  Any congenital anomaly/birth defect in a child conceived during the study or 
within 7 months after the last dose of GDC-0449 to a female patient or to a female 
partner of a male patient exposed to the agent during treatment or within 7 months after 
the last dose of GDC-0449 should be recorded and reported as an SAE. 
 
In addition, it is not known whether GDC-0449 that may be present in seminal fluid 
would cause teratogenic effects in a fetus born to the female partner of a male subject.  
Sexually active male subjects should utilize a barrier form of contraception, even those 
who have had a vasectomy, during study treatment and for 7months after the last dose.  
Male patients should advise their partners to use an additional method of contraception 
during the study and for at least 7 months after discontinuation of GDC-0449.  Male 
subjects should also not donate sperm during treatment or up to 7 months after the last 
dose. 


Protocol Amendment 12, date December 4, 2014 
56
 
 
 
Risk of Male Germ Cell Degeneration 
Effects on testes and epididymides characterized by mild to moderate germ cell 
degeneration in seminiferous tubules, relative paucity of spermatozoa, and increased 
cellular debris in epididymides were observed in male dogs at all dose levels tested and 
were consistent with the pharmacologic activity of the drug.  There were no changes in 
Leydig or Sertoli cells in any animal.  Evidence of partial recovery was noted after a 4-
week recovery period. 
 
Germ cell degeneration in male patients is likely to occur at pharmacologically active 
doses.  There is no specific mitigation strategy for this GDC-0449 toxicity; however, 
male patients should be made aware of it during the consent process. Although this effect 
is expected to be reversible with discontinuation of dosing, long-term effects on male 
fertility cannot be excluded at this time. 
 
 
7.4.2 Adverse Event List(s) for nab-Paclitaxel 
 
The most common toxicities reported in previous clinical trials included:  
 
•  
Myelosuppression, predominantly neutropenia. Grade 4 neutropenia was reported 
and typically resolved in < 7 days and did not require colony stimulating factor support.  
 
•  
Peripheral neuropathy, predominantly sensory. Grade 3 peripheral neuropathy 
was reported and typically improved to Grade 1 or 2 within 21 days of interrupting the 
nab-Paclitaxel dose. Following resolution of the peripheral neuropathy to acceptable 
levels, clinicians were able to restart nab-Paclitaxel dosing at a lower dose levels.  
 
•  
Nausea and vomiting. Nausea and vomiting were seen, typically at Grade 1 or 2 
levels. This AE responded well to standard anti-emetic regimens.  
 
•  
Myalgias and arthralgias. Myalgias and arthralgias were reported and typically 
were Grade 1 or 2; these were responsive to standard acetaminophen-containing 
medication. 
 
•  
Mucositis. Mucositis was reported typically Grade 1 or 2. It was not dose limiting 
 
•  
Alopecia. Alopecia was reported by most patients and was similar to that seen 
with Taxol. 
 
7.4.3 Adverse Event List(s) for Gemcitabine 
 
The most common toxicities reported with gemcitabine are: 
 
• 
Hematologic - In studies in pancreatic cancer, myelosuppression is the dose-
limiting toxicity with Gemzar®, but <1% of patients discontinued therapy for anemia, 


Protocol Amendment 12, date December 4, 2014 
57
leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of 
patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss 
(hemorrhage), from any cause, was reported in 16% of patients; less than 1% of patients 
required platelet transfusions. Patients should be monitored for myelosuppression during 
Gemzar therapy and dosage modified or suspended according to the degree of 
hematologic toxicity   
 
• 
Gastrointestinal - Nausea and vomiting were commonly reported (69%) but were 
usually of mild to moderate severity. Severe nausea and vomiting (WHO Grade 3/4) 
occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis 
by 11% of patients.   
 
 
• 
Hepatic - In clinical trials, Gemzar was associated with transient elevations of one 
or both serum transaminases in approximately 70% of patients, but there was no evidence 
of increasing hepatic toxicity with either longer duration of exposure to Gemzar or with 
greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, 
has been reported very rarely in patients receiving Gemzar.   
 
• 
Renal - In clinical trials, mild proteinuria and hematuria were commonly reported. 
Hemolytic Uremic Syndrome (HUS) has been reported rarely (0.25%) with the use of 
Gemzar. Renal failure may not be reversible even with discontinuation of therapy and 
dialysis may be required.  
 
 
• 
Fever - The overall incidence of fever was 41%. This is in contrast to the 
incidence of infection (16%) and indicates that Gemzar may cause fever in the absence of 
clinical infection. Fever was frequently associated with other flu-like symptoms and was 
usually mild and clinically manageable.   
 
• 
Rash - Rash was reported in 30% of patients. The rash was typically a macular or 
finely granular maculopapular pruritic eruption of mild to moderate severity involving 
the trunk and extremities. Pruritus was reported for 13% of patients.  
 
• 
Pulmonary- In clinical trials, dyspnea, unrelated to underlying disease, has been 
reported in association with Gemzar therapy. Dyspnea was occasionally accompanied by 
bronchospasm. Pulmonary toxicity has been reported with the use of Gemzar. The 
etiology of these effects is unknown. If such effects develop, Gemzar should be 
discontinued. Early use of supportive care measures may help ameliorate these 
conditions. 
• 
Neurotoxicity - There was a 10% incidence of mild paresthesias and a <1% rate of 
severe paresthesias 
 
• 
Edema: Edema (13%), peripheral edema (20%) %), and generalized edema (<1%) 
were reported. Less than 1% of patients discontinued due to edema. 
 
• 
Flu-like Symptoms - “Flu syndrome” was reported for 19% of patients. Individual 


Protocol Amendment 12, date December 4, 2014 
58
symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia were commonly 
reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, 
rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients 
discontinued due to flu-like symptoms.   
 
• 
Infection - Infections were reported for 16% of patients. Sepsis was rarely reported.   
 
• 
Alopecia- Hair loss, usually minimal, was reported by 15% of patients 
 
Please see gemcitabine prescribing information for more details on the known 
precautions, warnings, and adverse reactions of gemcitabine (current version of 
Prescribing Information is provided in the Study Manual). 
 
7.5 Reporting Adverse Events 
 
The Investigator is responsible for recording, reporting and following all adverse events, regardless 
of causality, observed during the study period, starting with initial study drug administration and 
ending at the time the patient goes off study or 30 days after patient’s last dose of study drug, 
whichever is later. Events occurring within 30 days prior to study drug administration should be 
recorded as pre-treatment signs and symptoms. 
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, are collected and reported to the FDA, appropriate IRB(s), and Genentech, Inc. in 
accordance with CFR 312.32 (IND Safety Reports). 
 
“Lack of efficacy” (progressive disease) is not considered an adverse event. The signs and symptoms 
or clinical sequelae resulting from lack of efficacy should be reported if they fulfill the adverse event 
or SAE definitions. 
 
Laboratory Results as Serious Adverse Events 
 
According to the NCI CTCAE system of adverse event grading, laboratory values of Grade 3 or 4 
are described as “severe” or “life-threatening.” For example, a neutrophils count <500/mm3 would 
meet laboratory criteria as Grade 4 (“life-threatening”). This description is not always synonymous 
with the assessment of the “serious” criteria of an AE as “life threatening”. 
 
In order for adverse events to be considered serious by “life-threatening” criteria, it must be 
medically judged as possessing “an immediate risk of death from the event as it occurred,” not 
because of the theoretical potential for life-threatening consequences. In the case of a neutrophil 
count <500/mm3, the AE would be captured as an AE of Grade 4 neutropenia, but it would not 
automatically be considered a SAE unless the investigational physician determined this represented 
an immediately life-threatening event for the patient. 
 
Specifically, uncomplicated Grade 4 neutropenia should not be reported as a SAE. 
Neutropenia associated with fever, infection, or hospitalization should be reported as a SAE. 
 


Protocol Amendment 12, date December 4, 2014 
59
Investigator Reporting of AEs and SAEs 
 
The Investigator or designee must completely and promptly record each adverse event using the 
eCRF, regardless of relationship to study drug as determined by the Investigator. The Investigator 
must assess AE/SAE causality for any patients treated at his/her site. The Investigator should 
attempt, if possible, to establish a diagnosis based on the patient's signs and symptoms. When a 
diagnosis for the reported signs or symptoms is known, the Investigator should report the diagnosis, 
not the symptoms, as the adverse event. 
 
Clinically significant laboratory abnormalities present at the Baseline visit will be recorded as pre-
treatment signs and symptoms. After study treatment administration, laboratory abnormalities will 
not be recorded as adverse events unless considered clinically significant by the Investigator, and 
clinically significant laboratory abnormalities will not be recorded as serious AEs unless the event 
meets the definition of serious. 
 
AEs and SAEs should be reported on the electronic Case Report Forms provided by CRAB.  
 
Reporting Serious Adverse Events (SAEs) 
 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and initiation of study treatment [or “initiation of any study procedures”] and ends 30 days 
[or insert other time period] following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators should only report 
SAEs that are attributed to prior study treatment. 
 
ALL sites should report ALL Serious adverse events, regardless of causality, to ALL of the 
following: 
 
1. Coordinating Site (Johns Hopkins Hospital) 
2. Genentech Safety Group 
3. Cancer Research and Biostatistics (CRAB) 
4. Institution IRB 
 
Timelines for reporting SAE’s 
 
1. Participating sites are responsible for reporting SAE’s to the Coordinating Site (Johns 
Hopkins) within 24 hours of becoming aware of the event occurrence.  All SAEs should be 
recorded on the Serious Adverse Event Reporting Form accessible on the website. This 2 page 
form must be completed and faxed to: 
 
Study Coordinating Site 
Daniel Laheru MD (Prinicipal Investigator) 
Yvette Cetasaan, CCRP  
Fax: 443-287-6566 
 


Protocol Amendment 12, date December 4, 2014 
60
2. Participating sites are responsible for reporting to their Institution IRB in accordance with their 
institution guidelines.  
 
3. Participating sites are responsible for reporting to the Genentech Safety Group by facsimile 
within 24 hours of becoming aware of the event occurrence.  All SAEs should be recorded on 
CRAB eCRF and faxed to: 
 
Genentech Drug Safety  
Fax: (650) 225-4682 or (650) 225-5288 
 
4. Participating sites are responsible for reporting to Cancer Research and Biostatistics (CRAB) 
within 24 hours of becoming aware of the event occurrence.  All SAEs should be recorded on 
CRAB eCRF. 
 
The Johns Hopkins Investigators will report all SAEs on CRAB eCRF and faxed to all the following 
agencies: 
 
1. IRB- within 3 days if the SAE is related to the study drug. If the SAE is not considered related to 
the study drug within 10 days.  
 
 
Johns Hopkins Medicine IRB 
Reed Hall B-130 
1620 McElderry St. 
Baltimore, MD 21205-1911 
Phone: 410-955-3008 
 
2. Genentech Drug Safety- within 24 hrs  
Fax: (650) 225-4682 or (650) 225-5288 
 
3. FDA- .  As per section 7.6 
 
4. CRAB- within 24 hrs 
 
Follow up on SAE reports should also be send to all the above agencies within two weeks of receipt 
of information at the site. 
 
Investigators must report all SAEs to Genentech within the timelines described below. The 
completed Medwatch/case report should be faxed immediately upon completion to Genentech Drug 
Safety at: 
 
(650) 225 4682 
OR 
(650) 225 5288 
 
• 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 


Protocol Amendment 12, date December 4, 2014 
61
becomes available. 
• 
Serious AE reports that are related to the [study drug] and AEs of Special Interest (regardless of 
causality)  will be transmitted to Genentech within fifteen (15) calendar days of the Awareness Date. 
• 
Serious AE reports that are unrelated to the [study drug] will be transmitted to Genentech within 
thirty (30) calendar days of the Awareness Date. 
• 
Additional Reporting Requirements to Genentech include the following: 
• 
Any reports of pregnancy following the start of administration with the [study drug] will be 
transmitted to Genentech within thirty (30) calendar days of the Awareness Date.  
• 
All Non-serious Adverse Events originating from the Study will be forwarded in a quarterly 
report to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational product 
and suspect medication 
 
Follow-up Information 
 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  
 
 


Protocol Amendment 12, date December 4, 2014 
62
• 
Summarizing new information and faxing it with a cover letter including patient identifiers (i.e. 
D.O.B. initial, patient number), protocol description and number, if assigned, brief adverse event 
description, and notation that additional or follow-up information is being submitted (The patient 
identifiers are important so that the new information is added to the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or current 
status of the patient for whom and adverse event was reported. For questions regarding SAE 
reporting, you may contact the Genentech Drug Safety representative noted above or the MSL 
assigned to the study. Relevant follow-up information should be submitted to Genentech Drug Safety 
as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm 
 
 
7.6  Safety Reporting Requirements for IND Holders 
 
For Investigator Sponsored IND Studies, there are some additional reporting requirements for the 
FDA in accordance with the guidance set forth in 21 CFR 212.32. Sponsor-investigators of studies 
conducted under an IND must comply with the following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse event 
that is unexpected and assessed by the investigator to be possibly related to the use of GDC-
0449.  An unexpected adverse event is one that is not already described in the Investigator Brochure.  
Such reports are to be telephoned or faxed to the FDA and Genentech within 7 calendar days of first 
learning of the event.  Each telephone call or fax transmission (see fax number below) should be 
directed to the FDA new drug review division in the Center for Drug Evaluation and Research or in 
the product review division for the Center for Biologics Evaluation and Research, whichever is 
responsible for the review of the IND. 
 
15 Calendar-Day Written Report:   
The Sponsor-Investigator is also required to notify the FDA and all participating investigators, in a 
written IND Safety Report, of any serious, unexpected AE that is considered possibly related to the 
use of GDC-0449.  An unexpected adverse event is one that is not already described in the 
Investigator Brochure. 
 
Written IND Safety Reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning similar 
events should be analyzed.  The new report should contain comments on the significance of the new 
event in light of the previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech Drug Safety, and all participating investigators within 15 calendar days of first learning 


Protocol Amendment 12, date December 4, 2014 
63
of the event.   In this study electronic CRF will be used. 
 
FDA fax number for IND Safety Reports: 
1 (800) FDA - 0178 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must also be 
faxed to: 
 
1. Genentech Drug Safety  
Fax: (650) 225-4682 or (650) 225-5288 
For questions related to safety reporting, contact: 
 
Genentech Drug Safety 
Tel: 
1-888-835-2555 
 (Please use the safety reporting fax cover sheet attached to this document for your fax transmission) 
 
b. IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator shall within 60 days of 
the anniversary date that the IND went into effect submit a brief report of the progress of the 
investigation.  Please refer to Code of Federal Regulations, 21 CFR § 312.32 for a list of the 
elements required for the annual report.  All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to Genentech.  Copies of such reports should be mailed to: 
 
Genentech, Inc. 
ATTN: GDC-0449 IST Coordinator  
1 DNA Way, Mailstop 445-A 
South San Francisco, CA 94080-4990  
Tel: (650) 225-7121 (Oncology Hotline) 
 
STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to Genentech. 
This includes all IND annual reports and the Clinical Study Report (final study report). Additionally, 
any literature articles that are a result of the study should be sent to Genentech. Copies of such 
reports should be mailed to the assigned Clinical Operations contact for the study: 
 
 
Vismodegib (GDC0449) Protocols 
Email: hedgehog-gsur@gene.com 
Fax: 866-741-3639 
7.7 Data and Safety Monitoring Plan 
 
This is a Level II study under the SKCCC Data Safety Monitoring Plan (DSMP).  Data Monitoring 
of this study will occur after the first three patients are enrolled and every six months thereafter.   
 
The study will be monitored internally by the Principal Investigator and externally by CRO in 


Protocol Amendment 12, date December 4, 2014 
64
accordance with SKCCC guidelines.   
 
7.7.1     Internal review in all participating centers 
 
The PI in each participating center will have a regular internal monitoring. 
 
The internal review should occur after the first three patients are enrolled and have completed two cycles 
of therapy. The process should occur every six months thereafter. The PI at each institution will review 
data to assure the validity of data, as well as, the safety of the subjects. The PI will also monitor the 
progress of the trial. The PI will review safety reports and clinical trial efficacy endpoints and to 
confirm that the safety outcomes favor continuation of the study. 
  
The PI will be responsible for maintaining the clinical protocol, reporting adverse events, assuring 
that consent is obtained and documented, reporting of unexpected outcomes, and reporting the status 
of the trial in the annual report submitted to the IRB. Content of the report will include year-to-date 
and full trial data on: accrual and eligibility, protocol compliance, treatment administration, toxicity 
and adverse events, response, survival, regulatory compliance, compliance with prearranged 
statistical goals. The following will be reviewed: 
 
- Original, signed consent forms to ensure that one is available for each subject.  
 
- Case report forms and source documentation for validity and consistency in the completed entries, 
as well as, accuracy, legibility, signatures and dates.  
 
- Treatment administration records to ensure concurrence between dispensing records and CRFs as 
to subject identity, and dosage of study drug administered.  
 
- Compliance with the protocol will also be checked.  
 
- Pharmacy drug accountability records for accuracy and completeness, and study drug storage to 
ensure proper maintenance and supply levels.  
 
7.7.2  External review in all participating centers 
 
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO in accordance 
with SKCCC guidelines.  Trial monitoring and reporting will be done through the Safety Monitoring 
Committee (SMC) at SKCCC.  
 
Participating sites: The protocol will be monitored by an external CRO (TD2). A report of the reviews 
will be submitted to Johns Hopkins principal investigator and SKCCC CRO.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 


Protocol Amendment 12, date December 4, 2014 
65
8.1 GDC-0449 
 
Route of Administration: 
Oral 
 
Mode of Action:  
GDC-0449 provides anticancer responses by inhibiting the 
Hedgehog pathway.  The Hedgehog signaling pathway 
controls cell differentiation, growth, and proliferation.  It is 
most active during embryogenesis but may also play a role in 
the regulation of adult stem cells involved in the maintenance 
and regeneration of adult tissues. 
 
How Supplied:   
GDC-0449 is supplied by Genentech/ JHH Investigational 
Drug Services (IDS). It is available as:  
 25-mg 
orange, 
size 
3 
capsules 
containing 
microcrystalline cellulose, sodium lauryl sulfate, talc, sodium 
glycolate and magnesium stearate as excipients.   
 150-mg grey and pink, size 1 capsules containing 
microcrystalline cellulose, lactose monohydrate, sodium 
lauryl sulfate, povidone, talc, sodium glycolate, and 
magnesium stearate.  
Capsules are packaged in 75-mL round, white, high-density 
polyethylene (HDPE) bottles and closed with 38/400 two-
piece HDPE child-resistant caps.  Each bottle contains 32 
capsules. 
 
                      Clinical Formulation: 
For the clinical studies, hard gelatin capsules containing 150 
mg vismodegib are available. For the 150 mg strength, 
placebo capsules are also available. 
 
The 150-mg vismodegib drug product is a hard gelatin 
capsule formulation for oral administration. The capsule fill 
consists of vismodegib and the following excipients: 
microcrystalline cellulose PH101, lactose monohydrate, 
sodium lauryl sulfate, 
povidone K29/32, sodium starch glycolate, talc, magnesium 
stearate, and purified water. All of these excipients are 
compendial (USP/NF-EP) grade. The capsule shell consists 
 
of gelatin, red iron oxide, black iron oxide, and 
titanium dioxide. A compendial-grade black printing ink may 
be used. 
 
The placebo for the 150-mg drug product is a hard gelatin 
capsule formulation for oral administration. The capsule fill 
consists of the following excipients, without the active 
pharmaceutical ingredient (API): microcrystalline cellulose 
PH102, lactose monohydrate, sodium lauryl sulfate, sodium 


Protocol Amendment 12, date December 4, 2014 
66
starch glycolate, talc, and magnesium stearate. All of these 
excipients are compendial (USP/NF-EP) grade. The capsule 
shell consists of gelatin, red iron oxide, black iron oxide, and 
titanium dioxide. A compendial-grade black printing ink may 
be used. 
 
Storage:   
GDC-0449 capsules should be stored in the recommended 
storage conditions at 59°F and 86°F (15°C and 30°C) and 
should 
be 
protected 
from 
excessive 
exposure 
to 
light. Information on the shelf life of the capsules is provided 
on the label. 
 
Drug Administration:           Patients should take GDC-0449 at approximately the  
                        same time each day, with or without food.  If a patient  
                       misses a dose (e.g., due to emesis), he or she should  
                        be instructed not to take or make up that dose and to  
                         resume dosing with the next scheduled dose.  Missed  
                       doses should not be made up.  
 
Patient Care Implications:  The terminal half-life of GDC-0449 is currently unknown, 
but is expected to be longer than 1 week, and may be as high 
as 2 to 3 weeks.  If plasma levels of GDC-0449 need to be 
lowered emergently, animal studies suggest that oral 
administration of activated charcoal may lower drug plasma 
levels more quickly than dose cessation alone. 
 
Drug Interactions:   
Avoid any concurrent drug metabolized by  
                         cytochrome P450 that has a narrow therapeutic index. 
 
Supply:                                  GDC-0449 will be obtained from JHH IDS. 
 
 
 
8.2 nab-Paclitaxel 
 
Route of Administration: 
Intravenous 
 
Packaging, Labeling, and Storage of Study Drug:     
 
Nab-Paclitaxel will be supplied by Abraxis BioScience (Abraxis) 
/JHHIDS, in single-use vials. Each single-use 50 mL vial will contain 
paclitaxel (100 mg) and approximately 900 mg human albumin (HA) as a 
stabilizer. Each vial will be labeled according to country-specific 
regulatory requirements for labeling of investigational products. 
Unreconstituted nab-paclitaxel should be stored at controlled room 
temperature (25°C or 77°F; excursions permitted to 15- 30ºC [See USP 


Protocol Amendment 12, date December 4, 2014 
67
controlled room temperature]). Reconstituted nab-paclitaxel should be 
used immediately. If not used immediately, the vial of reconstituted Nab-
Paclitaxel must be placed in its carton and be placed in a refrigerator at 2° 
to 8°C (36° to 46°F) for a maximum of 8 hours. Both forms should be 
stored in an area free of environmental extremes and must be accessible 
only to study personnel. Temperature records for nab-paclitaxel must be 
made available to the Abraxis or other sponsor nominated monitoring 
teams for verification of proper study drug storage.  
 
 
 
 
Administration 
 
NOTE: It is not a requirement to use filter needles in the preparation 
of, or in-line filters during the administration of nab-paclitaxel. In any 
event, filters of pore-size less than 15 micrometers must not be used. 
 
nab-paclitaxel will be reconstituted by appropriate study personnel and 
administered to the patient at the study site. The Investigator will calculate 
the body surface area (BSA) of the patient in order to determine the total 
amount of paclitaxel to be administered. 
 
Reconstitution and use of nab-paclitaxel: 
 
1. Calculate the patient’s BSA according to standard institutional methods. 
BSA will be calculated at Baseline and recalculated only if body weight 
changes by more than 10%. Dosing BSA may be capped if the treating 
physician believes it is in the best interest of an obese patient. 
 
2. Calculate the total dose (in mg) to be administered by: 
Total Dose (mg) = BSA x (study dose mg/m2) 
 
3. Calculate the total number of vials required by: 
Total Number of Vials = Total Dose (mg) 100 (mg/vial) 
Round up the number of vials to be reconstituted to the next higher whole 
number when a fractional number of vials is obtained by the above 
formula (e.g., if the total number of vials = 4.05 or 4.5, then 5 vials would 
be reconstituted). 
 
4. Using sterile technique, prepare the vials for reconstitution. 
 
5. Swab the rubber stoppers with alcohol. 
 
6. Reconstitute each nab-paclitaxel vial by using a 50 or 60 cc sterile 
syringe to inject 20 mL of 0.9% Sodium Chloride Injection or equivalent 


Protocol Amendment 12, date December 4, 2014 
68
into each vial over a period of not less than 1 minute (Note: Change the 
syringes after reconstituting every 3 vials). 
 
◦ Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, over a 
minimum of 1 minute, using the sterile syringe directing the solution flow 
onto the inside wall of the vial. 
 
◦ DO NOT INJECT the 0.9% Sodium Chloride Injection solution directly 
onto the lyophilized cake as this will result in foaming. 
 
◦ Once the injection is complete, allow the vial to sit for a minimum of 5 
minutes to ensure proper wetting of the lyophilized cake/powder. 
 
◦ Gently swirl and/or invert the vial slowly for at least 2 minutes until 
complete dissolution of any cake/powder occurs. Avoid generation of 
foam. 
 
◦ If foaming or clumping occurs, stand solution for at least 15 minutes 
until foam subsides. 
 
◦ Each mL of reconstituted product will contain 5 mg of paclitaxel. 
 
7. Calculate the exact total dosing volume of 5 mg/mL suspension 
required for the patient: 
Dosing volume (mL) = Total dose (mg) / 5 (mg/mL) 
 
8. The reconstituted sample should be milky and homogeneous without 
visible particulates. If unsuspended powder is visible, the vial should be 
gently inverted again to ensure complete resuspension, prior to use. 
 
9. Use immediately following reconstitution. If not used immediately, 
replace the reconstituted vial in the carton and store reconstituted nab-
Paclitaxel in a refrigerator for not more than 8 hours. 
 
10. Using a new, sterile 50 or 60 cc syringe, withdraw the reconstituted 
nab-Paclitaxel solution. Do not remove the rubber stopper from the nab-
Paclitaxel vials as this can compromise the sterility of the drug 
preparation. 
 
11. Inject the calculated dosing volume of reconstituted nab-Paclitaxel 
suspension into an empty sterile, standard PVC IV bag, using an injection 
port. Inject perpendicularly into the center of the injection port to avoid 
dislodging plastic material into the IV bag. Repeat steps 9 and 10 until the 
patient’s entire required dose is injected into the IV bag. 
 
12. Remove the injection port. 


Protocol Amendment 12, date December 4, 2014 
69
 
13. Once the exact volume of reconstituted nab-Paclitaxel has been 
withdrawn from the vials, discard any excess solution left over in 
accordance with standard operating procedures for cytotoxic drugs. 
 
14. Administer the calculated dosing volume of reconstituted nab-
Paclitaxel suspension by IV infusion over 30 minutes. The use of in-line 
filters is not necessary; if used, in-line filters with pore sizes of < 15 
microns (15 μm) should not be used. 
 
Supply:            nab-Paclitaxel will be obtained from JHH IDS. 
 
 
8.3  
Gemcitabine 
 
Route of Administration: 
Intravenous 
 
Description: 
For 
complete 
details 
on 
drug 
administration, 
storage, 
clinical 
pharmacology, and the human pharmacokinetics of gemcitabine, please 
see the gemcitabine package insert (current version of Prescribing 
Information is provided in the Study Manual). 
 
Formulation: 
Gemcitabine (difluorodeoxycytidine) is a pyrimidine  
antimetabolite, which is an analogue of deoxycytidine. It was initially 
synthesized as a potential antiviral drug but selected for anticancer 
development because of its activity in in-vivo and in vitro tumors. 
Gemcitabine is approved for the treatment of patients with pancreatic 
cancer and will be obtained commercially. Gemcitabine should be 
stored, reconstituted and administered according to the manufacturer’s 
recommendation 
 
Packaging, Labeling, and Storage of Gemcitabine:     
 
Instructions for Storing Gemcitabine 
Store at controlled room temperature (20° to 25°C) (68° to 77°F). The 
USP has defined controlled room temperature as “A temperature 
maintained thermostatically that encompasses the usual and customary 
working environment of 20° to 25°C (68° to 77°F); that results in a mean 
kinetic temperature calculated to be not more than 25°C; and that allows 
for excursions between 15° and 30°C (59° and 86°F) that are experienced 
in pharmacies, hospitals, and warehouses.” 
 
Administration: 
 


Protocol Amendment 12, date December 4, 2014 
70
Preparation and administration of gemcitabine should be per the 
gemcitabine package insert (current version of Prescribing Information is 
provided in the Study Manual). 
 
Instructions for Use/Handling of Gemcitabine 
The recommended diluent for reconstitution of gemcitabine is 0.9% 
Sodium Chloride Injection without preservatives. Due to solubility 
considerations, the maximum concentration for gemcitabine upon 
reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 
40 mg/mL may result in incomplete dissolution, and should be avoided. 
To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-
mg vial or 25 mL of 0.9% Sodium Chloride Injection to the 1-g vial. 
Shake to dissolve. These dilutions each yield a gemcitabine concentration 
of 38 mg/mL which includes accounting for the displacement volume of 
the lyophilized powder (0.26 mL for the 200-mg vial or 1.3 mL for the 1-g 
vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, 
respectively. Complete withdrawal of the vial contents will provide 200 
mg or 1 g of gemcitabine, respectively. The appropriate amount of drug 
may be administered as prepared or further diluted with 0.9% Sodium 
Chloride Injection to concentrations as low as 0.1 mg/mL. Reconstituted 
gemcitabine is a clear, colorless to light straw-colored solution. After 
reconstitution with 0.9% Sodium Chloride Injection, the pH of the 
resulting solution lies in the range of 2.7 to 3.3. The solution should be 
inspected visually for particulate matter and discoloration, prior to 
administration, whenever solution or container permits. If particulate 
matter or discoloration is found, do not administer.  
 
When prepared as directed, gemcitabine solutions are stable for 24 hours 
at controlled room temperature 20° to 25°C (68° to 77°F) [See USP]. 
Discard unused portion. Solutions of reconstituted gemcitabine should not 
be refrigerated, as crystallization may occur. The compatibility of 
gemcitabine with other drugs has not been studied. No incompatibilities 
have been observed with infusion bottles or polyvinyl chloride bags and 
administration sets. Unopened vials of gemcitabine are stable until the 
expiration date indicated on the package when stored at controlled room 
temperature 20° to 25°C (68° to 77°F) [See USP]. 
 
Supply:           Will be obtained by commercial means 
 
 
 
 
 
 
 


Protocol Amendment 12, date December 4, 2014 
71
8.3  
Study Medication Accountability and Destruction  
(GDC-0449 and nab-Paclitaxel) 
 
All study drug required for completion of this study will be provided by Johns Hopkins Hospital (JHH) 
Investigational Drug Services (IDS).  
 
The recipient will acknowledge receipt of the drug by returning the appropriate documentation form 
indicating shipment content and condition. Damaged supplies will be replaced. 
 
Accurate records of all study drug received at, dispensed from, returned to and disposed of by the study 
site should be recorded by using the Drug Inventory Log. Inspections of the study drug supply for 
inventory purposes and assurance of proper storage will be conducted as necessary. Any significant 
discrepancy will be recorded and reported to JHH IDS or their designee and a plan for resolution will be 
documented. 
 
Study drugs will not be loaned or dispensed by the Investigator to another Investigator or site, unless 
specifically requested by JHH IDS in writing. 
 
Temperature records for nab-Paclitaxel must be made available to the JHH IDS or other Sponsor 
nominated monitoring teams for verification of proper study drug storage. 
 
Only completely unused study drug vials (nab-Paclitaxel) should be retained by the site until a 
representative from JHH IDS or other JHH IDS-designated personnel have completed an inventory. 
Partially used and completely used vials should be destroyed according to the site’s guidelines, and their 
disposition should be recorded on the Investigational Drug Accountability Record Form. 
 
Study drug will either be disposed of at the study site according to the study site’s institutional standard 
operating procedure or returned to JHH IDS with the appropriate documentation. JHH IDS or someone 
else designated by the JHH IDS will personally inspect the study drug inventories before returning or 
destroying supplies of either medication. If the study site chooses to destroy study drug, the method of 
destruction must be documented and JHH IDS must evaluate and approve the study site’s drug 
destruction standard operating procedure prior to the initiation of drug destruction by the study site. 
 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Laboratory Correlative Studies 
 
We will evaluate two sources of patient material (tumor core biopsies and blood) in order to 
evaluate the effects of GDC-0449 on the tumor-initiating CSC compartment in treated tumors.  
We will also evaluate the effects combination therapy with nab-paclitaxel on circulating 
biomarker levels, including CA 19-9 and SPARC.  Tumor core biopsies and blood samples will 
be obtained pre- and post-treatment in patients.  
 
Biopsies:  Pre-treatment biopsies will be done at screening within 14 days before starting cycle 
1. The second post-treatment biopsy will occur after two months of being on the study.  


Protocol Amendment 12, date December 4, 2014 
72
 
Patients who  have response to therapy (partial response or complete response) but then subsequently 
develop disease progression while on treatment may be asked to provide an optional third biopsy. 
This will be utilized to evaluate the hedgehog signaling pathway markers (section 9.1.5.3) or tests to 
evaluate for mechanisms of acquired resistance.  
 
9.1.1 Specimen collection techniques 
 
9.1.1.1. Core biopsy of tumor tissue 
 
9.1.1.1.1 Patient preparation instructions for core biopsy procedure 
 
Detailed instructions may be provided to patients who are planning to have a tumor biopsy and 
their health care providers. A tumor biopsy eligibility checklist will be completed prior to the 
tumor biopsies by a member of the clinical study team. 
 
Medication and Supplement Restrictions: 
 Must be off Plavix, Coumadin, aspirin and aspirin-containing medications, herbal, fish oil based 
(omega 3), and vitamin E supplements for 7 days prior to procedure 
 Must be off all non-steroidal anti-inflammatory drugs (NSAIDs) for 4 days prior to procedure 
(this includes but is not limited to ibuprofen, naproxen, celecoxib, indomethacin, etodolac 
 Must be off Heparin for 6 hours prior to procedure. 
 
Labwork: 
 PT/PTT, and the platelet level must be within normal ranges within 7 days of the procedure. 
 
Day of Procedure Restrictions: 
 If procedure is in the morning, NPO after 12 midnight, 
 If procedure is in the afternoon, may have a liquid breakfast only 
 
9.1.1.1.2. Biopsy Procedure 
Biopsies will be done by routine U/S or CT-guided procedures depending on the imaging 
characteristics of the area to be biopsied. 18-22 G core biopsy needles will be used, and 2-4 
samples will be obtained from the lesion.  Prior to biopsy, potential biopsy "targets" will be 
evaluated by a radiologist, to assess whether the lesion can be safely biopsied.  
 
Analgesia and Anesthesia 
Local anesthesia will be achieved with lidocaine 2% injection. Post-procedure analgesia, which 
is rarely needed, will consist of acetaminophen (<3 gm total in any 24-hour period), NSAID’s 
(for patients with platelet count > 50,000 mm3 without overt bleeding), or oxycodone as needed. 
Unexpectedly severe post-procedure pain will be immediately evaluated by the study subject’s 
primary oncologist or research personnel. 
 
Anatomical sites to be biopsied 
Biopsies will be obtained only from sites that constitute minimal risk to the subject. The biopsy 
service will make the final decision independent of the principal investigator or co-investigators.  


Protocol Amendment 12, date December 4, 2014 
73
It is not possible to designate every conceivable site, but acceptable areas include:  
 liver metastasis (not immediately adjacent to major vessels) 
 peripheral accessible lymph nodes (cervical, axillary, inguinal, extremities) 
 Primary pancreatic mass by Endoscopic ultrasound and core biopsy 
 
Of these, the liver is the most commonly biopsied site in patients with advanced pancreatic 
cancer, in our experience.  Sites that will not be biopsied for research purposes only include: 
- lung 
- brain 
- mediastinum 
- intra-pelvic viscera 
- any site deemed by the patient’s primary oncologist, study investigator, or radiologist to 
represent greater than minimal risk to the subject. 
 
JHH/JHU and Published Experience 
At Johns Hopkins, the following data is available regarding biopsy complication rates. This data 
was compiled by the biopsy service for fiscal year 2002: 
-     There were 0 complications of 89 lymph node biopsies 
-     There were 0 complications of 479 liver core biopsies. 
 
Published literature on the complications of tumor biopsies is typically organ-specific. For study 
subjects with colorectal cancer, it is expected that the liver will be the most common site of 
tumor biopsies. For liver biopsies, published reviews quote a complication rate of 0.06 – 
0.32%.The complication rate does not appear to be affected by peri-hepatic ascites. Extrapolation 
to an oncology study population is somewhat problematic given that the indication for such 
biopsies in the general population is often severe liver disease or dysfunction; such patients 
would not be candidates for oncology clinical trials. 
 
9.1.1.1.3. Fine needle aspiration biopsy (FNAB) as an alternative procedure to core biopsy 
 
In the unlikely event that no sites amenable to core biopsy are available, we will obtain tumor 
material via ultrasound-guided FNA of the primary tumor, a routine diagnostic procedure for 
establishing the diagnosis of pancreatic adenocarcinoma.  An FNAB will be performed using a 
standard technique using 22 to 27 G needle, per standard radiologic practice, including on-site 
microscopic evaluation by a cytopathologist, or a specially trained cytotechnologist. A maximum 
of four FNA “passes” will be performed. The first pass will be used for on-site examination of 
the material, to determine presence and quality of lesional tissue. The subsequent passes will be 
performed either for tissue procurement for the end-point assays, or to guide the radiologist to 
the appropriate area of the lesion.  The first FNA pass will be examined on air-dried, DiffQuik-
stained slides, as well as ethanol-fixed for Papanicolaou staining. Second and third FNA pass 
will be used for mRNA collection in RNAlater buffer (Ambion, Inc.).  The fourth pass will be 
used for suspension in 10% neutral buffered formalin, then processed using the thrombin clot 
technique, and embedded in paraffin.  The FNAB material collected in RNALater will be used 
for the real time quantitative PCR assays, as described subsequently (see section 9.1.5.), and the 
formalin fixed “cytospin” sample will be used for immunohistochemical assessment of the CSC 
compartment using a panel of biomarkers.   


Protocol Amendment 12, date December 4, 2014 
74
 
9.1.1.2. Blood 
Blood samples for the biomarkers CA19-9 and SPARC will be collected at the beginning of the 
first two cycles and every eight weeks afterwards. CA19-9 is considered standard of care. Blood 
samples for circulating stem cells will be collected twice during the study. The first sample will 
be obtained at the beginning of treatment (cycle one day 1). The second sample will be obtained 
at the beginning of cycle 3. We will collect approximately 150mL of blood (20mL of serum for 
banking in order to perform biomarker studies, and 120mL of PBMCs for circulating CSCs.) 
 
9.1.2. Handling of specimens 
 
9.1.2.1. Core biopsy 
 
Samples of core biopsy will be equally divided into containers marked as “formalin” (containing 
10% neutral buffered formalin), or “RNA” (containing RNAlater, Ambion, Inc.).  Samples fixed 
in formalin will be processed as per routine protocols for archival samples, and 5µM recuts from 
the paraffin-embedded blocks will be obtained as follows: one reference hematoxylin and eosin 
slide, and five serial unstained slides on ChemMate (Ventana Medical Systems, Inc).  One or 
more of the latter sections will be utilized for immunohistochemical analysis of the CSC 
compartment using a panel of biomarkers, including aldehyde dehydrogenase (ALDH), CD24, 
CD44, and CD133.  Samples fixed in RNAlater will undergo total mRNA extraction using the 
RNEasy Mini Kit (Qiagen, Inc.), followed by reverse transcription to cDNA using the 
SuperScript II cDNA Synthesis kit (Invitrogen).  Real time quantitative PCR (qRT-PCR) 
analysis will be performed for transcript levels of Gli1, Ptch, Aldh, CD24 and CD44 in the 
samples, using SDHA as a housekeeping gene control. Further details on these assays are 
indicated in section 9.1.5. 
 
9.1.2.2. Blood 
PBMCs will be separated from whole blood using the Ficoll Hypaque density gradient 
centrifugation method, and used for flow cytometry for circulating CSCs as described in section 
9.1.5.  The residual serum will be stored at -800C, and used for measurement of circulating 
CA19-9 and SPARC levels.  
 
 
 
9.1.3. Shipping of Specimens 
 
All samples collected for laboratory correlative studies will be shipped to: 
 
Anirban Maitra, MBBS 
Associate Professor of Pathology and Oncology 
The Sol Goldman Pancreatic Cancer Research Center 
Johns Hopkins University School of Medicine 
Room 345, CRB II 
1550 Orleans Street, 
Baltimore, MD 21212 


Protocol Amendment 12, date December 4, 2014 
75
Ph 410 955 3511 / Fax 410 614 0671 
Email: amaitra1@jhmi.edu 
 
9.1.4. Sites performing correlative studies 
 
Johns Hopkins University 
Translational Genomics (TGEN), Inc. 
University of Pennsylvania 
 (Note: Only archival core biopsy specimens will be obtained from patients recruited in Spain 
due to logistics and restrictions on international shipping of fresh human tissues). 
 
9.1.5. Specific laboratory assays  
 
9.1.5.1. Immunohistochemical analysis of the CSC compartment 
 
Multiple lines of evidence suggest that Hh antagonists impact the survival of tumorigenic CSC 
populations in solid tumors, including pancreatic cancer.  Studies in orthotopic xenograft models 
of pancreatic cancer demonstrate that Hh inhibitors significantly reduce the proportion of CSCs.  
We hypothesize that the addition of GDC-0449 in the treatment cocktail (beginning at cycle 2) 
will similarly diminish the proportion of tumorigenic CSCs in pancreatic cancer lesions, and 
thereby, improve PFS by limiting subsequent metastatic events.  To test this hypothesis, we will 
obtain pre-and post-treatment biopsies in patients enrolled in this trial, and interrogate the CSC 
compartment in matched biopsies using a diverse panel of immunohistochemical markers.  The 
biomarkers included are ALDH, CD24, CD44, and CD133, which have all been shown to label 
distinct, and partially non-overlapping, subsets of CSCs in solid tumors.  These CSC markers are 
routinely used, and published, in the Maitra laboratory.  Unstained 5µM thick ChemMate slides 
will be stained with antibodies against these markers (all obtained from Cell Signaling 
Technologies, Ltd), and chromogenic detection performed using the Catalyzed Signal 
Amplification kit (Dako).  Quantitative Image Analysis for CSC markers will be performed 
using the Frida Image Analysis Software (http://bui2.win.ad.jhu.edu/frida/).  The percentage of 
cells staining for each CSC marker will be utilized for calculating the mean and standard 
deviation in pre- and post-biopsy cohorts, and any statistical significance in difference calculated 
using Chi-square analysis.  Patients enrolled in the trial will be stratified as “progressors” versus 
“non-progressors” based on defined criteria, and differences in CSC amelioration between these 
two cohorts compared as a potential measure of treatment response to Hh antagonists.  In a 
subset of ~10 patients, we will also determine if anti-metabolite therapy increases the proportion 
of CSCs at the culmination of cycle 1 of therapy, based on previous preclinical data in xenograft 
models.  We anticipate these correlative studies will establish a framework for judging the in 
vivo efficacy of CSC-directed therapies in future trials with this class of antagonists. 
 
9.1.5.2. Quantitative real time PCR analysis for CSC markers 
 
The rationale for analyzing CSC-related transcripts (ALDH, CD24 and CD44) remains identical 
to that of immunohistochemical analysis, but provides an additional layer of internal validation.  
Moreover, in the event that adequate material is not obtained from core biopsies, qRT-PCR will 
be the assay of choice in FNAB material.  Expression analysis will be performed on cDNA 


Protocol Amendment 12, date December 4, 2014 
76
synthesized from total mRNA obtained from samples preserved in RNAlater buffer.  All of the 
qRT-PCR primers are routinely used in the Maitra laboratory, and the assay will be performed on 
a ABI 7500 Fast real-Time PCR machine (Applied Biosystems), using SDHA as a housekeeping 
gene.  Relative fold expression of various transcripts will be calculated using the 2-ΔΔCt method 
(Schmittgen and Livak, 2001).  All of the assays will be performed in triplicate.   
 
9.1.5.3. Quantitative real time PCR analysis for Hh gene targets 
 
In addition to evaluation of the CSC compartment, we will also evaluate expression of key Hh 
gene targets, Gli1 and Ptch, which are known to be downregulated in the tumor tissues 
secondary to Hh inhibitor therapy.  While recent studies have shown that bulk of these Hh targets 
are expressed in the stromal (rather than epithelial) compartment in pancreatic cancer, this will 
not be differentiated in the assays performed.  The rationale for these assays is to establish a 
tissue-specific pharmacodynamic measure of drug availability to the tumor site, and to correlate 
with pharmacokinetic analysis of GDC-0449.  All of the qRT-PCR primers are routinely used in 
the Maitra laboratory, and the assay will be performed on a ABI 7500 Fast real-Time PCR 
machine (Applied Biosystems), using SDHA as a housekeeping gene.  Relative fold expression 
of various transcripts will be calculated using the 2-ΔΔCt method (Schmittgen and Livak, 2001).  
All of the assays will be performed in triplicate.   
 
9.1.5.4. Flow cytometry for circulating CSCs 
 
The published data correlating circulating tumor cells (CTCs) with prognosis is uneven, with a 
wide range of correlation (or lack thereof) in various solid tumors.  The underlying hypothesis 
for this correlative study is that only circulating CSCs (rather than the entire complement of 
CTCs) is responsible for metastatic seeding and colonization at secondary sites, and therefore 
likely to be a more reliable measure of PFS.  Gradient centrifuged PBMCs will be analyzed for 
the fraction of circulating CSCs using the Aldefluor reagent (Stem Cell Technologies), which 
provides a quantitative measure of enzyme activity in viable cells.  Cells with highest ALDH 
activity will be gated.  Additionally, surface co-expression of CD24/CD44 will be analyzed in 
order to further enrich for the population of circulating CSCs.  Normal peripheral blood cells 
(i.e., B and T cells) may also express the CD44 and CD24, but they do not appear to express 
ALDH, and we would not expect to detect CD24+CD44+ALDH+ cells in normal individuals. 
Furthermore, cells will also be stained with a monoclonal antibody against ESA that is not 
expressed by lymphocytes, but is expressed by pancreatic CSC.  For further confirmation of 
epithelial origin, CD24+CD44+ALDH+ cells will be isolated by FACS, cytocentrifuged onto 
glass slides then stained for the expression of epithelial-specific cytokeratins CK9 and CK19 by 
standard immunohistochemical techniques.  It is anticipated that in patients with advanced 
pancreatic cancer, there will be a reduction in the proportion of circulating CSCs upon treatment 
with GDC-0449, especially in patients that have a tangible improvement in subsequent PFS.   
 
9.1.5.5. Circulating CA19-9 and SPARC 
 
ELISA will be performed on plasma samples for circulating CA19-9 and SPARC levels.  
Standard assay formats for ELISA will be utilized, including kits for CA19-9 (Calbiochem, Inc.) 
and SPARC (Hematologic Technologies, Inc).  CA19-9 is the standard-of-care tumor marker for 


Protocol Amendment 12, date December 4, 2014 
77
pancreatic cancer, and measurement of this analyte will be used as a surrogate tumor response 
measure to therapy.  CA19-9 should be analyzed locally at each participating site using standard 
laboratory measures. 
 
SPARC (secreted protein acidic and rich in cysteine, a.k.a. osteonectin) is abundantly expressed 
in the stroma of pancreatic cancers, and is an albumin-binding protein that is responsible for 
enrichment of nab-paclitaxel in the peritumoral milieu.  Recent preclinical data have shown that 
nab-paclitaxel therapy ameliorates the tumor stroma, and enhances delivery of gemcitabine to the 
site of cancer.  Thus, it is anticipated that reduction in circulating SPARC levels post-therapy 
with nab-paclitaxel will be a surrogate measure for stromal depletion at the tumor site.  
Reduction in pre-treatment circulating SPARC levels will be correlated with PFS. In this 
protocol we wish to obtain data on a potential correlation between plasma SPARC protein 
expression and response to albumin-bound drugs therapy. This method will become a potential 
means of following treatment response of nab-Paclitaxel drugs.  
 
Patient plasma will be extracted at different time points during the course of the treatment and 
used as the analyte for SPARC ELISA (enzyme-linked immunosorbent assay). To obtain the 
analyte, collect 10cc of blood in a vacutainer containing sodium heparin. The use of a heparin-
based anticoagulant containing platelet inhibitors is required to minimize the contribution of 
osteonectin in plasma due to platelet activation during phlebotomy. Plasma processed from the 
blood should be frozen at -20oC and shipped to the Alta Analytical for analysis.  
 
 
 
 
 
ALTA Analytical Laboratory  
Attention: Trang Le  
Project Manager/Principal Investigator  
Immunochemistry Services  
Intertek Chemicals and Pharmaceuticals  
3985 Sorrento Valley Blvd., Suite C  
San Diego, CA-92121  
Tel: 858-558-2599  
Fax: 858-558-2600  
Email: trang.le@intertek.com 
 
 


Protocol Amendment 12, date December 4, 2014 
78
 
10. STUDY CALENDAR 
   
 
 
Cycle 1 
 
Cycle 2 
 
Cycle 3 on 
 
 
   
 
Pre- 
Study 
 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
Day 
8 
Day 
15 
Day 
22 
Day 
1 
 
Day 
8 
 
Day 
15 
 
Day 
22 
Every  
8 weeks 
End of 
Studyc 
 
GDC-0449 
 
 
 
 
 
 
 
 
X --------------------------------------------------- X 
 
 
Gemcitabine 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Nab-Paclitaxel 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X 
 
X-------------------------------------------------------------------------------------------------X 
X 
 
Concurrent procedures 
 
X 
 
X-------------------------------------------------------------------------------------------------X 
X 
 
Adverse event evaluation 
 
 
 
X-------------------------------------------------------------------------------------------------X 
X 
 
Peripheral Neuropathy 
Evaluation 
 
 
 
X-------------------------------------------------------------------------------------------------X 
X 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
Weight 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
BSA calculation 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
ECOG Performance 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
CBC w/diff, plateletsg 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Serum chemistrya,Mg, 
phosphateg 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 Complete Urinalysisg 
    X 
 
 
 
 
 
PT, PTTg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG (as indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiologic evaluation  
CT scan or MRI 
 
X 
 
Radiologic measurements should be performed every 8 weeks.   
Xc 
 
Pregnancy Testg 
 
Xb 
 
Every 4weeks if regular menstrual cycles. Every 2 weeks if irregular menstrual cycles 
Xc 
 
Biopsy for correlative studies 
 
Xf 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Serum CA 19-9g and SPARC 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Blood Circulating CSCg 
 
 
 
X 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
Phone f/u for Survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 Taste Questionnaire 
  
  
X
X
  
  
  
 
 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein,  
          SGOT [AST], SGPT [ALT], sodium. 
b: 
Pregnancy test (women of childbearing potential)., at screening, within 10-14 days and within 24 hrs prior to first dose of GDC-0449    
c  End of-study evaluation,   
f . pretreatment biopsy within 14 days before first treatment day         
g.   All blood tests and biopsies will be done within +/- 3 days 
 


Protocol Amendment 12, date December 4, 2014 
79
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans and 
x-rays must be done 14 days prior to the start of therapy.  In the event that the patient's condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next 
cycle of therapy. 
 
             
11. MEASUREMENT OF EFFECT 
 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following 
initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
 
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 


Protocol Amendment 12, date December 4, 2014 
80
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.   
 
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 no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  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 those that lend themselves to reproducible 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.  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 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. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 


Protocol Amendment 12, date December 4, 2014 
81
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If 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 in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 


Protocol Amendment 12, date December 4, 2014 
82
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.   
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 


Protocol Amendment 12, date December 4, 2014 
83
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
 
11.1.4 Response Criteria 
 
 
 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): 
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 (PR): 
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline 
sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that 
is the smallest on study).  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 progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on 
study. 
 
 
 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the 
normal limits. 
 


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Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
 
 
 
11.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
 
 
 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
PD 


Protocol Amendment 12, date December 4, 2014 
85
No 
Any 
Any 
Yes 
PD 
*  See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
**  Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 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 the objective progression even 
after discontinuation of treatment. 
 
 
 
 
 
 
 
 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 


Protocol Amendment 12, date December 4, 2014 
86
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
 
 
11.1.6 Response Review 
 
Response on imaging studies will be assessed by expert radiologists based on above 
RECIST 1.1 criteria. 
 
 


Protocol Amendment 12, date December 4, 2014 
87
 
12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
This is an open-label, single arm, multi-center, Phase II trial. 
 
Primary Endpoints(s)  
 
 PFS as defined by the time from first therapy received to the earlier documented disease 
progression or death from any cause. PFS will be determined by the investigator.  Imaging 
studies to assess response will be evaluated by expert radiologists using RECIST 1.1 criteria. 
 
Secondary Endpoint(s) 
 
Efficacy endpoints 
 Overall survival from the time of cycle 1, day 1 until death from any cause 
 Objective tumor response (partial response, complete response) or stable disease based on CT 
scans (or MRI scans if patient is allergic to contrast agent or has some other contraindication to a 
CT scan). These will be evaluated according to RECIST 1.1 criteria. 
 
Safety endpoints 
 Number of grade 3 and 4 toxicities according to National Cancer Institute Common Toxicity 
Criteria for Adverse Events (NCI CTCAE; Version 4.0) that occur after Cycle 1, day 1 
 Incidence, nature and severity of all adverse events that occur on or after Cycle 1, Day 1 
 
Correlative studies endpoints 
 Quantitative pancreatic cancer stem cell identification using functional assays and phenotypic 
assays. Functional assays include immunohistochemistry or RT-PCR for ALDH bright cells. 
Phenotypic assays include immunohistochemistry or flow cytometry for pancreatic cancer stem 
cell markers (CD24+/CD44+/ESA+ and CD133+) in tissue biopsy and peripheral blood.  
 Semi-quantitative measurement of hedgehog ligand expressions in pre-post biopsies and 
hedgehog signaling pathway downregulation as measured by Gli 1 and Patch 
 Biomarker changes as measured by serum CA19-9 and plasma SPARC levels 
 
12.2 
Statistical Considerations 
This is a single-arm, Phase II trial of Gemcitabine, nab-Paclitaxel and GDC-0449 in patients with 
previously untreated metastatic adenocarcinoma of the pancreas.  Progression-free survival (PFS) is 
the primary endpoint.  Eighty patients will be accrued. 
 
 
12.2.1 
Primary Endpoint Analysis Plan 
PFS will be timed from the first treatment received (cycle 1, day 1) until the earlier of disease 
progression or death due to any cause.  The product-limit (Kaplan-Meier) that estimate the specific 


Protocol Amendment 12, date December 4, 2014 
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survival functions will be calculated.  Median survival will be calculated from the Kaplan-Meier 
estimate, along with a 80 % confidence interval.  The proportion surviving to one year will be 
calculated, along with a 80 % exact binomial confidence interval. 
The null hypothesis that the median survival is less than or equal to 7.9 months will be tested using a 
one-sided test at a 0.1 significance level. 
 
12.2.2 
Secondary Endpoint Analysis Plans 
1 Overall survival will be summarized using the product-limit (Kaplan-Meier) estimator.  Median 
OS and 1-year surviving proportion will be estimated as in the primary objective. 
2 Objective tumor response will be summarized by the proportion of patients (with 95% exact 
binomial confidence intervals) that achieve a confirmed complete or partial response based on 
radiology assessment of response using RECIST 1.1 response guidelines. Confirmation will be at 
least 4 weeks after the initial response. 
3 The number and attribution of Grade 3 and 4 adverse events will be tabulated. Safety will also be 
assessed through summaries of all adverse events, including serious adverse events and adverse 
events leading to discontinuation of chemotherapy or GDC-0449. All treatment-emergent adverse 
events will be graded by NCI CTCAE, Version 4.0. 
4 Hematology parameters: In order to investigate the maximal degree of myelosuppression, the 
NCI CTCAE grade for WBC, ANC, platelet count and hemoglobin will be summarized by the most 
severe grade in each treatment cycle and by the most severe grade during the study. The incidence of 
patients with NCI CTCAE hematology values of Grade 3 or 4 that occurred after the first dose of 
study drug also will be presented. Data for patients with Grade 3 or 4 hematology values will be 
listed. The nadir of each of these parameters will be presented in each cycle and overall. For ANC 
and WBC, time to overall nadir and time to recovery will be analyzed using the Kaplan-Meier 
method. 
5 Clinical chemistry: Liver and renal function will be summarized using the NCI CTCAE for 
alkaline phosphatase, serum glutamate oxaloacetate transaminase (SGOT), total bilirubin, and 
creatinine. The number and percentage of patients that have each NCI CTCAE grade will be 
summarized using the most severe grade for the first cycle of therapy and for anytime during the 
study. The incidence of patients with NCI CTCAE chemistry values of Grade 3 or 4 that occurred 
after the first dose of study drug also will be presented. Data for patients with Grade 3 or 4 chemistry 
values will be listed. 
6 The percent of cancer stem cells measured in primary tissue and peripheral blood will be 
determined. The percent change from the pre to the post-treatment biopsies will be calculated for  
the clinical outcomes (PFS, OS, and response rate).  These endpoints will be summarized using 
means, standard deviations, medians and ranges.   
7 Hh- ligand expression in tissue by IHC or flow cytometry will be quantified as either continuous 
or semi-quantitative measurement. The effect of Hh expression and/or pathway signaling on primary 
and secondary endpoints may be examined using proportional hazards 
regression (for PFS, OS and other time-to-event-endpoints) or logistic regression (for dichotomous 
endpoints, such as objective response). 
8 SPARC and CA19-9: Logistic regression will be used to assess the relationship between SPARC 


Protocol Amendment 12, date December 4, 2014 
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and CA19-9 and objective response.  Product-limit (Cox) regression will be used to assess the 
relationship between these markers as predictors of response, PFS and OS. 
 
12.2.3 
Justification of Design 
This Phase II trial is designed to make a preliminary assessment of the efficacy of treatment, as 
measured by PFS.  In previous trials the use of chemotherapy with gemcitabine and nab-paclitaxel, 
the median PFS was 7.9 months. We have powered our study with the assumption of 24 months 
accrual with 12 months follow up. Based upon these assumptions, a sample size of 80 patients will 
have an 80% power to detect an increase in the median progression free survival to 10.4 months 
from the null rate of 8 months using a one sided type 1 error of 0.10.  The one-sided test with 0.10 
significance level is appropriate for an early Phase II proof-of-principle study designed to 
accumulate evidence motivating a later multi-center confirmatory Phase III study with stricter test 
criteria. 
This trial is hypothesis-generating and is only able to detect a relatively large benefit (30% 
increases) of GDC-0449 added to chemotherapy use with gemcitabine and nab-paclitaxel. In 
particular, this trial will not have adequate power to detect minimum clinically meaningful 
differences between current treatment and historical control (gemcitabine and nab-paclitaxel). Thus, 
formal hypothesis testing is limited in that statistically negative outcomes do not necessarily rule out 
clinically significant treatment effects. 
 
12.2.4 Safety Monitoring 
This trial will combine three agents and we must allow for the possibility of an interaction between 
the treatments in terms of toxicity as well as efficacy. In phase 1 and 2 studies, the combination of 
gemcitabine and nab paclitaxel were associated with grade 3 or higher toxicities in at most 36% of 
patients (the most significant being neutropenia).  No neutropenia or myelosuppression was reported 
with GDC-0449.  Therefore, we set the upper boundary for an acceptable level of grade 3 or higher 
hematologic toxicity at 50%. 
 
Toxicities will be recorded and evaluated for severity according to the National Cancer Institute 
Common Toxicity Criteria for Adverse Events (NCI CTCAE; Version 4.0).  The number of 
individuals with any toxicities of grade 3 or higher will be tabulated.   
 
Toxicity and adverse events will be closely monitored by the study statistician and the principal 
investigators throughout the study. After the first 10 patients have been accrued and treated on to this 
study accrual will be temporarily halted until these patients have been assessed for toxicity for one 
cycle of treatment with GDC. If five or more of the first ten patients experience grade 3 hematologic 
toxicities that are possibly, probably or definitely related to study treatment, safety of this study will 
be re-evaluated by the principal investigators to determine whether they are unexpected and pose an 
excessive safety risk and whether the study needs to be permanently closed to accrual. In addition, 
accrual to the trial will be halted if unexpected, significant, or unacceptable risk to patients occurs at 
any time during this study.  A thorough safety review by the principal investigators will then 
determine whether the trial needs to be terminated. 
 
12.2.5 Futility Monitoring 
 


Protocol Amendment 12, date December 4, 2014 
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An interim futility analysis will be performed once 66% of the patients (53) have completed 6 
months of follow-up.   At that time, we will construct 99.5% confidence intervals for progression 
free survival.  If the upper bound of the CI does not contain the alternative PFS (7.05) months 
and the other efficacy outcomes do not show benefit then we will halt the trial for futility.  This test 
is equivalent to "spending" 0.0025 of the type I error   
 
12.3 
Sample Size/Accrual Rate 
 
We have powered our study with the assumption of 24 months accrual with 12 months follow up. 
Based upon these assumptions, a sample size of 72 patients will have an 80% power to detect an 
increase in the median progression free survival to 7.15 months from the null rate of 5.5 months (HR 
= 1.3) using a one sided type 1 error of 0.10.  Up to an additional 10% will be accrued in order to 
control for loss to follow-up.  The expected accrual rate is between 4-5 patients per month.  
Rationale: We have decided to decrease the sample size based on the following points:  
-New data presented at ASCO GI and now published at NEJM demonstrated the PFS of gem/abraxane based on 
phase 3 study is 5.5 mo (MPACT study, Von Hoff NEJM 2014). Given these findings reducing the sample size will 
not alter the power initially planned for the study. Our study would still have 80% power with N=72 if PFS of 5.5 
months (as per MPACT study)  were known at study design, and study planned to detect a 30% increase in median 
PFS from 5.5 months to 7.15 months at the 1-sided 10% significance level, upper bound used for futility should 
have been 7.15.  
-Accrual has been significantly slow over the past two years as new standard treatments have become available 
(gem/abraxane and FOLFIRINOX) and less patients are participating in our first line clinical trials.  
-New data (one study) has become available demonstrating that hedgehog inhibitors have not increased progression 
free survival in patients with pancreatic cancer (Kim et al. CCR Oct 2014) 
-We have evaluated our data in every six months basis at the AACR SU2C meetings (planned to review the trial) 
and our mPFS remains 5.5 mo with upper limit CI not including 7.15 
 
 
 
Rationale for changing the statistical analysis 
 
When the study was originally designed, previous trials using gemcitabine and nab-paclitaxel 
reported a PFS of 7.9 months.  A sample size of 80 participants recruited over a 2 year period and 
followed for a minimum of 1 year would provide 80% power to detect an increase in PFS from a 
median of 8 months to 10.4 months using a one sided type I error rate of 10%.  An interim futility 
analysis was included to enable us to halt the trial if the efficacy after 50% of the patients completed 
6 months of follow-up was much lower than expected, specifically if the upper bound of the 99.5% 
confidence interval did not include the alternative (10.4 months).  The interim analysis was 
completed and the estimated median was 5.0 months with a 99.5% confidence interval of 4.4 to 7.2 
months.  Since the upper bound was much lower than the hypothesized alternative, recruitment of 
the trial was halted.  Participants already enrolled in the trial continued follow-up. 
 
On previous phase 2 PFS was 7.9 months. On January 25, 2013 the results of a large (N = 861) 
phase III trial of gemcitabine and nab-paclitaxel were reported. This is the data that would have been 
used if these results were available at the time of design of this clinical trial. The median PFS was 
5.5 months, which a much lower value than was previously reported.  In light of the new 
information, we re-ran our power calculations and interim analysis guidelines to see if the new 
reference value would have impacted our decision to halt the trial.  Using the same accrual and 


Protocol Amendment 12, date December 4, 2014 
91
follow-up assumptions outlined above, we would have 80% power to detect an increase in median 
PFS from 5.5 months (the new reference) to 7.05 months (HR = 1.28) with a one-sided type I error 
rate of 10%.  The interim stopping rule therefore changed to comparing the upper boundary of the 
99.5% confidence interval to 7.05.  In this case the observed upper boundary was 7.2 months; hence 
the stopping criteria would not be met. Given the updated phase III data and we believe that it is 
appropriate to re-open accrual.  
 
 
12.4    Stratification Factors 
None 
 
12.5    Reporting and Exclusions 
 
        
12.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with GDC-0449, gemcitabine and nab-paclitaxel 
 
 
12.5.2 Evaluation of response.  All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if they 
are ineligible.  Each patient will be assigned one of the following categories:  1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) 
early death from malignant disease, 6) early death from toxicity, 7) early death 
because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type 
of data in a clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) should be included in the main analysis of 
the response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  
Precise definitions for categories 4-9 will be protocol specific.  
 
 
 


Protocol Amendment 12, date December 4, 2014 
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Jemal, A., et al., Cancer statistics, 2009. CA Cancer J Clin, 2009. 59(4): p. 225-49. 
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Burris, H.A., 3rd, et al., Improvements in survival and clinical benefit with gemcitabine as first-
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15(6): p. 2403-13. 
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D. D. Von Hoff, R.R., M. Borad, D. Laheru, L. Smith, T. Wood, R. Korn, N. Desai, J. Iglesias, 
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Thayer, S.P., et al., Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. 
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Berman, D.M., et al., Widespread requirement for Hedgehog ligand stimulation in growth of 
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Tian, H., et al., Hedgehog signaling is restricted to the stromal compartment during pancreatic 
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Curran, T. and J.M. Ng, Cancer: Hedgehog's other great trick. Nature, 2008. 455(7211): p. 293-
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Li, C., et al., Identification of pancreatic cancer stem cells. Cancer Res, 2007. 67(3): p. 1030-7. 
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Hermann, P.C., et al., Distinct populations of cancer stem cells determine tumor growth and 
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P. M. LoRusso, C.M.R., M. J. Borad, L. Vernillet, W. C. Darbonne, H. Mackey, J. F. DiMartino, 
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Von Hoff, D.D., et al., Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N 
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Jimeno, A., et al., A direct pancreatic cancer xenograft model as a platform for cancer stem cell 


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19. 
Olive, K.P., et al., Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a 
mouse model of pancreatic cancer. Science, 2009. 324(5933): p. 1457-61. 
20. 
D. D. Von Hoff, R.R., M. Borad, D. Laheru, L. Smith, T. Wood, R. Korn, N. Desai, J. Iglesias, 
M. Hidalgo; TGen, Scottsdale, AZ; Mayo Clinic, Scottsdale, AZ; Johns Hopkins, Baltimore, 
MD; South Texas Oncology and Hematology, San Antonio, TX; University of Alabama, 
Birmingham, AL; Scottsdale Medical Imaging, Scottsdale, AZ; Abraxis BioScience, Los 
Angeles, CA SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-P) 
in patients with advanced metastatic pancreatic cancer: A phase I/II study. J Clin Oncol, 2009. 
27:15s, 2009 (suppl; abstr 4525)  
21. 
Ivanova, A., B.F. Qaqish, and M.J. Schell, Continuous toxicity monitoring in phase II trials in 
oncology. Biometrics, 2005. 61(2): p. 540-5. 
22. 
Pocock S: Group sequential methods in the design and analysis of clinical trials. Biometrika: 
191-199. 
 
  
 
 
 


Protocol Amendment 12, date December 4, 2014 
94
 
Appendices 
 
 APPENDIX A 
 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


Protocol Amendment 12, date December 4, 2014 
95
 
APPENDIX B   
Definition of Women of Childbearing Potential and  
Acceptable and Unacceptable Forms of Contraception 
 
Women of childbearing potential are defined as follows: 
 Patients with regular menses 
 Patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes 
withdrawal bleeding 
 Women who have had a tubal ligation 
Women are considered not to be of childbearing potential for the following reasons: 
 The patient has undergone hysterectomy and/or bilateral oophorectomy. 
 The patient is post-menopausal defined by amenorrhea for at least 1 year in a woman  45 years 
old. 
Women of childbearing potential are required to use two forms of acceptable contraception, 
including one barrier method with spermicide, during their participation in the study and for 12 
months following discontinuation of GDC-0449. 
The following are acceptable forms of barrier contraception: 
 Latex condom (always used with spermicide) 
 Diaphragm (always used with spermicide) 
 Cervical cap (always used with spermicide) 
 Male subject must use condoms at all times, even after a vasectomy, during sexual 
intercourse with female partner of reproductive potential during treatment with GDC-0449, 
and for 2 months after the last dose to avoid exposing a pregnant partner and unborn fetus to 
GDC-0449. 
 
The following are acceptable forms of secondary contraception, when used with a barrier method: 
 Tubal ligation  
 Partner’s vasectomy 
 Combination hormonal contraceptives including birth control pills, patches, rings, 
or injections,medroxyprogesterone acetate depot, with the exception of the progesterone-only 
“minipill”  


Protocol Amendment 12, date December 4, 2014 
96
 Intrauterine device (non–progesterone T) 
 Vaginal sponge (containing spermicide) 
In addition, 100% commitment to abstinence is considered an acceptable form of contraception.he 
following are unacceptable forms of contraception for women of childbearing potential: 
 IUD progesterone T  
 Progesterone-only “minipill” 
 Female condom 
 Natural family planning (rhythm method) or breastfeeding 
 Fertility awareness 
 Withdrawal 
 Cervical shield 
 


Protocol Amendment 12, date December 4, 2014 
1
 
 
 
 
 
APPENDIX C 
 
LIST OF CYP3A4 INHIBITORS AND INDUCERS 
 
 
 
CYP3A4 Inhibitors 
Acetominophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (3) 
When GDC-0449  is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of GDC-0449 is 
the potential outcome. The co-administration of ‘inducers’ would potentially lower plasma GDC-0449 concentrations. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, 
Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed.   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at CYTOCHROME P450 DRUG 
INTERACTION TABLE (Version 5.0 released on January 12, 2009)  http://medicine.iupui.edu/clinpharm/ddis/ 
 
(1)   Investigator’s Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006. 
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
 
Updated on May 1, 2007 
 
 
 
7.3.5 


 
2
 
APPENDIX D 
PATIENT’S MEDICATION DIARY 
 
Today’s date _____________________ 
Agent:  GDC-0449 
Patient Name_____________________(initials acceptable)  
 Patient Study ID __________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take GDC-0449 150mg (___capsule(s)) once daily.  You should take the capsule(s) at approximately the 
same time each day with a full glass of water (200mls) with or without food. 
3. 
Record the date, the number of capsules of each size of capsule that you took, and when you took them.   
4.      If you forget to take you daily dose or vomit  a dose you will not need to make up missed dose. 
5. 
If you have any comments or notice any side effects, please record them in the Comments column.   
6. 
Please bring this form and your bottles of GDC-0449 capsules when you return for each appointment. 
 
Day 
 
Date 
 
Time of dose  
# of capsules taken
Comments
 
150 mg 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
Patient’s signature_______________________________________________________________________ 
 
 
Physician’s Office will complete this section: 
1. Date patient started protocol treatment _______________________________________________________________  
2. Date patient was removed from study ________________________________________________________________  
3. Patient’s planned total daily dose ___________________________________________________________________  
4. Total number of capsules taken this month  ___________________________________________________________  
5. Physician/Nurse/Data Manager’s Signature  ___________________________________________________________  
V2 -1/20/11 


 
3
 
 
 
 
APPENDIX E 
 
 
 
 
 
 
 
 
 
An eligibility form must be completed for every subject 
and must be kept in the research chart. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
4
Instructions: 
This eligibility checklist must be completed in its entirety.   
 
Yes        No                  ELIGIBILITY CRITERIA: (All answers must be YES) 
 
_____ ____ 
 1.         Patients has histologically or cytologically confirmed metastatic adenocarcinoma 
                                    of the pancreas. Patients with islet cells tumors are excluded. 
 
 
 
 
_____ ____     2.       Patients has measurable disease, defined as at least one lesion that can      
                                       be accurately measured in at least one dimension (longest diameter to be 
                                       recorded) as >20 mm with conventional techniques or as >10 mm with spiral 
                                       CT scan.   
                                       
_____    ____    3.        Patient has NOT received previous radiotherapy, surgery or chemotherapy or                  
                                    investigational drug therapy for the treatment of metastatic disease.  
 
If the patient received radiotherapy, chemotherapy or investigational therapy in 
the adjuvant setting it should be completed 3 weeks prior to enrollment. If a 
patient received gemcitabine in the adjuvant setting, tumor  recurrence must have 
occurred at least six months after completing the last dose of gemcitabine                                      
 
_____     _____ 4.         Age >18 years.   
                                       
_____     _____ 5.         Life expectancy of greater than 1 month. 
 
_____     _____ 6.         ECOG performance status <1 (Karnofsky >70%; see Appendix A). 
                                   ECOG PS: ________ 
 
_____     _____ 7.         Patients has adequate organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/mcL 
- 
absolute neutrophil count 
 
>1,500/mcL 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
total bilirubin 
 
 
 
 
< 1.5 ULN 
- 
AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal, 
unless liver metastases are clearly present, then 
< 5X ULN is allowed 
- 
creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
creatinine clearance  
 
Creatinine clearance >50 mL/min/1.73 m2 for 
patients. Serum creatinine < 2 mg/mL 
 
 
 


 
5
Instructions: 
This eligibility checklist must be completed in its entirety.   
 
Yes        No                  ELIGIBILITY CRITERIA: (All answers must be YES) 
 
_____    ____ 8             Patient is asymptomatic from jaundice and ascites prior to Day 1 of therapy.  
                                     Pain symptoms should be stable. 
 
_____   ____ 9             Patient is NOT pregnant or lactating. Not planning pregnancy during treatment and  
                                   for 7 months after last dose of treatment 
 
_____   _____ 10            Patient has agreed to practice effective contraceptive measures throughout                                     
                                         the study. 
                                     
                                 Women of childbearing potential are required to have a negative serum pregnancy  
                                 test (with a sensitivity of at least 25 mIU/mL) 
                                       
      Women of childbearing potential are defined as follows: 
• 
Patients with regular menses 
• 
Patients with amenorrhea, irregular cycles, or using a contraceptive 
      method that precludes withdrawal bleeding 
• 
Women who have had a tubal ligation 
 
     Women are considered not to be of childbearing potential for the following   
      reasons: 
•    The patient has undergone hysterectomy and/or bilateral oophorectomy. 
•    The patient is post-menopausal defined by amenorrhea for at least 1 year  
      in a woman > 45 years old. 
      
_____     ____ 11.         For sexually active males: Patient is willing to use of barrier form of  
                                      contraception, even if they have had a vasectomy, during the study and for 2    
                                      months after stopping GDC-0449.                                                                                                        
  
_____     ____ 12.         Patient agrees NOT to donate blood products for 7 months after stopping  
                                       GDC-0449 
 
_____     ____ 13.         Patient has given written informed consent to participate in this study. 
 
_____     ____ 14.         Patient is NOT receiving concurrent anticancer therapy or any other 
                                   investigational agents while on study. 
 
_____     ____ 15.      Patient does NOT have uncontrolled brain metastases. Patients with brain  
                                   metastases must have been previously treated and well controlled for at least  
                                   three months (defined as clinically stable, no edema, no steroids and stable 
                                   in 2 scans at least 4 weeks apart)                                        


 
6
Instructions: 
This eligibility checklist must be completed in its entirety.   
 
____ ____    16.              History has NO history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to GDC-0449 or other agents used in the study. 
 
____ ____    17.             Patients is NOT taking medications with narrow therapeutic indices that are  
metabolized by cytochrome P450 (CYP450), including warfarin sodium 
(Coumadin®). 
 
____ ____    18.             Patient does NOT have an uncontrolled intercurrent illness including, but  
                                    not limited to, ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 
____ ____    19.             Patient has NOT undergone a major surgery within the past 4 weeks, other than  
diagnostic surgery (i.e. surgery done to obtain a biopsy for diagnosis without 
removal of an organ)  
 
____ ____   20.         Patient does NOT has history of other disease, metabolic dysfunction,  
                                   physical examination finding, or clinical laboratory fining 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 render 
                                   the patient at high risk from treatment complications 
 
_____ ____21.         Patient agrees to have two biopsies during the study 
                                        
                                                                          
 
 
Confirmation of Eligibility 
 
 
Patient meets all Inclusion Criteria as defined by the protocol. 
 
 
 
______________________________                                                         _________________________________                                 
Signature of site Study Coordinator                                                             Printed name of site Study Coordinator  
 
Phone:  ____________________________ 
 
Fax to return registration:  _________________ 
 
 
 
 
 
 
 
 
Email contact:  ____________________________ 
 
 
 


 
7
 
APPENDIX F 
Registration Form 
Please supply the following information for all patients who sign informed consent.* 
 
Please Print Legibly  
 
Study Number: 
      
 
Patient’s History Number 
      
(optional) 
 
Patient’s Name: 
      
 
   
 
      
 
 
 
     First Name 
 
 
    Middle Initial  
 
Last Name 
 
Patient’s Date of Birth: 
   
 
   
 
     
 
 
           Month 
 
Day 
         Year 
 
 
    Estimated start date: ___/____/____ 
 
 
    
_________________________________________________                 _________________ 
Signature of PE/Designee Completing Form                                             Date 
 
* Note: If a subject has more than one consent form for the same study, only complete this form ONE 
time.  
 
Attach this completed form to the eligibility check list, consent and fax to the attention of 
Rosalind Walker, RN at 443-287-6566 
 
To be completed By Johns Hopkins University 
 
Registration Confirmed: _______Yes _______ No   Patient ID Number: __ __ __ - __ __ __ 
 
Johns Hopkins Representative Signature: __________________   
Date:____________ 
 
 
Race: ( all that apply) 
Ethnicity: ( one)
Gender: ( one)
 American Indian or Alaskan Native   
 Hispanic or Latino 
 Male 
 Asian 
 Not Hispanic or Latino 
 Female 
 Black or African American 
 Unknown 
 
 Native Hawaiian or Other Pacific Islander 
 
 White 
 
 Other 
 
 Unknown 
 
Patient’s USA Zip Code: 
    
  
 
    
Foreign Country (if does not reside in US): 
      
Type of Cancer: 
      
(e.g. colon, lung, ALL, etc.) 


 
8
 
APPENDIX G: PROTOCOL SIGNATURE PAGE 
 
 
Protocol Number: J1013, NA_00036883 
 
 
 
A Phase II Study of Gemcitabine and nab-Paclitaxel in Combination with GDC-0449 
(Hedgehog Inhibitor) in Patients with Previously Untreated Metastatic Adenocarcinoma of 
the Pancreas 
 
 
Protocol Amendment 12, date December 4, 2014 
 
IND Number: 108819 
 
Sponsor: SU2C 
 
Coordinating Center: Johns Hopkins University 
 
 
I have read and understand the contents of the clinical protocol and agree to perform this 
study in accordance with the protocol and Good Clinical Practice (GCP) 21 CFR Parts and 
applicable regulations/guidelines.  
 
I agree to conduct the clinical study in accordance with these principals and the procedures 
described in this protocol. I am aware of my responsibilities as an investigator. 
 
 
PI Name:  
______________________  
 
 
Title:   
_______________________________   
 
Address:        _________________________________ 
 
 
 
_________________________________ 
 
 
 
_________________________________ 
                                       
    
PI Signature: _________________________________ 
 
 
Date:  
_________________ 
 
 
 


 
9
APPENDIX H: MEDICAL MONITOR SIGNATURE PAGE 
 
Protocol Number: J1013, NA_00036883 
 
 
Medical Monitor Signature Page 
 
 
A Phase II Study of Gemcitabine and nab-Paclitaxel in Combination with GDC-0449 
(Hedgehog Inhibitor) in Patients with Previously Untreated Metastatic Adenocarcinoma of 
the Pancreas 
 
 
Protocol Amendment 12, date December 4, 2014 
 
 
IND Number: 108819 
 
Sponsor: SU2C 
 
Coordinating Center: Johns Hopkins University 
 
 
I have read and approved the protocol and appendices. My signature, in conjunction with 
the signature of the investigator, confirms the agreement of both parties that the clinical 
trial will be conducted in accordance with the protocol and all applicable laws and 
regulations, including, but not limited to, the ICH Guidelines for  the Good Clinical 
Practice (GCP) and US 21 CFR Parts and the ethical principles that have their origins in 
the Declaration of Helsinki, as well as all applicable privacy laws.  
 
 
Name:  
______________________  
 
 
Title:   
_______________________________   
 
Address:        _________________________________ 
 
 
 
_________________________________ 
 
 
 
_________________________________ 
                                       
    
Medical Monitor Signature: _________________________________ 
 
 
Date:  
_______________ 
 


 
10
APPENDIX I: AMENDMENTS SUMMARIES 
 
 
Amendment 1, June 8, 2010 
 
1. Section 3.1.10 was updated to explain that sexually active male patients need a barrier of 
contraception until 12 months after stopping GDC-0449.  
2. In the dose modification section (section 6.2), the second paragraph in the portion entitled 
“Peripheral Neuropathy” was modified to clarify that nab-Paclitaxel will be hold in 
patients with grade 3 neuropathy until resolution to ≤ grade 1 neuropathy, regardless of 
suspected cause. In the same section the protocol now states that GDC-0449 should be 
held for grade 3 neuropathy until resolution to ≤ grade 1 neuropathy.   
 
Amendment 2, June 11, 2010 
1. The protocol was modified in section 5.3.1 to reflect there is a potential for GDC-0449 to 
also inhibit CYP1A2 and 2D6 in addition to 2C8, 2C9, and 2C19. Caution should be 
exercised and dose reduction of the concomitant substrate drug be considered when 
dosing GDC-0449 concurrently with medications with narrow therapeutic windows that 
are substrates of CYP1A2 and 2D6. In the same section a table of drugs that may 
interfere with CYP1A2 and 2D6 was added. 
 
Amendment 3, July 6, 2010 
 
1. Section 3.1.1: Eligibility criteria made clear to reflect that biopsy is required within 14 
days before starting treatment. 
2. Protocol Cover Page 
3. Table of contents was updated to reflect changes 
4. Version date in the protocol was changed to protocol amendment 3, date July 6, 2010 
5. Study calendar was modified. Circulating stem cells are collected also at the time of the 
second biopsy. 
 
 


 
11
 
 Amendment 4, August 16, 2010 
 
1. Protocol cover page, the principal Investigator has been changed at  Translational 
Genomics Research Institute, Scottsdale AZ site, they deleted Dan Van Hoff, MD as the  
     principal investigator and added Ramesh K. Ramanathan, MD as the principal  
     investigator.  
 
 
2. Protocol cover page, deleted Ana De Jesus-Acosta, MD as the co-investigator. Added Ana  
De Jesus-Acosta as the Co-Principal Investigator. Added Pamela Johnson as the co- 
           investigator. 
 
3. Protocol cover page, added Van Andel Research Institute, MI as the new site; added 
    Timothy J. O’Rourke, M.D. as the principal investigator for the site. 
 
4. It was added to eligibility checklist that biopsies are required in this study. Already 
     included in the inclusion criteria and consent forms. 
 
5. Version date in the protocol was changed to protocol amendment 4, date August 16, 2010 
 
6. Section 4 and 7.5 were modified to reflect the registration process using a centralized 
uniform database by CRAB. This includes electronic forms for adverse events and 
serious adverse events reporting. 
 
7. Section 5.1 follow up for survival will be done by telephone contact 
8. Changed fax number from 410-502-0834 to 443-287-6566 for the study 
 
9. Added Urinalysis test at the screening.  
 
 
10.  In section 9: Amount of blood that will be obtained for circulating cancer stem cells was   
 
decreased to 150 ml. 
 
11. Inserted Appendix G–Protocol signature page 
 
12. Inserted Appendix H- Medical Monitor Signature page 
 
 
13. Added drug destruction accountability instructions for nab-Paclitaxel and GDC-0449 in 
section 8 (pharmaceutical information) 
 
 
14. Section 9.1.5 for collection of SPARC and CA19-9 was updated 
 
 


 
12
15. Laboratory manual for processing of correlative studies samples was modified 
 
16. Modified statistical section 12.1.4 for practical purposes of multicenter trial. 
 
 
17. Updated Appendix I- Summary of changes 
 
18. Table of contents was updated to reflect changes. 
19. Study calendar modified Day 28 changed to day 22. 
20. Baseline CT scans will be done within 14 days prior to starting treatment. Section 5.1.2, 
5.1.3 and Study calendar were modified to reflect this.  
21. Protocol page 60, added “JHH Investigational Drug Services (IDS)” to section How 
Supplied GDC-0449. 
22. Protocol page 61, added “Supply:   GDC-0449 will be obtained from JHH IDS.” 
23. Protocol page 61, added “JHHIDS” in section “Packaging, Labeling, and Storage of Study 
Drug:”  
24. Protocol page 63, deleted “Upon receipt of the study drug supplies, the Investigator or 
designee will conduct an inventory and sign both copies of the study drug receipt and 
forward one copy to the address indicated on the form. One copy of the receipt and the 
packing slip must be retained in the Investigator'’s regulatory file records. A 
representative from Abraxis or his/her designee will inspect the study drug inventory, and 
will arrange for the return of any remaining unused study drug. No study drug may be 
returned without the representative from Abraxis or other Abraxis-designated personnel 
first inspecting the study drug inventory.  Study drug may be destroyed according to the 
institutional policy of study sites.  Supply: Will be obtained from Abraxis Bioscience 
using a commercial Badge” from section “Reconstitution and use of nab-paclitaxel #14”. 
25. Protocol page 64, added “Supply: nab-Paclitaxel will be obtained from JHH IDS.” 
26. Protocol page 64, added “Gemcitabine” in section “Packaging, Labeling, and Storage” 
27. Protocol page 66, added section 8.3 Study Medication Accountability and destruction  
(GDC-0449 and nab-Paclitaxel)  
 
 
 
 


 
13
Amendment 5, February 1, 2011 
 
1. Protocol cover page, deleted principal investigator Manual Hidalgo, MD. 
 
2. Protocol cover page, deleted site Centro Integral Oncology Clara Campal, Madrid Spain 
 
3. On foot section, insert  “ Protocol amendment 5, date February 1, 2011  
4. Page 3, added “Oct 19, 2010” as the approval date for amendment 4 
5. On page 46, Table 4 modified 
6. On page 47-48, modified the “Table 5. Dose Modifications for Hematologic Toxicity 
within a Cycle” 
7. On page 75, the shipping contacts for SPARC at section 9.1.5.5 was modified 
8. Apendix D: updated Patient Medication Diary 
9. On page 9, Table of contents was updated to reflect changes. 
10. On page 29, we removed second bullet 
11. On page 39, added “Guidelines for administration of GCSF are described in Table 5 but 
will be to the discretion of the investigator and according to institutional guidelines.” In 
section 5.2.4 
12. On page 72, deleted “National cancer Research Center (CNIO), Madrid” from section 
9.1.4 
13. On page 87, added “and treated on” and “with GDC” in section 12.2.4 
 
Amendment 6, August 3, 2011 
 
1. On foot section, insert  “ Protocol amendment 6, date August 3, 2011  
2. Modified the name of the study drug on the title page and page 3 
3. Deleted principal investigator: Timothy J. O’Rourke, MD from the title page 
4. Deleted “Van Andel Research Institute, MI  ” sub site from the title page  
5. Added IRB approval date on page 3 
6. Table of Contents has been updated 
7. Table 5 modified 


 
14
8. Section 2.4.1: The list of potential risks of GDC-0449 was updated. A list of the safety 
IND reports submitted to IND was added.  
9. Page 20, section “changed “12” to “7” months in section -–Reproductive and 
developmental Toxicity 
10. Eligibility criteria 3.1.10 was modified. Sexually active males must use a barrier form of 
contraception during GDC-0449 treatment and for 7 months after last dose. Based on the 
new Investigator Brochure. Eligibility checklist was modified to reflect this change. 
11. Eligibility criteria 3.1.11 was modified. The time period after which patients can donate 
blood or blood products following treatment with GDC-0449 was reduced from 12 
months to 7 months. Based on new Investigator Brochure. Eligibility checklist was 
modified to reflect this change. 
12. Page 42, changed 12 month to 7 month 
13. Eligibility criteria 3.2.8 was modified. Women pregnant and nursing women are 
excluded. Women planning to become pregnant during treatment or 7 months after last 
dose of treatment are excluded. Based on new Investigator Brochure. Eligibility checklist 
was modified to reflect this change. 
14. Section 7.4.1 adverse events of GDC-0449 were updated. Added ageusia and hypogeusia. 
15. Section 5.3.1 CYP2C8 inhibitors updated 
16. Section 9.1: An optional biopsy upon progression for patients with previous response to 
therapy was added. 
17. Study Calendar modified to explain that taste questionnaire will be filled at the beginning 
of cycle 2 and cycle 3 
18. Taste Questionnaire added as appendix J 
 
 
 
 


 
15
Amendment 7, January 11, 2012 
 
1. On foot section, insert  “ Protocol amendment 7, date January11, 2012  
2. Added the IRB approval date August 30, 2011 for the amendment 6 on the page 3. 
3. Table of Contents has been updated 
4. Section 9.1 (Correlative studies) has been modified. The second biopsy and blood sample 
collection for circulating stem cells will occur in all patients after receiving two cycles of 
treatment. Will be perform on Cycle 3, Day 1.  
5. Study Calendar (Section 10) modified to explain that second research biopsy and second 
blood sample for circulating stem cells will be obtained after two cycles of treatment. 
6. Consent form modified to reflect above changes. 
 
 
 
 
 
Amendment 8, February 7, 2012 
 
1. On foot section, insert  “ Protocol amendment 8, date February 15, 2012  
2. Added the IRB approval date February 7, 2012 for the amendment 8 on the page 3. 
3. University of Pennsylvania will re-open enrollment. See attached letter. 
4. Table at section 6.2 was modified. Additional 25% dose modifications are permissible to 
establish the tolerable dose for an individual patient. 
5. Section 6 modified. Delays for toxicities can be permitted up to 4 weeks (28 days). If 
longer than 28 days patients will be discontinued from the study. 
 
 
Amendment 9, February 22, 2013 
 
1. Section 12.25 and 12.3 for statistics and futility analysis were modified in light of new 
data available from a large Phase III study conducted using Gemcitabine and Abraxane 
presented in ASCO GI 2013. 
2. Study reopens to enrollment. 
 
 
 
 
 


 
16
Amendment 10, April 16, 2013 
 
1. Eligibility 3.1.10 was modified. Male patients need to use a form of contraception for a 
period of 2 months after stopping GDC-0449. Time was changed from 7 months to 2 
months as per updated IB.  
2. Eligibility checklist was modified to reflect above change. 
 
 
Amendment 11, August 16, 2013 
 
1. Updated safety language and precautions 
2. Updated contraception language 
3. Updated storage language 
 
 
 
 
 
Amendment 12, December 4, 2014 
 
1. Revised accrual number from 80 to 72 
2. Revised on site monitoring from CRAB to CRO QA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
17
 
 
 
 
 
 
 
 
 
 
 
APPENDIX J: GENENTECH FAX COVER SHEET 
 
 


 
18
 
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH 
 
AE / SAE FAX No: (650) 225-4682 
 
Alternate Fax No: (650) 225-5288 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 
 


 
19
 
 
 
 
 
 
 
 
 
 
 
APPENDIX K: TASTE AND SMELL QUESTIONNAIRE


 
20
A Phase II Study of Gemcitabine and Nab-Paclitaxel in Combination With GDC-
0449 (Hedgehog Inhibitor) in Patients With Previously Untreated Metastatic 
Adenocarcinoma of the Pancreas: Changes in Smell and/or Taste 
 
TASTE INFORMATION 
 
1. Since beginning this clinical trial, have you experienced a change in your 
sense of taste? Check all of the following statements that apply to you now: 
 
 
    My sense of taste has NOT CHANGED (If not, please skip to question 
#13) 
 
    My sense of taste is ALTERED, that is, things taste peculiar 
 
 
 
    I experience a taste when nothing is there (PHANTOM TASTE) 
 
 
    My sense of taste is HEIGHTENED (Hypersensitive) 
 
 
    My sense of taste is DIMINISHED (partial loss) 
 
 
    My sense of taste is ABSENT (complete loss) 
 
2.  When did you notice this change?           /        /            (Month/Day/Year)  
 
3. For each type of taste problem you experience, indicate by a check how your  
 symptoms have changed in the past week: 
 
 
Unchanged 
Improved 
Worsened 
 
 
TASTE LOSS 
 
 
 
HYPERSENSITIVITY 
 
 
 
TASTE ALTERED 
 
 
 
PHANTOM TASTE(S) 
 
 
 
 
4. For each of the following taste qualities, indicate with a check whether your 
perception of it is currently normal, diminished, absent, altered or heightened: 
 
Normal Diminished
Absent 
Altered 
Heightened
 
 
 
 
  SWEET 
 
 
 
 
 
 
  SALTY 
 
 
 
 
 
 
  SOUR(e.g.,       
          lemon, vinegar) 
 
 
 
 
 
 
  BITTER(e.g.,  
    tonic water, medicine) 
 
 
 
 
 
 
 
IF YOU DO NOT EXPERIENCE ALTEREDTASTE, PLEASE SKIP TO QUESTION #7 
 
 
 
 
 
 
 
 


 
21
 
5.  The kinds of things that taste ALTERED (different) to you are (check all that 
apply): 
 
FOODS/BEVERAGES (specify):    
 
 
 
 
 
 
 
 
TOBACCO PRODUCTS (specify):   
 
 
 
 
 
 
 
 
OTHER (specify):    
 
 
 
 
 
 
 
 
 
 
EVERYTHING TASTES ALTERED 
_________________________________________ 
6.  Does everything you believe to be altered now taste the same to you? 
 
NO, THINGS STILL TASTE DIFFERENTLY, BUT THEY DO NOT HAVE THE 
SAME QUALITY THEY USED TO. 
    YES, THEY ALL TASTE THE SAME. 
IF YOU DO NOT EXPERIENCE AN ORAL PHANTOM (a taste when nothing is there), 
PLEASE   SKIP TO QUESTION #13 
 
7.  Do you currently experience more than one type of oral phantom? 
 
   
NO 
 
   
YES 
 
8.  The oral phantom(s) is (check all that apply): 
 
Not at All 
Weakly 
Moderately
Strongly 
 
 
             SWEET 
 
 
 
 
             SALTY 
 
 
 
 
 
   SOUR 
 
 
 
 
 
   BITTER 
 
 
 
 
 
   ROTTEN 
 
 
 
 
 
   METALLIC 
 
 
 
 
 
   BURNING 
 
 
 
 
 
   TINGLING 
 
 
 
 
 
   OTHER 
 
 
 
 
 
 
Specify quality:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
22
 
9.  Does the oral phantom come from your (check all that apply): 
 
 
TONGUE (specify where): _____________________________________ 
 
 
THROAT 
 
 
GUMS 
 
 
DENTURES OR CAPS 
 
 
ROOF OF MOUTH 
 
SALIVA 
 
 
WHOLE MOUTH 
 
 
OTHER (specify):_____________________________________________  
 
 
10.  How often do you experience the oral phantom(s)? 
 
   
CONSTANTLY (ALWAYS PRESENT) 
 
   
DAILY 
 
   
AFTER EACH STUDY TREATMENT 
 
   
ONLY OCCASIONALLY 
              
OTHER (specify):_____________________________________________ 
 
 
11.  How long does your oral phantom usually last? 
 
THE PHANTOM IS ALWAYS THERE. 
 
24 HOURS OR MORE 
 
SEVERAL HOURS 
 
MINUTES 
 
BRIEF or TEMPORARY 
 
12.  How strong is your oral phantom(s) usually? 
 
VERY WEAK 
 
WEAK 
 
MODERATE 
 
STRONG 
 
 
 
 
 
 


 
23
SMELL INFORMATION 
 
13. Since beginning this clinical trial, have you experienced a change in your 
sense of smell? Check all of the following statements that apply to you now: 
 
  My sense of smell has NOT CHANGED (If not, please skip to question #23) 
  My sense of smell is ALTERED, that is, things smell peculiar 
 
 
  I experience a smell when nothing is there (PHANTOM SMELL) 
 
  My sense of smell is HEIGHTENED (Hypersensitive) 
 
  My sense of smell is DIMINISHED (partial loss) 
 
  My sense of smell is ABSENT (complete loss) 
 
 
14.  When did you notice this change?           /        /            (Month/Day/Year)  
 
 
15.  For each type of smell problem you experience, indicate by a check how your  
  symptoms have changed in the past week: 
 
 
Unchanged 
Improved 
Worsened 
 
 
SMELL LOSS 
 
 
 
HYPERSENSITIVITY 
 
 
 
SMELL DISTORTIONS 
 
 
 
PHANTOM SMELL(S) 
 
 
 
 
 
IF YOU DO NOT EXPERIENCE AN ALTEREDSMELL, PLEASE SKIP TO QUESTION 
#18 
 
 
16.  The kinds of odors that smell ALTERED (peculiar) to you are (check all that 
apply): 
 
 
FOODS/BEVERAGES (specify):    
 
 
 
 
 
 
 
 
 
PERFUMES (specify):   
 
 
 
 
 
 
 
 
 
 
 
TOBACCO PRODUCTS (specify):   
 
 
 
 
 
 
 
 
 
OTHER (specify):    
 
 
 
 
 
 
 
 
 
 
 
EVERYTHING SMELLS ALTERED ____________________________________ 
 
 
 
 
 
 


 
24
17.  Do all of the odors you believe to be altered now smell the same to you? 
 
NO, ODORS STILL SMELL DIFFERENT, BUT THEY DO NOT HAVE THE 
SAME QUALITY THEY USED TO. 
    YES, THEY ALL SMELL THE SAME. 
IF YOU DO NOT EXPERIENCE A PHANTOM SMELL, PLEASE SKIP TO QUESTION 
#23 
 
18.  Do you currently experience more than one type of phantom smell 
sensation? 
 
   
NO 
 
   
YES 
 
 
19.  The phantom odor(s) smell(s) like (check all that apply): 
 
Not at All
Weakly 
Moderately
Strongly 
 
 
 
  INFECTED TISSUE 
 
 
 
 
 
  SMOKY/BURNT 
 
 
 
 
 
  FECAL 
 
 
 
 
 
  ROTTEN 
 
 
 
 
 
  MUSTY/MOLDY 
 
 
 
 
 
  SWEET 
 
 
 
 
 
  METALLIC 
 
 
 
 
 
  CHEMICAL 
 
 
 
 
 
  OTHER 
 
 
 
 
 
Specify quality:  
 
 
 
 
 
 
 
 
 
 
 
20.  How often do you experience the phantom odor(s)? 
 
   
CONSTANTLY (ALWAYS PRESENT) 
 
   
DAILY 
 
   
AFTER EACH STUDY TREATMENT 
 
   
ONLY OCCASIONALLY 
 
 
 
 
 
 
 
 
 
 
 
 


 
25
 
21.  How long does your phantom usually last? 
   THE PHANTOM ODOR IS ALWAYS THERE. 
   24 HOURS OR MORE 
   SEVERAL HOURS 
   MINUTES 
   FLEETING 
 
 
22.  How strong is your phantom odor(s) usually? 
 
VERY WEAK 
 
WEAK 
 
MODERATE 
 
STRONG 
 
NUTRITIONAL INFORMATION 
 
23.  Since beginning this clinical trial, your appetite has been: 
 
 
BETTER 
 
 
UNCHANGED 
 
 
WORSE 
 
 
24.  Since beginning this clinical trial, you have enjoyed food: 
       MORE 
       THE SAME 
       LESS 
 
 
25.  Since beginning this clinical trial, have you changed the way you eat (e.g., 
types of foods, meal and snacking frequency)? 
       NO 
       YES (describe change):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26.  Since beginning this clinical trial, have you altered the amount of salt, sugar 
or spices you add to your food? 
       NO 
       YES (describe change):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
26
27.  Since beginning this clinical trial, have you started to strongly dislike or 
avoid certain foods? 
      NO 
      YES (specify foods):   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28.  Since beginning this clinical trial, have you had a strong desire or craving for 
certain foods? 
 
 
NO 
 
 
YES (specify foods craved):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
29.  Do you feel nauseated or sick to your stomach often? 
 NO 
 YES      
 
 
How severely? 
 
 
 
MILDLY 
 
 
 
EXTREMELY 
 
 
When?