Clinical trial NCT01431794
Conditions: Pancreatic Ductal Adenocarcinoma
Keywords: Pancreatic ductal adenocarcinoma (PDA)Neoplasms LDE225 nab-paclitaxel abraxane gemcitabine neoadjuvant cytotoxic hedgehog inhibitor stromal cells resectable PDA Pancreatic Diseases Carcinoma Sonidegib
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2011-12-27; Completion date: 2018-11-05
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label phase 1/2 study that will combine the chemotherapy agents gemcitabine and nab-paclitaxel with an oral hedgehog inhibitor LDE225 (Sonidegib). The objective is to assess tolerability and the resection rate of patients with borderline resectable pancreatic adenocarcinoma who use this treatment.

Detailed description:
The investigators propose treating 6-12 patients during the phase 1 portion and 40 patients in the phase 2 stage.

Phase 1 Stage:

Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 in combination with escalating doses (400mg, or 600mg, or 800mg) of LDE-225. After completion of neoadjuvant therapy, the subjects will receive combined chemotherapy and radiation. Then subjects who are eligible for resection will go ahead with surgery. Following resection, subjects will complete two additional cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 in combination with LDE-225.

Phase 2 Stage: In the Phase 2 stage the patients will be randomized to receive gemcitabine and nab-paclitaxel with or without the hedgehog inhibitor LDE225:

1. Arm A: Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m on days 1, 8 and 15 in combination with LDE-225 at the recommended phase 2 dose.
2. Arm B: Four cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m on days 1, 8 and 15.

After completion of neoadjuvant therapy, the subjects will receive combined chemotherapy and radiation. Then subjects who are eligible for resection will go ahead with surgery. Following resection, subjects will complete two additional cycles of the pre-surgical therapy.

Several correlative laboratory studies will be conducted during the course of this study. They were designed around the goals of providing us with a better understanding of how the stroma-tumor interaction and the intra-tumoral drug levels of gemcitabine are affected with the use of LDE-225. Two additional biopsies are required to participate in this study.

Arms: arm 1: Four cycles of Gemcitabine (gem) 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2 on days 1, 8, and 15 every 28 days cycle in combination with escalating doses of oral LDE225 (Sonidegib), 600 mg daily. arm 2: Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15 in combination with LDE-225 at the recommended phase 2 dose. Cycles repeated every 28 days. arm 3: Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15. Cycles repeated every 28 days. arm 4: Four cycles of Gemcitabine (gem) 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2 on days 1, 8, and 15 every 28 days cycle in combination with escalating doses of oral LDE225 (Sonidegib), 400 mg daily. arm 5: Four cycles of Gemcitabine (gem) 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2 on days 1, 8, and 15 every 28 days cycle in combination with escalating doses of oral LDE225 (Sonidegib), 800 mg daily.
Interventions: intervention 1: LDE225-600mg intervention 2: Gemcitabine intervention 3: nab-paclitaxel intervention 4: LDE225-400mg intervention 5: LDE225-800mg
Intervention descriptions: intervention 1: Phase I: oral LDE225 (Sonidegib), 600mg daily.

Phase II Arm A: LDE225 at the recommended phase 2 dose on Days 1, 8 and 15. Cycles repeated every 28 days. intervention 2: Four cycles of Gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days. intervention 3: Four cycles of nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days. intervention 4: Phase I: oral LDE225 (Sonidegib), 400mg daily. intervention 5: Phase I: oral LDE225 (Sonidegib), 800mg daily.

Protocol documents:
Prot_SAP_000.pdf: 
J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
1 
 
STUDY SYNOPSIS 
 
 
Title: Phase 1/2 Safety and Feasibility of Gemcitabine and Nab-Paclitaxel in combination with 
LDE-225 (Sonidegib) as Neoadjuvant Therapy in Patients with Borderline Resectable Pancreatic 
Adenocarcinoma. 
 
Novartis Study No: LDE225XUS03T 
 
Johns Hopkins IRB No: NA_00047491 
 
Johns Hopkins Internal No: J1130 
 
Principal Investigator:            Ana De Jesus-Acosta MD (email: adejesu1@jhmi.edu) 
                                                    
Co-Principal Investigator       Christopher Wolfgang, M.D., Ph.D. (email: cwolfga2@jhmi.edu) 
 
Co-Investigators:                     
 
Nilofer Azad, MD; Karen Bleich, MD; Steve Cho, MD; David 
Cosgrove, MD; Luis Diaz, MD; Ross Donehower, MD; Joseph 
Herman, MD; Karen Horton, MD; Elizabeth Jaffee, MD; Pamela 
Johnson, MD; Daniel Laheru, MD; Dung Le, MD; Keith 
McIntyre, CRNP; Siva Raman, MD; Zeshaan Rasheed, MD; 
Michelle Rudek-Renault, PhD, PharmD; Amy Ryan, CRNP; Eun 
Shin, MD; Richard Wahl, MD; Atif Zaheer, MD;  Lei Zheng, MD 
PhD; Stefan Zimmerman, MD;  
 
Program Manager:   
Tianna Dauses     (410) 502-7110, dauseti@jhmi.edu 
 
Sponsor:  Investigator Initiated 
 
Drug Supply: Novartis 
 
IND Sponsor:  
 
Ana De Jesus-Acosta, MD 
 
 
IND#:  
 
 
112289 
 
 
Statistician: 
                          Study Coordinator: 
 
 
Elizabeth Sugar 
Thomas Brown 
 
615 North Wolfe St, W5010 
550 North Broadway, Suite 415 
 
Baltimore, MD 21205 
Baltimore, MD 21205 
 
410-502-3913 
410-502-5328 
 
Fax: 410-502-4621 
Fax: 410-502-0834 
 
esugar@ jhsph.edu 
tbrown55@jhmi.edu  
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
2 
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Sheila Linden 
Thomas Brown 
 
550 North Broadway, Suite 415 
550 North Broadway, Suite 415 
 
Baltimore, MD 21205 
Baltimore, MD 21205 
 
410-614-4397 
410-502-5328 
 
Fax: 410-502-0834 
Fax: 410-502-0834 
 
Slinden2@jhmi.edu 
tbrown55@jhmi.edu 
 
 
Study Phase: Phase Ib/2                   
 
Patient Population:  Patients with borderline resectable pancreatic adenocarcinoma  
                                               
Concept and Rationale 
 
Pancreatic ductal adenocarcinoma (PDA) is one of the most dismal malignancies in the 
gastrointestinal tract and remains the fourth leading cause of cancer related mortality 1 . A 
subgroup of patients present with “borderline resectable” (BR) disease in which the tumor is 
technically resectable but has increased risk of positive margins, particularly if no pre-operative 
or “neoadjuvant” therapy is administered 2. There is a critical need to develop effective 
preoperative regimens to downstage the primary tumor to allow resection with negative margins 
in this group of patients. There is no established standard of care given the lack of prospective 
controlled studies.  
 
Commonly used regimens are extrapolation of therapies used in the metastatic setting and have 
focused on delivering cytotoxic agents to eliminate tumor cells. However, these cells compose 
only 10% of tumor bulk, with the remaining been composed by the tumor microenvironment or 
stroma. There is increasing interest on developing therapies that may target and eradicate the 
stromal compartment as a new therapeutic strategy for successful treatment in pancreatic cancer. 
Agents of interest for are hedgehog (Hh) inhibitors which will be evaluated in this study. 
 
The hedgehog (Hh) inhibitors are small molecules which block the Hh signaling pathway, also 
active in the stromal compartment through a paracrine mechanism 3-5. The tumor cells secrete Hh 
ligand and activate the pathway in the stromal cells. The Hh ligand in the extracellular space 
binds to Patched (PTCH1), a 12 pass transmembrane receptor reliving the inhibitory effect of 
PTCH1 on Smoothened (SMO). Signal transduction by SMO then leads to the activation and 
nuclear localization of GLI1 transcription factors and induction of Hh target genes resulting in 
tumor cell proliferation, invasion/migration, and metastatic tumor spread 6. In preclinical models, 
depletion of stromal compartment and revascularization of poorly perfused pancreatic tumors 
was achieved with a Hh inhibitor, IPI-926, on genetically engineered mouse models resulting in 
increased concentration of cytotoxic agent gemcitabine into the tumor and increased survival in 
the mouse models 7. Sonidegib is a potent, selective and orally bioavailable SMO antagonist. 
Treatment with sonidegib has shown in vivo efficacy in models of pancreatic cancer and is 
currently ongoing phase 1 study with minimal side effects8.  
 
Thus, agents that target the stroma may be an effective therapeutic strategy to eradicate the 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
3 
 
stroma, increase drug delivery and improve clinical outcomes. The following pilot phase 1/2 
study will evaluate if adding a Hh inhibitor in a neoadjuvant approach is safe and improves 
resection rate in patients with BR pancreatic cancer.  
 
Correlative studies aimed to elucidate how stromal depletion and drug delivery changes may 
affect the resection rate will be explored. The findings of this study will be the platform for 
larger phase II/III studies exploring these agents in patients with BR pancreatic adenocarcinoma. 
 
Objectives:   
 
Primary Objective (s) 
 
Primary objective for phase I component of the trial:  
 To evaluate the safety and feasibility of gemcitabine and nab-Paclitaxel combined with the 
Hh inhibitor sonidegib as neoadjuvant therapy in patients with borderline resectable PDA. 
 
Primary objective for phase II component of the trial:  
 To evaluate resection rate of two preoperative chemotherapy regimens in patients with 
borderline resectable PDA.  
 
Secondary Objectives (s) 
 To evaluate overall survival  
 To evaluate tumor response  
 To evaluate pathologic findings after neoadjuvant therapy. 
 To increase the precision of the estimates of toxicities related to treatment. 
 
Correlative Studies 
 To evaluate changes in stromal desmoplasia with the use of Hh inhibitors.  
 To evaluate changes of Hh signaling pathway on the biopsies and primary tumor using 
sonidegib.  
 To evaluate drug delivery of cytotoxic agents with or without the Hh inhibitor sonidegib.  
 
Primary Endpoint 
Primary endpoint for phase I component of the trial:  
 Safety Endpoints: Incidence, nature and severity of grade 3 and 4 toxicities that occur after 
Cycle 1, day 1. Grading according to National Cancer Institute Common Toxicity Criteria for 
Adverse Events (NCI CTCAE; version 4.0). 
 
Primary endpoint for phase II component of the trial: 
 Resection rate as defined by the percent of patients that undergo resection after completion of 
neoadjuvant therapy. 
 
Secondary Endpoints 
 Overall survival from day 1, cycle 1 
 Complete response, partial response, stable disease and progressive disease per RECIST 
criteria and PERCIST criteria 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
4 
 
 Post surgical pathologic findings including margin status, tumor differentiation and lymph 
node status after neoadjuvant therapy. 
 Toxicity rate, overall and stratified by grade and type. 
 
Correlative Endpoints: 
 Semiquantitative density of stroma. Results will be correlated with the primary endpoint 
resection rate. 
 Semi-quantitative measurement of Gli-1, SHH and PATCH on the biopsies and resected 
tumor.  
 Intratumoral gemcitabine triphosphate concentrations. Concentrations will be quantitated by 
UPLC with tandem mass spectrometry as previously done in preclinical models by our 
group9. 
 
Study Design:  Safety and feasibility Open label, Phase 1/2 trial. 
 
Phase 1 stage will be a single arm to find the maximal tolerated dose (MTD) of the combination 
of the three agents, which will be used in the phase II portion of the study, using 3 + 3 escalating 
design. The dose levels of gemcitabine (1000mg/m2) and nab-Paclitaxel (125 mg/m2) will be 
fixed. To minimize toxicities, the starting dose of sonidegib will be 600 mg daily, which is one 
dose level below the MTD at the single agent phase 1 study ongoing at Novartis.  If 0/3 or 1/6 
toxicities are observed for this combination, then the level of sonidegib will be escalated to 800 
mg.  If 1/3 or 2/6 toxicities are observed then the dose level will be deescalated to 400 mg. 
The MTD is defined as the highest dose at which 0 or 1 out of 6 toxicities are observed. If no 
toxicities are found with the combination of the two drugs, the recommended phase 2 dose will 
be equivalent to the final dose established on the ongoing Novartis phase 1 study which is 800 
mg. Toxicities will be evaluated after twomonth of therapy. The estimated number of patients for 
the phase 1 study is 6-12. The patients will have a pre-treatment and mid treatment biopsy which 
will be used for the correlative studies. Escalation will proceed as follows:   
 
Table 1: Phase 1 Dose Escalation Schedule 
 
 
Dose Level 
 
LDE 225 
(mg) 
Gemcitabine 
(mg/m2) 
Nab-Paclitaxel 
(mg/m2) 
Level -1 
400 
1000 
125 
Level 1 
600 
1000 
125 
Level 2 
800 
1000 
125 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
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1st cohort of 3 
patients at the 600 
mg LDE225 dose
(1-3)
Phase 1 Dose Escalating Schema for LDE225
DE-ESCALATE
1st cohort of 3 
patients at the 400 
mg LDE225 dose
(1-3)
2nd cohort of 3 
patients at the 600 
mg LDE225 dose
(4-6)
ESCALATE
1st cohort of 3 patients 
at the 800 mg LDE225 
dose
(1-3)
Clinical Hold-
Consider Protocol 
Amendments
2nd cohort of 3 
patients at the 400 
mg LDE225 dose
(4-6)
2nd cohort of 3 
patients at the 800 
mg LDE225 dose
(4-6)
Move on to Phase II 
trial at 800 mg 
LDE225 dose
Move on to Phase II 
trial at 600 mg 
LDE225 dose
Move on to Phase II 
trial at 400 mg 
LDE225 dose
# of DLTs
In cycle 2
# of DLTs
In cycle 2
# of DLTs
In cycle 2
0
1
2 or 3
0 or 1
2 or 3
0 or 1
>1 of 6
>1 of 6
0 or 1
2 or 3
>1 of 6
of 6
6 recruited
0 or 1
of 6
Cycle length= 28 days
DLT= dose limiting toxicity
1 of 6
Check Number of 
patients at the 600 
mg LDE225 dose
3 recruited
2nd cohort of 3 
patients at the 600 
mg LDE225 dose
(4-6)
0 or 1
of 6
Move on to Phase II 
trial at 600 mg 
LDE225 dose
 
 
 
Phase II stage (figure 1) will be an open label randomized study with two arms. The phase 2 
dose of sonidegib will be selected based on the findings of the above phase 1 study. The patients 
will have a pre-treatment and mid treatment biopsy which will be used for the correlative studies. 
Figure 1: In the Phase 2 stage the patients will be  
randomized to receive one of the following 
treatments: 
• Arm A: Four cycles of gemcitabine 1000 mg/m2 and 
Nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15 in 
combination with LDE-225 at the recommended phase 
2 dose. Cycles repeated every 28 days. 
• Arm B: Four cycles of gemcitabine 1000 mg/m2 and 
nab-Paclitaxel 125 mg/m2 on days 1, 8 and 15. Cycles 
repeated every 28 days.
0       4        8       12     16       20      27
C3
34      38
XRT
C5       C6 
Rest
C2
C4
C1
S
U
R
G
E
R
Y
Phase II Stage
Neoadjuvant  Study of Borderline Resectable Pancreatic Cancer
Resectable?
Yes
OFF STUDY
No
Enrollment
Pre-Rx Biopsy
week
Mid treatment 
Biopsy
Optional biopsy
Restage
Arm A:  Gem/ Nab-Paclitaxel/ LDE-225
Arm B:  Gem/Nab-Paclitaxel
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
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The primary endpoint for the phase II stage is the resection rate for each treatment arm, which is 
defined as the number of patients who complete neoadjuvant therapy and undergo resection.  
Secondary endpoints include overall survival from treatment initiation, response rates based 
upon RECIST and PERCIST criteria, post surgical pathologic characteristics (including margin 
status, tumor differentiation, lymph node status), as well as toxicity rates.  
 
 
Number of Patients:   
 
Estimated number of patients for phase 1 stage: 6-12 patients. Phase 2 stage: 40 patients (20 
patients per arm) 
 
Duration of Intervention and Evaluation 
 
Patients will receive a total of eight months of therapy from the onset of neoadjuvant therapy. 
They will continue on treatment unless they experience progressive disease, unacceptable 
toxicity, withdraw consent or the physician feels it is not 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 progression/recurrence and overall survival.  If an individual is lost to follow-up, 
then they will be censored at the time of the last contact.  
 
Statistical Methods 
 
Summary statistics for continuous outcomes (mean, SD, median, range) and categorical 
outcomes (count, percentage) will be calculated.  The number and grade of toxicities will be 
tabulated.  Percent of patients that achieved resection will be described with exact Binomial 95% 
confidence intervals. Kaplan-Meier techniques will be used to summarize time-to-event 
outcomes (overall survival and disease free survival) graphically and to estimate the median and 
one and two-year survival outcomes with 95% confidence intervals.  Cox proportional hazards 
functions will be used to estimate the effect of risk factors (e.g. tumor grade, nodal status) on 
overall survival.      
 
Patient Acceptability/Ethics and Concepts Issues: None 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
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Table of Contents 
STUDY SYNOPSIS ...................................................................................................................................................... 1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................................. 9 
1. 
OBJECTIVES ............................................................................................................................................... 11 
1.1 
Primary Objectives .......................................................................................................................... 11 
1.2 
Secondary Objectives ...................................................................................................................... 11 
2. 
BACKGROUND ........................................................................................................................................... 11 
2.1 
 Overview of Disease to be studied ................................................................................................. 11 
2.2 
 Rationale for this study/ Study Purpose ......................................................................................... 12 
2.3 
 Rationale for adding Nab-Paclitaxel .............................................................................................. 13 
2.4 
 Rationale for adding radiation therapy prior to surgery ................................................................. 13 
2.3 
 Study Drug LDE ............................................................................................................................ 13 
2.3.1 Overview of the hedgehog (Hh) pathway and its role in tumorigenesis ................................ 13 
2.3.2 Overview of Sonidegib .......................................................................................................... 14 
2.3.3 Clinical Experience with Sonidegib ....................................................................................... 16 
2.4 
 Other Drugs: Gemcitabine ............................................................................................................. 19 
2.5 Other Drugs: Nab-Paclitaxel ................................................................................................................... 21 
3. 
PATIENT SELECTION................................................................................................................................ 23 
3.1 
 Eligibility Criteria .......................................................................................................................... 23 
3.2 
 Exclusion Criteria .......................................................................................................................... 25 
3.3 
 Inclusion of Women and Minorities............................................................................................... 26 
4. 
TREATMENT PLAN ................................................................................................................................... 27 
4.1 
 Time to Event Schedule ................................................................................................................. 27 
4.1.1 Screening and Pre-study Assessments ................................................................................... 27 
4.1.2 Assessments during the study period ..................................................................................... 28 
4.1.3 Beginning of each cycle ......................................................................................................... 29 
4.1.4 Follow up assessments ........................................................................................................... 30 
4.1.5 Radiation Therapy .................................................................................................................. 32 
4.1.6  Surgery .................................................................................................................................. 33 
4.1.7 End of Therapy (EOT) Evaluation ......................................................................................... 34 
4.2 
 Agent Administration ..................................................................................................................... 34 
4.2.1 Sonidegib ............................................................................................................................... 38 
4.2.2 Gemcitabine ........................................................................................................................... 39 
4.2.3 Nab-Paclitaxel ........................................................................................................................ 39 
4.2.4 Other Modality (ies) or Procedures ........................................................................................ 39 
4.3 
 Definition of Dose-Limiting Toxicity ............................................................................................ 39 
4.4 
 General Concomitant Medication Supportive Care Guidelines with LDE .................................... 40 
4.4.1 Permitted concomitant therapy requiring caution and/or action ............................................ 40 
4.4.2 Prohibited concomitant therapy ............................................................................................. 41 
4.4.3 Contraception allowed/excluded ............................................................................................ 43 
4.4.4 Other Considerations .............................................................................................................. 44 
4.5 
 Duration of Therapy ....................................................................................................................... 45 
4.6 
 Duration of Follow Up ................................................................................................................... 45 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
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4.7 
 Criteria for Removal from Study ................................................................................................... 46 
5. 
DOSING DELAYS/DOSE MODIFICATIONS ........................................................................................... 46 
5.1 Sonidegib ................................................................................................................................................. 46 
5.2 Gemcitabine and nab-Paclitaxel .............................................................................................................. 51 
6. 
SAFETY MONITORING AND REPORTING ............................................................................................ 56 
6.1 Adverse Events ........................................................................................................................................ 56 
Definitions and reporting ................................................................................................................ 56 
6.2 Instructions for rapid notification of serious adverse events ................................................................... 57 
6.2.1 Reporting responsibility ......................................................................................................... 57 
6.2.2 Reporting procedures ............................................................................................................. 57 
6.3 Grading and Assessing Causality ............................................................................................................ 57 
6.4 Potential Risks for Study Drugs .............................................................................................................. 58 
6.4.1 Adverse Event List(s) for Sonidegib ...................................................................................... 58 
6.4.2 Adverse Event List(s) for Gemcitabine .................................................................................. 59 
6.4.3 Adverse Event List(s) for nab-Paclitaxel ............................................................................... 60 
6.5 Reporting Adverse Events ....................................................................................................................... 61 
6.5.1 Pregnancies ............................................................................................................................ 62 
6.5.2 Reporting Serious Adverse Events (SAEs) ............................................................................ 62 
6.6  Safety Reporting Requirements for IND Holders .................................................................................. 63 
6.7 Data and Safety Monitoring Plan ............................................................................................................ 64 
7. 
PHARMACEUTICAL INFORMATION ..................................................................................................... 65 
7.1 
Sonidegib ........................................................................................................................................ 65 
7.2 
Gemcitabine .................................................................................................................................... 67 
7.3 
nab-Paclitaxel ................................................................................................................... 69 
8. 
CORRELATIVE/SPECIAL STUDIES ......................................................................................................... 72 
10. 
MEASUREMENT OF EFFECT ................................................................................................................... 80 
10.1 
Antitumor Effect – Solid Tumors ................................................................................................... 80 
11. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 88 
11.1 
Study Design/Endpoints .................................................................................................................. 88 
11.2 
Sample Size/Accrual Rate ............................................................................................................... 88 
11.3 
Analysis .......................................................................................................................................... 89 
11.4 
Futility Assessment and Toxicity Monitoring Guidelines ............................................................... 90 
12 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES .................................................... 91 
12.1 Ethics and good clinical practice ........................................................................................................... 91 
12.2 Institutional Review Board/Independent Ethics Committee ................................................................. 91 
12.3 Informed consent ................................................................................................................................... 92 
12.4 Discontinuation of the study .................................................................................................................. 92 
12.5 Amendments to the protocol ................................................................................................................. 92 
12.6 Publication of results ............................................................................................................... 92 
12.7 Disclosure and confidentiality ................................................................................................. 93 
12.8 Declaration of Helsinki ........................................................................................................... 93 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
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Appendices .................................................................................................................................................................. 96 
APPENDIX A ................................................................................................................................................... 
APPENDIX B ................................................................................................................................................... 
APPENDIX C ................................................................................................................................................... 
APPENDIX D ................................................................................................................................................... 
APPENDIX E:................................................................................................................................................... 
APPENDIX F: AMENDMENT SUMMARIES ............................................................................................... 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
 
 
AE          
Adverse Event 
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) 
BR 
Borderline Resectable 
BSA 
Body Surface Area 
BUN      
Blood Urea Nitrogen 
CA19-9               
Carbohydrate Antigen 19-9 
CBC 
Complete Blood Count 
CI   
Confidence Interval 
CK 
Creatinine Kinase 
CR     
Complete Response 
CRO 
Clinical Research Organization 
CSC 
Cancer Stem Cells 
CT    
Computed Tomography 
CTCAE             
                
Common Terminology Criteria for Adverse 
Events 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
CRF 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
10 
 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
MRI                   
Magnetic Resonance Imaging 
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 
PDA 
Pancreatic Ductal Adenocarcinoma 
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 
SCLC 
Small Cell Lung Cancer 
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 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
11 
 
1. 
OBJECTIVES 
 
 
1.1 Primary Objectives 
 
This study combines the chemotherapy agents gemcitabine and nab-paclitaxel with an orally 
bioavailable hedgehog inhibitor, sonidegib, for the treatment of patients with borderline resectable 
pancreatic adenocarcinoma.  
 
Primary objective for phase I component of the trial:  
 To evaluate the safety and feasibility of gemcitabine and nab-paclitaxel combined with the 
Hh inhibitor sonidegib as neoadjuvant therapy in patients with borderline resectable PDA. 
 
Primary objective for phase II component of the trial:  
 To evaluate resection rate of two preoperative chemotherapy regimens in patients with 
borderline resectable pancreatic adenocarcinoma.  
 
 
1.2 Secondary Objectives 
 
 To evaluate overall survival 
 To evaluate tumor response  
 To evaluate pathologic findings after neoadjuvant therapy. 
 To increase the precision of the estimates of toxicities related to treatment. 
 
 
1.3 
Correlative Objectives 
 To evaluate changes in stromal desmoplasia with the use of Hh inhibitors.  
 To evaluate changes of Hh signaling pathway on the biopsies and primary tumor using 
sonidegib.  
 To evaluate drug delivery of cytotoxic agents with or without the Hh inhibitor sonidegib.  
 
 
2. 
BACKGROUND 
 
 
2.1  
Overview of Disease to be studied 
 
Pancreatic ductal adenocarcinoma (PDA) is one of the most dismal malignancies in the 
gastrointestinal tract and remains the fourth leading cause of cancer related mortality10. In 
patients with clearly resectable disease, surgery is often the initial treatment provided with 
curative intent. A subgroup of patients present with “borderline resectable” (BR) disease in 
which the tumor is technically resectable but has increased risk of positive margins, particularly 
if no pre-operative or “neoadjuvant” therapy is administered 2. Recent surgical consensus had 
developed a uniform definition of borderline resectable PDA including: (1) tumor associated 
deformity of the superior mesenteric vein (SMV) or portal vein (PV), (2) abutment of the SMV 
or PV < 1800, (3) short-segment occlusion of the SMV or PV amenable to resection and venous 
reconstruction, (4) short-segment involvement of the hepatic artery or its branches amenable to 
resection and reconstruction or (5) abutment of the superior mesenteric artery (SMA) < 1800 11. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
12 
 
Unfortunately, not all patients with BR disease are taken to surgery, which is an outcome that 
would translate in increased survival. The largest report published to date retrospectively studied 
160 BR patients. Using neoadjuvant chemotherapy or chemoradiation, resection was successfully 
achieved in 41% of the patients. Median survival was 40 months for the 66 borderline patients 
who completed all therapy and 13 months for the 94 patients who did not undergo 
pancreatectomy (P=0.001)12. In the absence of clinical trials to establish standard of care, pre-
operative therapy using gemcitabine-based regimens is recommended 11. Available regimens 
have focused on delivering cytotoxic agents to eliminate tumor cells. However, these cells 
compose only 10-30% of tumor bulk, with the remaining been composed by the surrounding 
tumor microenvironment or stroma. Abundant stromal desmoplasia is associated with decreased 
survival and poor outcomes 13,14. Thus, agents that may target the stroma are of interest in this 
disease. 
 
The hedgehog (Hh) signaling pathway is active in the stromal compartment through a paracrine 
mechanism 3-5. The tumor cells secrete Hh ligand which activates the pathway in the stromal 
cells. The Hh ligand in the extracellular space binds to Patched (PTCH), a 12 pass 
transmembrane receptor relieving the inhibitory effect of PTCH on Smoothened (SMO). Signal 
transduction by SMO leads to the activation and nuclear localization of GLI1 transcription 
factors and induction of Hh target genes resulting in tumor cell proliferation, invasion/migration, 
and metastatic tumor spread 6. In preclinical studies Hh inhibitors had demonstrated direct anti-
tumor effects when used in combination with the cytotoxic agent gemcitabine. Hh inhibitors 
resulted in depletion of the stromal compartment, revascularization of poorly perfused tumors, 
and increased concentration of gemcitabine into the tumor, resulting in increased gemcitabine 
sensitivity and tumor lysis in a transgenic PDA mouse model. This ultimately resulted in 
increased survival of the mice in this mouse model 7. In this study we will use the Hh inhibitor, 
sonidegib, which is a potent, selective and orally bioavailable SMO antagonist. Treatment with 
sonidegib has led to tumor regression in vivo in several genetically defined medulloblastoma 
models and has increased in vivo efficacy in models of PDA (Investigator’s brochure). Sonidegib 
is currently undergoing testing in a phase 1 clinical trial in which minimal side effects has been 
observed8.  
 
 
2.2  
Rationale for this study/ Study Purpose 
 
Here we propose a phase 1/2 safety and feasibility study to evaluate whether or not combining 
these agents in a neoadjuvant setting is safe and improves the resection rate in patients with BR 
PDA. The pre-operative agents will include the cytotoxic agent gemcitabine and nab-Paclitaxel 
with the Hh inhibitor sonidegib. Correlative aims to elucidate how Hh inhibitors disrupt stromal-
tumor signaling, provide clinical benefit, and affect drug delivery changes will be explored. We 
hypothesize that adding Hh inhibitors to cytotoxic agents is safe and will result in increased 
resection rates. Due to the lack of prospective controlled studies to estimate the true resection 
rate in patients with BR pancreatic cancer, stromal desmoplasia scores and intratumoral drug 
concentrations we will conduct a pilot safety and feasibility study.  
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
13 
 
 
2.3  
Rationale for adding Nab-Paclitaxel 
 
A new phase III trial was recently completed and final results were presented at the national 
meeting ASCO Gastrointestinal Malignancies in January 2013. The final results of the large 
randomized phase III trial in patients with metastatic pancreatic cancer included 861 patients 
randomized to nab-paclitaxel/gemcitabine (n=431) or gemcitabine (n=430). The results 
demonstrated that all clinical outcomes (survival, one year survival, objective response rates) 
favored the group of patients treated with gemcitabine and nab-Paclitaxel. Median OS was 8.5 
months for nab-paclitaxel/gemcitabine versus 6.7 months for gemcitabine (HR=0.72, 95% 
CI:0.617–0.835, P=0.000015). The 1-year survival rate was 35% versus 22% and 2-year survival 
was 9% versus 4% for nab-paclitaxel/gemcitabine versus gemcitabine, respectively. Median PFS 
was 5.5 for nab-paclitaxel/gemcitabine versus 3.7 months for gemcitabine (HR=0.69, 
95%CI:0.581–0.821, P=0.000024). ORR was 23% for nab-paclitaxel/gemcitabine versus 7% for 
gemcitabine, P=1.1x10-10. For the present study pre-operative regimens to enhance response are 
needed to successfully undergo surgery. Nab-Paclitaxel will now be presented to the FDA as a 
standard regimen for pancreas cancer. The NCCN guidelines endorse utilizing regimens used in 
the metastatic setting in patients with localized disease. This includes nab-Paclitaxel. For this 
reason, findings of the phase III study and the need for substantial responses prior to surgery 
Nab-Paclitaxel is added to the study.  
 
2.4  
Rationale for adding radiation therapy prior to surgery 
 
Specifically in patients with borderline resectable disease there are no standard regimens as no 
randomized controlled trial specific to borderline resectable PDAC has yet been completed. 
Radiation therapy has been given inconsistently either before or after surgery on single 
institution studies. At the time of the study design we included the radiation therapy after the 
surgery. We have now moved the radiation therapy prior to surgery for several reasons: 1) we 
had patients with local but no systemic progression while on treatment that needed radiation 
therapy prior to attempting definitive surgery. 2) It is more tolerable for the patients to receive 
the radiation therapy prior to surgery 3) The MD Anderson group published study that 
demonstrated benefit of chemoradiation therapy at the oncologically critical superior mesenteric 
artery (SMA) margin among patients with this disease stage. Patients who received 
chemoradiation, had longer SMA margin distances than those who did not. Patients who 
received chemoradiation and had a SMA margin of > 1 mm had the lowest recurrence rates. 
Administration of neoadjuvant chemoradiation and lower estimated blood loss were 
independently associated with longer progression-free survival on multivariate analysis (Katz, 
Wang et al. Journal of Gastrointestinal Surgery).  
 
 
 
2.3  
Study Drug LDE 
 
2.3.1 Overview of the hedgehog (Hh) pathway and its role in tumorigenesis 
Smoothened (Smo) is a G protein–coupled receptor (GPCR)–like molecule that positively 
regulates the Hedgehog (Hh) signal transduction pathway. Normally, the activity of Smo is 
repressed by the trans-membrane receptor Patched (PTCH). Upon Hh ligand (Sonic Hh, Indian 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
14 
 
Hh or Desert Hh) binding to PTCH, its inhibitory effect on Smo is attenuated and the pathway 
becomes activated, leading to the release of Gli transcription factors from a complex of cytosolic 
inhibitory proteins. Active Gli transcription factors are translocated into the nucleus to induce Hh 
target genes, which control cell proliferation, survival and differentiation. The Hh signaling 
pathway plays a critical role in the embryonic development and homeostasis of many human 
organs and tissues. Genetic alterations in the Hh pathway are linked to the development of 
several human tumors (basal cell carcinoma (BCC), medulloblastoma (MB) and 
rhabdomyosarcoma). Aberrant Hh signaling without evidence of genetic defects has also been 
linked with other tumors, such as pancreatic cancer, small cell lung cancer, gastro-intestinal 
tumors and ovarian cancer.  The pivotal role of Hh pathway in BCC was demonstrated in mice 
genetically engineered to express mutations of PTCH1 and SMO typically seen in human 
sporadic BCCs (Daya-Grosjean 2005).   
 
2.3.1.1 Inhibition of Hh pathway by small molecules 
 The inhibition of the Hh signaling pathway as a therapeutic approach has increasingly become 
an area of extensive research.  A number of small-molecule inhibitors of the Hh pathway, via 
smoothened inhibition, have progressed into clinical trials in a wide variety of cancers.  
GDC0449 (Roche)  is being evaluated in clinical trials in basal cell carcinoma, medulloblastoma 
(recurrent and refractory in adults and young patients), ovarian cancer, advanced pancreatic 
cancer, advanced sarcoma, locally advanced prostrate cancer, advanced breast cancer, advanced 
esophageal junction and SCLC. XL-139 (BMS) is currently undergoing testing in combination 
with chemotherapy in SCLC, gastric/esophageal, multiple myeloma and chronic myeloid 
leukemia (CML). Recently, clinical trials have been initiated with PF-04449913 (Pfizer) and IPI 
926 (Infinity) in combination in CML and in metastatic pancreatic cancer, respectively. 
The anti-tumor activity of Smo inhibitors has recently been demonstrated in patients with locally 
advanced or metastatic BCC and recurrent medulloblastoma (von Hoff et al 2009, Scales and 
Sauvage 2009, Siu L EORTC-NCI-AACR 2009, Ahnert JR ASCO 2010, Ahnert JR ESMO 
2010, Rudin et al ESMO 2010) and in superficial BCC in patients with Gorlin syndrome (De Rie 
et al 2010).  
 
2.3.2 Overview of Sonidegib 
Sonidegib is a potent selective and orally bioavailable SMO antagonist from a novel structural 
class  N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4’-(trifluoromethoxy)-1,1’-
[biphenyl]-3-carboxamide diphosphate, currently being tested in clinical trials in patients with 
cancer. 
 
2.3.2.1 Pharmacodynamics 
Sonidegib potently inhibits both human and mouse Smo at low nanomolar concentrations (11 
and 12 nM, respectively) in competitive binding in vitro assays. In a single dose 
pharmacokinetic–pharmacodynamic (PK-PD) study, 20 mg/kg sonidegib resulted in >90% 
inhibition Gli1 mRNA expression in tumor samples that was sustained for over 24 hrs. Daily 
multiple doses of sonidegib (20 mg/kg QD) caused >90% tumor regression in genetically defined 
in vivo MB xenograft models characterized by heterozygous deletion of PTCH.  


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
15 
 
 
2.3.2.2 Nonclinical pharmacokinetics and metabolism 
Sonidegib was well absorbed with good oral bioavailability, ranging from 68 to 100% in the 
mouse, rat, dog, and monkey after oral (p.o.) administration either in the form of a solution or a 
phosphate salt suspension. The compound showed low to moderate plasma clearance relative to 
blood flow in mouse, rat, dog and monkey. Sonidegib exhibits high protein binding 
(approximately 98% in mouse, rat, dog and human plasma), independent of concentration. The 
compound was extensively distributed into tissues and its volume of distribution (Vss) at steady-
state was greater than total body water (1.9-6.9L/kg). In rats, ~85% of sonidegib related 
radioactivity was eliminated into the feces, and renal excretion was minor, accounting for <3.0% 
of the administered dose.  
Clearance of sonidegib is primarily hepatic by CYP3A4. Sonidegib was extensively metabolized, 
with the major metabolic pathway being via mono- or dioxygenation, demethylation, and 
oxidation leading to carboxylic acid formation, dealkylation, and dehydrogenation 
monohydroxylation. The elimination of metabolites was mainly through the bile. 
Studies with human liver microsomes demonstrated that sonidegib is a competitive inhibitor of 
CYP2B6 (IC50 ~0.5 µM; Ki 0.045 µM), and CYP2C9 (IC50~5 µM; Ki 1.7 µM), but showed very 
little or no inhibition of CYP1A2, 2A6, 2C8, 2C19, 2D6, 2E1 or 3A4/5 at concentrations of up to 
100 µM. No apparent time-dependent inhibition of the major CYP450 enzymes was observed. 
Sonidegib is neither a substrate nor an inhibitor of P-glycoprotein (Pgp) or multi-resistance 
protein 2 (MRP2); but it has demonstrated inhibitory effects on breast cancer resistance protein 
(BCRP), with an estimated IC50 value of 1.5 M. The potential of sonidegib and its metabolites 
to undergo covalent binding to cellular macromolecules was found to be low. 
The results of toxicokinetics (TK) studies with sonidegib indicated that systemic exposure after 
oral administration, as measured by Cmax and AUC, was not linear and in general was less than 
dose-proportional in both rats and dogs.  There was drug accumulation after once daily repeat 
oral doses, which was more pronounced and dose-dependent in dogs.  There was an apparent 
gender difference in exposure in rats following multiple dosing, with female rats exhibiting 
higher exposure than male rats. Please refer to the [Investigator’s Brochure] for more details on 
the non-clinical toxicity, toxicokinetics and safety of sonidegib. 
 
2.3.2.3 Toxicity and safety Studies with Sonidegib 
The majority of adverse effects observed in toxicity studies in growing rats and dogs can be 
attributed to the pharmacologic action of sonidegib, and the effects in both species were similar.  
The most striking effects of sonidegib, which are consistent with literature reports on other Hh 
pathway inhibitors, were on bone and consisted of thinning or closure of growth plates in the 
sternum and femur and decreasing proliferating chondrocytes in the chostochondral junction of 
ribs. In addition, decreases in bone alkaline phosphatase were observed in dogs [Investigator 
Brochure]. The observations were more pronounced in rats, which is a species where the growth 
plate does not close.  Similar observations have been reported for other Smo inhibitors  in animal 
studies (e.g. GliLuc transgenic mice, IHH transgenic mice) including thinning and early closure 
of the growth plate, shortened bones, inhibition of tooth growth and abnormal bone structures, 
particularly the femur and tibia (Maeda 2007, Kimura 2008).  This is likely due to the role of the 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
16 
 
Hh pathway in bone development, particularly in the early stages of bone formation and growth 
(Kimura 2008).  
These effects are not likely to occur in the adult cancer patient population intended for the 
clinical studies due to the maturity of their skeletal system. However, it anticipated that Smo 
inhibition may likely affect the development of bones and teeth in growing children. Hence, 
monitoring for these effects will be required during therapy with Smo inhibitors in children. 
Preclinical cardiovascular safety pharmacology data do not indicate a clinical risk for QTc 
prolongation.  There is also no indication of effects on the central nervous and respiratory 
systems from the preclinical data. Please refer to the [Investigator’s Brochure] for more details 
on the non-clinical toxicity and safety of sonidegib. 
 
2.3.3 Clinical Experience with Sonidegib 
 
2.3.3.1 Clinical safety and efficacy 
  
Sonidegib is currently undergoing phase I evaluation in a first-in-human clinical trial, to assess 
the safety, tolerability, PK, PD and potential efficacy of continuous once daily oral 
administration in patients with malignant solid tumors [Study CLDE225X2101]. Data provided 
here are obtained from an active clinical trial database; therefore, they are preliminary and 
subject to change upon final QC review when the study is completed. 
As of October 29, 2010, data were available on 76 patients with cancer who have been treated 
with sonidegib at dose levels of 100, 200, 400, 800, 1000, 1500, and 3000 mg once daily (QD) 
and 400 and 750 mg twice daily (BID).  Once daily administration of sonidegib, up to 800 mg, 
has been found to be well tolerated. DLTs that are characterized by CTC grade 3 or 4 increases 
in plasma creatine phosphokinase (CK) (rhabdomyolysis) associated with muscle pain, muscular 
weakness and increased plasma myoglobin have been observed at once daily doses ≥1500 mg 
and twice daily doses ≥400 mg. Of the 13 patients who experienced CTC grade 3 or 4 CK 
elevation, ten were observed within the initial 6 weeks of treatment with sonidegib and three 
were observed after 6 weeks. None of the patients experienced impairment of renal function as a 
result of this toxicity.  Of the 13 patients who experienced these DLTs, eleven cases resolved 
over a period of up to 4 weeks following discontinuation of sonidegib therapy, with the 
remaining two cases taking up to 8 weeks to resolve. sonidegib 1000 mg QD is currently being 
evaluated, and as of January 04, 2011, 1 out of 4 evaluable patients at this dose had developed 
CTC grade 4 CK elevation associated with muscle cramps. This DLT occurred on Cycle 2 Day 8 
and the study treatment has since been withheld for this patient.   
 
Table  
Incidence of dose limiting toxicities in Study CLDE225X2101  
 
 
Elevated  plasma CK 
Dose of Sonidegib 
Number of 
patients treated 
Number of 
patients with 
CTCAE grade 3 
 
Number of 
patients with 
CTCAE grade 4 
 
Total  (CTCAE 
grade 3 or 4) 
100 mg QD  
6 
0 
0 
0 
200 mg QD  
6 
0 
0 
0 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
17 
 
400 mg QD  
5 
0 
0 
0 
800 mg QD  
19 
0 
0 
0 
400 mg BID  
8 
1 
1 
2 
1000 mg QD 
6 
0 
1 
1 
750 mg BID  
8 
0 
5 
5 
1500 mg QD  
9 
0 
3 
3 
3000 mg QD  
9 
0 
3 
3 
Total 
76 
1 
13 
14 
 
Commonly (>10%) reported CTCAE grade 1 or 2 that are suspected to be treatment-related 
include: nausea, vomiting, dysgeusia, decreased appetite, myalgia, muscle spasms and fatigue,  
(see Table 1-2). No treatment-related clinically significant changes in the other safety laboratory 
data (hematology, and urinalysis), vital signs or ECGs have been observed for any of the patients 
treated in the study. Refer to the Investigators Brochure for further details. 
 
Table Adverse events suspected to be related with sonidegib, occurring in ≥5% of 
patients 
AE (preferred term) 
All 
N= 76 
 
All grades 
N (%) 
Grade 3/4 
N (%) 
Nausea 
21 (27.6) 
0 
Dysgeusia 
19 (25.0) 
0 
Muscle spasms 
18 (23.7) 
0 
Blood creatine phosphokinase increased 
17 (22.4) 
12* (15.8) 
Decreased appetite 
11 (14.5) 
0 
Fatigue 
11 (14.5) 
0 
Vomiting 
9 (11.8) 
0 
Myalgia 
8 (10.5) 
0 
Alopecia 
7 (9.2) 
0 
Weight decreased 
6 (7.9) 
0 
Diarrhea 
5 (6.6) 
0 
Headache 
5 (6.6) 
0 
Lethargy 
5 (6.6) 
0 
Aspartate amino transferase increased 
4 (5.3) 
2 (2.6) 
Asthenia 
4 (5.3) 
2 (2.6) 
Myositis 
4 (5.3) 
2 (2.6) 
Pain in extremity 
4 (5.3) 
0 
* An additional patient who experienced grade 4 CK elevation was not captured 
in this table because the investigator had indicated the event was not treatment-
related in the clinical database. However, the patient had high systemic sonidegib 
exposure, which was consistent with other patients who experienced DLTs. Also, 
the DLT of CK elevation at 1000 mg QD occurred after the database cut-off date 
on Oct 29, 2010. 


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18 
 
 
Clinical Efficacy 
 
Preliminary antitumor activity and evidence of disease stabilization has been observed with 
sonidegib treatment. Of the 5 patients with recurrent medulloblastoma (MB) treated, one patient 
achieved a partial response (PR) according to RECIST after 2 months of treatment (200 mg QD) 
and the response was maintained for 4 months. A second MB patient with bone metastases also 
achieved a partial metabolic response (PMR) on FDG-PET after 2 months of therapy (1500 mg 
QD). This metabolic response was associated with improvement in bone pain and was 
maintained for ~10 months. In addition, among the 10 patients with locally advanced and 
metastatic BCC, tumor responses and disease stabilization have been observed  as follows: 
 One patient with metastatic BCC has remained on therapy (200 mg QD) for > 18 months 
with stable disease (SD);  
 A patient with multiple-recurrent infiltrating BCC on 400 mg BID achieved complete 
clinical and histological response (CR) after 4 months of therapy and is still tolerating 
treatment after 10 months; 
 A Gorlin patient with locally advanced multifocal BCC, who was treated with 400 mg 
BID, achieved a partial response (PR) despite coming off treatment after approximately 6 
weeks due to grade 4 CK elevation.  
 A Gorlin syndrome patient with locally advanced multifocal BCC experienced a PR after 
only 7 weeks of therapy (800 mg QD);  
 A patient with locally advanced auricular BCC has remained on study treatment (800 mg 
QD) for >5 months with SD; and  
 Two metastatic BCC patients (800 mg and 1000 mg QD) experienced PRs after 2 months 
on therapy.  
 
In summary, 1 CR, 4 PRs and 2 prolonged SDs have been observed. Based on the limited 
number of pre- and post-treatment tumor biopsies (from 4 BCC patients), sonidegib caused at 
least 95% reduction in Gli1 mRNA expression compared with baseline values (day 28 compared 
with day 1), except for the Gorlin syndrome patient at 800 mg QD, where the target inhibition in 
tumor appeared to be modest (40%) on day 28. Of note, the CR and complete histological 
clearance observed at 400 mg BID was associated with a 99% reduction in Gli1 mRNA 
expression in tumor.  
 
2.3.3.2 Clinical Pharmacokinetics and pharmacodynamics 
The available preliminary PK data demonstrate that the median peak plasma concentrations of 
sonidegib occurs at 4 hours (range: 2-24 hours) after dosing. Plasma exposure to sonidegib 
(Cmax and AUC) after single dose administration increases dose-proportionally from 100-
800 mg and appears to plateau at higher dose levels  (1500 mg to 3000 mg). On cycle 1 Day 15 
Cmax and AUC increase linearly with doses up to 400 mg/day, and in a less than dose-
proportional manner with higher doses (800 to 3000mg/day). sonidegib exposure at 400 mg BID 
demonstrates ~30% higher mean AUC on day 15 compared with exposure at 800 mg QD, and 
AUC at 750mg BID is approximately 18% greater than the AUC achieved at 1500 mg QD. The 
median accumulation index is 3-fold (range: 0.5-12), and 6-fold (range: 2.22-22.1.) for Cmax and 
AUC, respectively, on cycle 1 Day 15 compared with the single PK run-in dose. Due to the long 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
19 
 
apparent terminal half-life of sonidegib, an accurate terminal half-life cannot be calculated using 
a non-compartmental approach. The estimated effective half-life, calculated on the basis of the 
accumulation index across dose groups, is greater than 4 days (range: 1-14 days). Successive 
measurements of plasma trough concentrations (Cmin) over time suggest that steady-state appears 
to be achieved after 28 days of daily dosing. Trough levels on day 15 (pre-dose) correlate well 
with AUC and Cmax on day 15 during daily administration of sonidegib. The inter-patient 
coefficient of variation in sonidegib AUC is 40 to 58% across the dose range of 100 mg to 3000 
mg/day. Exploratory analyses suggest that the odds of observing a CK DLT increase with AUC 
on day 15.  In addition, the probability of a CK DLT is expected to be low (< 0.16) for exposure 
levels (AUC day 15) below 41 µM*hr (equivalent to an average steady state concentration of 
approximately 1.7 µM).  
Analyses of skin punch biopsies taken at baseline and at the end of the first treatment cycle (day 
28) have shown evidence of potent target modulation, as measured by Gli1 mRNA, in a dose- 
and exposure-dependent manner. The available data shows that sonidegib caused up to 95% 
mean reduction in Gli1 expression in skin compared with baseline values. The maximum 
observed inhibition of the target in skin (as measured by Gli1 expression) was observed at 1500 
mg QD. Based on the limited data on PD effect in tumor biopsies (n=4 paired samples), where 
up to 99% reduction in Gli1 expression was observed, skin is a good surrogate tissue for 
assessing target inhibition. On the whole, the changes in Gli1 expression in skin appeared to be 
highly variable, particularly within the 800 mg QD cohort, where a relatively large number of 
paired samples were obtained compared with the other doses. Sonidegib, at 800 mg QD, 
demonstrated a mean reduction in Gli1 mRNA in skin of approximately 74% (n=13, range: 8.3% 
- 95.8%) compared with baseline values after 28 days of therapy. At 200 mg QD, approximately 
68% (n=4, range: 25.9% - 89.3%) reduction in Gli1 expression in skin was observed, with 87% 
reduction in the MB patient who achieved objective partial response. 
 
 
 
2.4  
Other Drugs: 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.   


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
20 
 
 
• 
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. 
 
• 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
21 
 
precautions, warnings, and adverse reactions of gemcitabine (current version of 
Prescribing Information is provided in the Study Manual).  
 
                  2.5 Other Drugs: 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.  
 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
22 
 
(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 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. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
23 
 
 
3. 
PATIENT SELECTION 
 
 
3.1  
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed adenocarcinoma 
of the pancreas. Patients who have not undergone biopsy but have highly 
suspected adenocarcinoma of the pancreas with borderline resectable features 
on imaging study may also be eligible for study and undergo the pretreatment 
biopsy as per protocol. The biopsy must confirm adenocarcinoma of the 
pancreas to continue on study. Biopsy is required within 14 days of starting 
therapy. 
 
3.2.2   Patients must have borderline resectable pancreatic adenocarcinoma defined 
by one of the following criteria: 
 
(1)  Tumor associated deformity of the superior mesenteric vein (SMV) or portal 
vein (PV)  
(2)  Abutment of the SMV or PV < 1800  
(3)  Short-segment occlusion of the SMV or PV amenable to resection and venous 
reconstruction  
(4)  Short-segment involvement of the hepatic artery or its branches amenable to 
resection and reconstruction or  
(5)  Abutment of the superior mesenteric artery (SMA) < 1800 
 
3.1.3 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. 
 
3.1.4 Patient must have received no previous radiotherapy, surgical resection, 
chemotherapy or investigational drug therapy for pancreatic adenocarcinoma. 
 
3.1.5 Age >18 years.  Because no dosing or adverse event data are currently 
available on the use of   sonidegib in combination with gemcitabine in patients 
<18 years of age, children are excluded from this study but will be eligible for 
future pediatric phase 2 combination trials. 
 
3.1.6 Life expectancy of greater than 1 month. 
 
3.1.7 ECOG performance status <1 (Karnofsky >70%; see Appendix A). 
 
3.1.8 Patients must have adequate organ and marrow function as defined below: 
 
- 
leukocytes  
 
 
 
 
>3,000/mcL 
- 
absolute neutrophil count  
>1,500/mcL 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
24 
 
- 
platelets 
 
 
 
 
 
>100,000/mcL 
- 
total bilirubin  
 
 
 
< 1.5 ULN 
-     plasma creatinine  
        phosphokinase (CK)             < 1.5 x ULN 
- 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal  
- 
creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
creatinine clearance  
 
Creatinine clearance >50 mL/min/1.73 m2 
for patients with serum creatinine < 2 
mg/mL 
 
3.1.9   Patients should be asymptomatic for jaundice and ascites prior to Day 1. Pain                     
           symptoms should be stable. 
 
3.1.10 The effects of sonidegib on the developing human fetus are unknown.  For 
this reason and because other 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) for the duration of study participation, and for at least 20 
months after the final dose of study treatment.  For appropriate methods of 
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 sonidegib 
(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. A positive urine test must be confirmed by 
a serum pregnancy test.  Prior to dispensing sonidegib, the investigator must 
confirm and document the patient’s use of two contraceptive methods, dates 
of negative pregnancy test, and confirm the patient understands of the possible 
teratogenic potential of sonidegib. 
 
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. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
25 
 
 
3.1.11 For sexually active males, use of barrier form of contraception, even if they 
have had a vasectomy, during the study and for 6 months after stopping 
sonidegib is required. Males should not donate sperm during treatment, and 
for up to six months after last dose. 
 
3.1.12 All patients should agree not to donate blood products for 12 months after 
stopping sonidegib 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.13 Patient is willing to have two biopsies while on treatment for correlative 
studies. 
 
 
3.2 
 
Exclusion Criteria 
 
3.2.1 Patients 
who 
have 
had 
previous 
radiotherapy, 
surgical 
resection, 
chemotherapy or investigational drug therapy for pancreatic adenocarcinoma. 
 
3.2.2 Patients may not be receiving any other investigational agents. 
 
3.2.3   Patient has known metastatic disease. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to sonidegib 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 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. 
 
3.2.7 Pregnant women 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 sonidegib, breastfeeding should be discontinued if the 
mother is treated with sonidegib.   
 
                  3.2.8   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. 
                


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
26 
 
                 3.2.9   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 
 
3.2.10 Patients who are receiving treatment with medications known to be moderate  
and strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by 
CYP2B6 or CYP2C9 that have narrow therapeutic index, and that cannot be 
discontinued before starting treatment with sonidegib. Medications that are 
strong CYP3A4/5 inhibitors should be discontinued at least 7 days and strong 
CYP3A/5 inducers for at least 2 weeks prior to starting treatment with 
sonidegib. 
 
                 3.2.11 a) Patients who have neuromuscular disorders (e.g. inflammatory myopathies,            
                            muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy)     
                            or are on concomitant treatment with drugs that are recognized to cause   
                            rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and  
                            gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting  
                            sonidegib treatment.  If it is essential that the patient stays on a statin to control  
                             hyperlididemia, only pravastatin may be used with extra caution.  
                             b)  Patients who are planning on embarking on a new strenuous exercise  
                             regimen after initiation of study treatment. NB: Muscular activities, such as  
                             strenuous exercise, that can result in significant increases in plasma CK levels  
                             should be avoided whilst on sonidegib treatment. 
 
3.2.12 Impaired cardiac function or clinically significant heart disease, including any one 
of the following: 
 Angina pectoris within 3 months 
 Acute myocardial infarction within 3 months 
 QTcF > 450 msec for males and > 470 msec for females on the screening ECG 
 A past medical history of clinically significant ECG abnormalities or a family history 
of prolonged QT-interval syndrome 
 Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled 
hypertension, history of labile hypertension, or history of poor compliance with an 
antihypertensive regimen) 
 
 
                 3.2.12 Patients unwilling or unable to comply with the protocol. 
 
3.3 
 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial.  
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
27 
 
 
4. 
TREATMENT PLAN 
 
 
4.1  
Time to Event Schedule 
 
4.1.1 Screening and Pre-study Assessments 
                      
Pretreatment biopsy for correlative studies, must be obtained within 14 days 
before cycle 1, day 1 
 
The following evaluations and procedures will be performed within 28 days prior 
to Day 1: 
 
• Signed informed consent 
 
Clinical evaluations; 
• Medical Oncology and Surgical Oncology evaluation      
  
• 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, AST, and ALT ), Creatinine Kinase (CK). 
 
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) 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
28 
 
within 10-14 days and within 24 hours prior to the first dose of sonidegib 
(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.  A positive urine test must be confirmed 
by a serum pregnancy test.  Prior to dispensing sonidegib, 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 sonidegib. 
 
• 12-lead ECG 
 
• Tumor assessment (per RECIST 1.1; see section 10). 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).  Imaging will be done at 
baseline, end of cycle 2, cycle 4, before radiation therapy, 4 weeks after radiation 
therapy and at the end of cycle 6. 
 
• PET Scan must be obtained within 14 days before cycle 1, day 1 and after cycle 
4. 
 
4.1.2 Assessments during the study period 
 
The study period begins on Day 1 of Cycle 1. 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. Imaging 
will be done at baseline, end of cycle 2, cycle 4, before radiation therapy, 4 weeks 
after radiation therapy and at the end of cycle 6. 
 
• 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). 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-unscheduled visit with additional laboratory tests may be performed. 
 
• Sonidegib and gemcitabine should be administered as specified in 5.2 and study 
calendar in section 10.  
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
29 
 
4.1.3 Beginning of each cycle 
 
The following assessments will be performed on Day 1 of each treatment 
cycle: 
 
• Drug will be dispensed to the patient on this day. Sonidegib 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 
 
• 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 each cycle) 
 
• 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 ) , Creatinine Kinase (CK). 
 
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 C). 
 
• Record concurrent medications. 
 
• Record cancer-related medical or surgical procedures. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
30 
 
• Record adverse events. 
 
4.1.4 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) will be done at baseline, 
end of cycle 2, cycle 4, before radiation therapy, 4 weeks after radiation therapy 
and at the end of cycle 6.  An unscheduled CT scan for suspected progression may 
be performed at any time; 
 
• PET scan will be done at baseline and at the end of cycle 4. 
 
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 and CK. Labs can be obtained within three 
days prior to treatment. 
 
• Adverse event evaluation. 
 
Mid Treatment Biopsy 
 
Will be obtained at the end of cycle 2. Labs (PT/PTT) can be obtained within a 
window of 7 days prior to the procedure. 
 
Sample for Circulating Cancer Stem Cells 
 
Will be obtained at the enrollment and at the end of cycle 4. A window of ± 3 
days will be allowed. 
 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
31 
 
chemotherapy has been stopped, every 3-4 weeks): Weight, pulse, blood pressure, 
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). 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. A positive urine test must be confirmed by a serum pregnancy 
test.   
 
• Record concurrent medications. 
 
• Record cancer-related medical or surgical procedures. 
 
• Record adverse events. 
 
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 will be followed for 30 days after the patient’s last 
dose of study drug. 
 
• 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; 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
32 
 
• Concurrent procedures; 
• Vital signs; 
• ECOG Performance Status scale; 
• CBC, differential, platelet count, and clinical chemistries; 
 
 
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 with the patient’s treating physician. 
 
 
4.1.5 Radiation Therapy 
 
All patients will receive neoadjuvant radiation therapy starting 4 weeks after last dose of 
chemotherapy. Standard either 3D conformal or intensity modulated radiation therapy 
(IMRT) planning techniques are allowed on this study.  A window of +/- two weeks is 
allowed.  Patients should undergo a restaging CT of the chest, abdomen, and pelvis with 
oral and intravenous contrast within 2 weeks of finishing chemotherapy.  The patients 
may receive this treatment at Johns Hopkins or locally. 5-FU/Capecitabine -based 
chemotherapy and radiation therapy as adjuvant treatment following surgical resection of 
pancreatic adenocarcinoma are the accepted standard of care as described by a number of 
pancreas cancer groups including the RTOG, the American College of Surgeons 
Oncology Group (ACOSOG) and the National Comprehensive Cancer Network (NCCN) 
pancreatic adenocarcinoma practice guideline expert panel. We will be using 
capecitabine at a dose of 825 mg/m2 orally twice daily on the days of radiation therapy. 
 Patients should undergo a CT simulation (thin slices through the pancreas/bed) with IV 
(assuming adequate kidney function) and oral contrast.  Preoperative CT scans and 
strategically- placed surgical clips are used to determine the tumor bed.  
 The PTV should be defined per the ICRU-62 guidelines.  The initial clinical treatment 
volume (CTV) includes high risk peri-pancreatic lymph nodes, anastomoses (optional), 
pancreatic tumor bed derived from pre-surgical imaging and strategically- placed surgical 
clips.  CTV expansions are needed to include possible microscopic disease.  Further 
expansion to the planning treatment volume (PTV) includes ITV for target/breathing 
motion and additional margin for patient set-up error (SM).  Organs at risk (OARs) such 
as kidneys should also be contoured and evaluated in the dose volume histogram (DVH). 
 Conformal, intensity modulated radiation therapy (IMRT) and breathhold/gating 
techniques can result in improved PTV coverage with decreased dose to organs at risk 
(OARs). If small CTV expansions are used for PTV, breathing motion and set-up error 
should be evaluated or controlled  per the AAPM task group 76 guidelines 
(ABC/tracking/4D-CT scan/cone beam CT). 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
33 
 
 
 45-46 Gy (1.8-2.0 Gy fractions) is delivered to the initial PTV (tumor bed, surgical 
anastomosis, and regional lymph nodes).  Additional radiation (~5-15 Gy) may be 
administered to the tumor bed/area of involved margins.  It is preferred that high energy 
photon beams (>6 MV) are used.   
 
 Atlases to assist with contouring and adjuvant radiation therapy planning are located at 
(http://www.rtog.org/atlases/pancreasAtlas/main.html).  
 
 
Radiation Normal Tissue Volume Constraints 
Structure 
Adjuvant/Resected Constraints 
Kidney 
(L & R) 
If two functioning kidneys present, not more 
than 50% of the right and 65% of the left kidney 
should receive < 18 Gy.  For IMRT planning 
mean dose to bilateral kidneys should be ≤18 
Gy.  If only one kidney is present not more than 
15% should receive ≥ 18 Gy and no more than 
30% should receive ≥ 14 Gy. 
Stomach, 
duodenum, 
jejunum 
Max dose ≤55Gy; <10% of each organ volume 
can receive between 50-53.99 Gy.  < 15% of 
each organ volume can receive 45-49.99 Gy. 
Liver 
Mean liver dose ≤ 25 Gy. 
Spinal cord 
Max dose ≤ 45Gy 
*Adapted from RTOG 0936 (3-D conformal, 1.8-50.5) and RTOG 1102 (IMRT, 2.2 to 55 Gy) 
**Adapted from RTOG 0848 (3-D or IMRT) 
 
4.1.6  Surgery 
 
At the end of 4 cycles of chemotherapy and radiation therapy the patients will undergo 
CT and PET scans within 2 weeks. Each case will be discussed at the pancreatic cancer 
conference including the surgeons and the principal investigators to determine if the 
patient is candidate for resection. To avoid bias during the phase II portion of this study, 
the surgeons will not be informed at this point if the patients have been receiving the 
hedgehog inhibitor sonidegib.  If the patient is deemed candidate for resection the surgery 
will occur four weeks after finishing radiation. A window of +/- two weeks is allowed. 
Standard surgery techniques will be decided by the surgeon. All patients must undergo 
the surgery at Johns Hopkins. 
 
If a patient is not deemed candidate for surgical resection he/she will be off study. It will 
be recommended to the treating oncologist to proceed with alternative standard 
treatments. An optional biopsy can be obtained at this point.  
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
34 
 
4.1.7 End of Therapy (EOT) Evaluation 
 
 
An EOT evaluation should be performed for all patients who end treatment. 
Patients who have the EOT evaluation after completing all planned therapy 
(chemotherapy, surgery, radiation) will continue on follow up for any evidence of 
progression/recurrence and survival as specified in section 4.6.  
 
The following procedures will be completed at the EOT Visit: 
 
• Physical examination 
 
• Weight assessment 
 
• Concomitant medication evaluation 
 
• Concurrent procedures 
 
• Vital signs 
 
• ECOG performance status scale 
 
• Clinical chemistry panel 
 
• CBC, differential and platelet count 
 
• 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. 
 
 
4.2 
 
Agent Administration 
The investigator needs to instruct the patient to take the study drug as per protocol.  All 
dosages prescribed and dispensed to the patient and any dose change or interruption must 
be recorded in the dosage administration record CRF, as appropriately. 
 
Phase 1 Study: 
 
Following the determination of eligibility patients will receive the following treatment:  
Four cycles of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/ m2on days 1, 8, and 15 
every 28 days cycle in combination with oral sonidegib 600 mg daily.  


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
35 
 
If the patient lives out of town and opts to receive gemcitabine and nab-Paclitaxel treatment 
locally it will be allowed with communications between the local treating oncologist and the 
study team members. All treatment and doses will occur as specified in this protocol.   On the 
first day of each cycle all patients will need to have their evaluation and treatment with the 
Johns Hopkins investigators in order to participate in the study. Sonidegib (oral drug) will 
only be dispensed at Johns Hopkins Hospital. Day 8 and 15 intravenous Gemcitabine and 
nab-Paclitaxel treatments can be provided locally at the doses specified on this protocol. 
Patients will continue taking oral sonidegib as specified in the protocol. 
 
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 
Sonidegib 
Morning or PM.  
600 mg  
PO in the a.m.  
Daily  
 
Dose escalation for subsequent cohort for sonidegib will occur as follows: 
 
Dose Level 
 
LDE 225 
(mg) 
Gemcitabine 
(mg/m2) 
Nab-Paclitaxel 
(mg/m2) 
Level -1 
400 
1000 
125 
Level 1 
600 
1000 
125 
Level 2 
800 
1000 
125 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
36 
 
1st cohort of 3 
patients at the 600 
mg LDE225 dose
(1-3)
Phase 1 Dose Escalating Schema for LDE225
DE-ESCALATE
1st cohort of 3 
patients at the 400 
mg LDE225 dose
(1-3)
2nd cohort of 3 
patients at the 600 
mg LDE225 dose
(4-6)
ESCALATE
1st cohort of 3 patients 
at the 800 mg LDE225 
dose
(1-3)
Clinical Hold-
Consider Protocol 
Amendments
2nd cohort of 3 
patients at the 400 
mg LDE225 dose
(4-6)
2nd cohort of 3 
patients at the 800 
mg LDE225 dose
(4-6)
Move on to Phase II 
trial at 800 mg 
LDE225 dose
Move on to Phase II 
trial at 600 mg 
LDE225 dose
Move on to Phase II 
trial at 400 mg 
LDE225 dose
# of DLTs
In cycle 2
# of DLTs
In cycle 2
# of DLTs
In cycle 2
0
1
2 or 3
0 or 1
2 or 3
0 or 1
>1 of 6
>1 of 6
0 or 1
2 or 3
>1 of 6
of 6
6 recruited
0 or 1
of 6
Cycle length= 28 days
DLT= dose limiting toxicity
1 of 6
Check Number of 
patients at the 600 
mg LDE225 dose
3 recruited
2nd cohort of 3 
patients at the 600 
mg LDE225 dose
(4-6)
0 or 1
of 6
Move on to Phase II 
trial at 600 mg 
LDE225 dose
 
 
 
 
Phase 2 Study: 
 
In the Phase 2 stage the patients will be randomize (1:1) to receive one of the following 
treatments:  
 
• 
Arm A: Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 
1, 8 and 15 in combination with sonidegib at the recommended phase 2 dose. Cycles 
repeated every 28 days. 
 
• 
Arm B: Four cycles of gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 
1, 8 and 15. Cycles repeated every 28 days. 
If the patient lives out of town and opts to receive gemcitabine and nab-Paclitaxel treatment 
locally it will be allowed with communications between the local treating oncologist and the 
study team members. All treatment and doses will occur as specified in this protocol.   On the 
first day of each cycle all patients will need to have their evaluation and treatment with the 
Johns Hopkins investigators in order to participate in the study. Sonidegib (oral drug) will 
only be dispensed at Johns Hopkins Hospital. Day 8 and 15 intravenous Gemcitabine and 
nab-Paclitaxel treatments can be provided locally at the doses specified on this protocol. 
Patients will continue taking oral sonidegib as specified in the protocol. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
37 
 
 
An overview of the schedule of study assessments is provided in the Study Calendar in 
section 9. 
 
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 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 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. 
 
The 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. 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
38 
 
 
 
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 
sonidegib 
Morning or PM.  
600 mg  
PO in the a.m.  
Daily  
 
 
4.2.1 Sonidegib 
 
4.2.1.1 Administration  
 
Sonidegib will be administered beginning on Cycle 1, Day 1 once daily by oral dosing, in 
combination with gemcitabine as described in section 4.1. Therapy should continue until one 
of the conditions specified in section 4.5 occurs. 
 
Table Treatment and treatment schedule 
Study treatments 
Pharmaceutical form and route of 
administration 
Dose 
Frequency and/or 
regimen 
Sonidegib 
Capsule for oral use 
 q.d. 
Daily 
 
Sonidegib will be administered orally, on a continuous once daily dosing schedule at a dose 
of 600 mg. Participating patients will receive flat doses on mg/day basis and not according to 
their body weight or body surface area. Sonidegib is supplied as 200-mg hard gelatin 
capsules in bottles. Patients will receive 3 capsules of sonidegib. Medication labels will be in 
the local language and comply with the legal requirements of each country. 
 
Patients will be dosed on flat scale of 600 mg daily dosing of sonidegib. Hard gelatin 
capsules at 200 mg are available.  
Sonidegib should be taken as follows: 
 Patients should be instructed to take their once-a day dose at approximately the same time 
each day 
 Each daily dose of sonidegib should be taken with a glass of water and consumed over as 
short a time as possible (e.g. 1 capsule every 2 minutes) 
 Patients should be instructed to swallow capsules whole and to not chew or open them 
 Each daily dose of sonidegib should be taken 2 hours after a light breakfast (e.g., consisting 
of juice, toast and jam). If breakfast was completed at 08:00 a.m., then study drug 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
39 
 
administration should occur at 10:00 a.m. Food intake should be avoided for at least 1 hour 
after study drug administration 
 Patients must avoid grapefruit, pomegranate, star fruit and Seville (sour) oranges during the 
entire study. The juices and products containing these fruits may also be avoided. 
 If vomiting occurs during the course of the treatment, then no re-dosing of the patient is 
allowed before the next scheduled dose 
 If the patient forgets to take his/her daily morning dose, then he/she should take sonidegib 
within 6 hours after the missed dose. If more than 6 hours have passed, then that day’s dose 
should be omitted and the patient should continue treatment with the next scheduled dose 
 Patients should inform the investigational site staff of any missed or delayed dose 
 
4.2.2 Gemcitabine 
 
Gemcitabine Premedication 
 
Please see gemcitabine prescribing information for recommended premedication strategies. 
 
4.2.3 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. 
 
 
 
4.2.4 Other Modality (ies) or Procedures 
      
 
4.3  
Definition of Dose-Limiting Toxicity 
 
DLTs include any non-hematologic Grade 3/4 toxicity considered possibly related to 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
40 
 
sonidegib occurring during the first two cycles (56 days). Grade 3 nausea, or 
vomiting will be considered a DLT only if unresponsive to therapy. Grade 4 
neutropenia, leucopenia, and decreased hemoglobin will be considered DLTs.  
 
Toxicities will be evaluated after two months of therapy. The MTD is defined as the 
highest dose for which  1/6 dose limiting toxicities (DLTs) are observed.  
 
 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level 
will be declared the maximally administered 
dose (highest dose administered).  Three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
 If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is 
declared the maximally administered dose.  
Three (3) additional patients will be entered 
at the next lowest dose level if only 3 
patients were treated previously at that dose. 
<1 out of 6 at highest dose level 
below the maximally 
administered dose 
This is generally the recommended phase 2 dose. 
At least 6 patients must be entered at the 
recommended phase 2 dose. 
 
 
 
4.4  
General Concomitant Medication Supportive Care Guidelines with LDE 
 
4.4.1 Permitted concomitant therapy requiring caution and/or action  
Sonidegib is an inhibitor of breast cancer resistance protein (BCRP) in vitro. 
Therefore substrates, especially those with a narrow therapeutic range, should be 
used with caution. BCRP substrates include zidovudine, pantoprazole, cimetidine, 
sulfasalazine, nitrofuratoin, mitoxantrone, methotrexate, topotecan, imatinib, and 
irinotecan. However, the use of mitoxantrone, methotrexate, topotecan, imatinib, 
irinotecan or statins is generally prohibited during this study. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
41 
 
In vitro drug metabolism studies reveal that the metabolism of sonidegib is 
mediated by CYP3A4 and also a potent inhibitor of CYP2C9 and CYP2B6. Clinical 
studies have not yet been performed to confirm the potential effect of sonidegib on 
substrates drugs metabolized by CYP2C9 in patients. Also, it is not known the 
potential effect of low and moderate CYP3A4 inhibitors and inducers on sonidegib 
clearance. Therefore, investigators, at their discretion, may administer concomitant 
medications known to be metabolized by CYP2C9 and CYP2B6, except drugs 
which have narrow therapeutic index/sensitive substrates for these two isoforms and 
statins. Caution is advised when sonidegib is co-administered with drugs that are 
moderate inhibitors or inducers of CYP3A4. Patients receiving such medications 
must be monitored closely for any potentiation of toxicity or decrease of clinical 
benefit due to any individual concomitant medications, and may require dose 
titration or adjustment. 
 
4.4.2 Prohibited concomitant therapy 
                 Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. 
Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) other 
than the study treatments must not be given to patients while the patient is on the 
study medication. If such agents are required for a patient then the patient must be 
discontinued from the treatment portion of the study. 
                 Strong CYP3A inhibitors and inducers 
No clinical studies have been performed to confirm if sonidegib is a sensitive 
CYP3A4 substrate, hence concomitant use of strong CYP3A4 inhibitors and 
inducers is not permitted.  
Patients receiving concomitant medications known to strongly inhibit and/or induce 
CYP3A4/5 that are deemed medically necessary should be excluded from the study. 
A partial list of drugs that are inducers, and inhibitors of CYP3A4/5 is included in 
the table below. The above list  of medications has been generated by Novartis 
Oncology 
Clinical 
Pharmacology 
(OncCP) 
 (DDI database document: last update August 2010) that is compiled by using 
information listed under “draft guidance for industry, drug interaction studies, 
CDER 2006”, Indiana University School of Medicine drug interaction tables at 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable, and “drug interaction from 
University of Washington. Patients should be instructed not to take grapefruit, St 
John Wort or Seville (sour) orange juice while receiving sonidegib treatment 
throughout the study due to potential CYP3A4/5 inhibition. The other drugs without 
an asterisk should be carefully used as concomitant therapy. 
 
Medications that are CYP3A4/5 inducers or inhibitors 
Medications 
 
Inhibitors 
HIV antivirals: indinavir, nelfinavir, ritonavir*, saquinavir 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
42 
 
Medications 
 
 
Antibiotics: azithromycin, ciprofloxacin, chloramphenicol, clarithromycin, erythromycin*, 
fluconazole&, itraconazole*, ketoconazole*,  voriconazole*, telithromycine, posaconazole, 
norfloxacin 
 
Calcium channel blockers: diltiazem&, verapamil& 
 
Antidepressants: , fluvoxamine, nefazodone* 
 
Miscellaneous: amiodarone, cimetidine, delavirdine, diethyl-dithiocarbamate (chlorzoxazone), 
interleukin-10*, mifepristone, mibefradil , grape fruit juice&, isoniazid&, apepritant& 
Inducers 
HIV antivirals: efavirenz, nevirapine 
 
Anticonvulsants: barbiturates**, carbamazepine**, Oxcarbazepine**, phenytoin**, 
phenobarbital** 
 
Systemic glucocorticoids: dexamethasone&, glucocorticoids, hydrocortisone, prednisolone, 
prednisone 
 
Antibiotics: rifabutin**, rifampicin**,rifapentine** 
 
Antidiabetics: pioglitazone, troglitazone 
 
Miscellaneous: modafinil, hormone replacement therapy, oral contraceptives, St John’s wort** 
*- Known strong inhibitors of CYP3A4 are estimated to cause a≥ 5 fold increase in the AUC values or a 
≥80% decrease in clearance of a CYP3A4 substrate;  
& -a moderate inhibitor is estimated to cause a ≥2-but < 5 fold increase in the AUC values or a 50-80% decrease 
in the clearance of a sensitive substrate when the inhibitor is given at the highest approved dose.  
** -Known strong inducers of CYP3A4/5 (AUC decrease by 50-80%) 
 
Medications that are CYP2B6 and CYP2C9 substrates (narrow therapeutic index) 
Sonidegib is a potent inhibitor of drugs metabolized by the cytochromes CYP2B6 and CYP2C9 
in vitro. Because of the potential risk for drug-drug interactions, using concomitant medications 
known to be metabolized by these enzymes that have low therapeutic index (see table below) is 
not permitted in the study. The other drugs without an asterisk should be carefully used as 
concomitant therapy. 
Drugs metabolized by CYP2B6 and CYP2C9 
CYPs 
Drugs metabolized by CYPs 
CYP2B6 
Bupropion , cyclophosphamide, efavirenz, ifosfamide,  methadone 
CYP2C9 
NSAIDs: diclofenac, ibuprofen, lornoxicam, meloxicam, naproxen, piroxicam, suprofen 
 
Oral hypoglycemic agents:  tolbutamide, glipizide 
 
Angiotensin II blockers: losartan, irbesartan 
 
Sulfonylureas: glyburide/glibenclamide, glipizide, glimepiride, tolbutamide 
 
Miscellaneous: amitriptyline, celecoxib, fluoxetine, pravastatin&, glyburide, nateglinide, 
phenytoin, rosiglitazone, tamoxifen, torsemide, warfarin*, quinidine* 
* -narrow therapeutic index: drugs whose exposure-response indicates that increases in their exposure levels by 
the concomitant use of potent inhibitors may lead to serious safety concerns (e.g. Torsade de Pointes) are not 
allowed 
&- statins – If it is essential that the patient takes a statin to control hyperlididemia [see Section 5.1.7.5], then 
only pravastatin may be used with extra caution. Pravastatin has the lowest potential of cause rhabdomyolysis 
compared with other statins  (3 cases/ 6 millions of prescription from 1994 to 2002) (Evans et al. 2002) and the 
lowest risk for drug-drug interactions with sonidegib, as it is primarily transformed in the liver cytosol by 
sulfonation, not by CYP2C9 or CYP3A4. (Evans et al. 2002) 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
43 
 
Warfarin and coumadin derivatives 
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumadin-
derivative anticoagulants are not permitted since sonidegib is a competitive 
inhibitor of CYP2C9 based on the in vitro data. An alternative, therapeutic 
anticoagulation may be accomplished using low-molecular weight heparin. 
Drugs that may increase risk of rhabdomyolysis when used concomitantly with 
sonidegib  
Selected drugs that may increase risk of myopathy and rhabdomyolysis when used 
concomitantly with sonidegib should be avoided. Such drugs should be 
discontinued for at least 2 weeks prior to initiation of sonidegib and it must be 
ensured the plasma CK is within the normal range at baseline. The list compiled 
below is based on reported association of the individual drugs with muscle toxicity 
and in addition to the potential risk of clinically relevant PK drug-drug interaction 
with sonidegib through inhibitory effects on CYP3A4 
 (enzyme metabolized  sonidegib) or the inhibitory effect on CYP2C9 by sonidegib 
of drugs that may induced rhabdomyolysis. 
 Azoles antifungals:   Itraconazole, ketoconazole,  fluconazole,  voriconazole 
 Macrolides:   azithromycin,  clarithromycin,  erythromycin,  telitromycin 
 Fibrates: gemfibrozil 
 3-hydroxy-3 methyl-glutaryl (HMG) Coa reductase inhibitors ( Statins): 
Atovastatin, Fluvastatin, Fluvastatin XL, Lovastatin, Pravastatin*,  Rosuvastatin-  
and Simvastatin 
 
Antiretrovirals: Indonavir and ritonavir 
 
Others: phenobarbital, barbiturates,  phenytoin and isoniazid 
 
* If it is essential that the patient stays on a statin to control hyperlididemia [see 
Section 5.1.7.5], only pravastatin may be used with extra caution; CK should be 
monitored weekly during the first 8 weeks on concomitant treatment with sonidegib and 
then bi-weekly thereafter for 8 weeks and then every four weeks . 
 
4.4.3 Contraception allowed/excluded 
The use of oral contraceptives and implantable hormonal contraception is not 
allowed during the study, as detailed in the exclusion criteria. 
 Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective contraception during the study and 
through 20 months after the final dose of study treatment. Highly effective contraception 
is defined as either: 
1. Total abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.  
2. Sterilization: Patient has had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment  


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
44 
 
3. Male partner sterilization (with the appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate). [For female study patients, the vasectomised 
male partner should be the sole partner for that patient]  
4. Use a combination of the following (both a+b):  
a. Placement of a non-hormonal intrauterine device (IUD) or non-hormonal 
intrauterine system (IUS) 
b. Barrier method of contraception: Condom or Occlusive cap (diaphragm or 
cervical vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.  
Note: Hormonal contraception methods (e.g. oral, injected, implanted) are not allowed 
as it cannot be ruled out that the study drug decreases the effectiveness of hormonal 
contraception 
Note: Woman are considered post-menopausal and not child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or six months of 
spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 20 
pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential  
 Male patient must use highly effective (double barrier) methods of contraception (e.g., 
spermicidal gel plus condom) for the entire duration of the study, and continuing using 
contraception and refrain from fathering a child for 6 months following the study drug. A 
condom is required to be used also by vasectomized men as well as during intercourse 
with a male partner in order to prevent delivery of the study treatment via seminal fluid 
 
Sexually active males who are unwilling to use a condom during intercourse while taking 
drug and for 6 months after stopping investigational medications and agree not to father a 
child in this period are excluded from participating in this trial 
   
 
4.4.4 Other Considerations 
 
            Concomitant and Excluded Therapies 
 
For information regarding other drugs that may interact with gemcitabine and affect 
their metabolism, pharmacokinetics, or excretion, please see the gemcitabine package 
insert. 
 
            Supportive Care and administration of additional therapies 
 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
45 
 
Investigator. Irradiation is not allowed during the study other than specified in the 
treatment protocol. 
 
Medications required to treat adverse events and manage cancer symptoms, 
concurrent stable disease (e.g., controlled hypertension) and supportive care agents 
such as erythropoietin, granulocyte growth factors, or blood transfusion, and pain 
medications are allowed (use of growth factors, erythropoietin, blood transfusion or 
granulocyte colony-stimulating factor (G-CSF) is not permitted, until the patients 
have developed dose-limiting anemia or neutropenia). The patient needs to notify the 
investigational site about any new medications he/she takes after the start of the study 
medication. All medications (other than study drug) and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the 
patient starts treatment with study drug must be listed on the CRF. 
 
 
4.5  
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for      
6 cycles (4 pre-operative and 2 post operative cycles)   or until one of the following 
criteria applies: 
 
 Disease progression to unresectable or metastatic disease, 
 
 Patient is not eligible for resection after four cycles of treatment, 
 
 Intercurrent illness that prevents further administration of treatment, 
 
 Unacceptable adverse event(s), 
 
 Patient decides to withdraw from the study, or 
 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 Intolerable (Grade 3 or 4) toxicity most probably attributable to sonidegib or 
other agents 
 
 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 
 
 
4.6  
Duration of Follow Up 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
46 
 
Patients will be followed for 18 months after removal from study or until death, 
whichever occurs first.  Unacceptable adverse events will be followed until resolution 
or stabilization of the adverse event. Follow up will occur every 3 months by phone 
call (patient or treating physician). Patients will be followed for disease 
progression/recurrence and overall survival which will be documented in eCRF. 
 
 
4.7  
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 4.5 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
5. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
      5.1 Sonidegib 
 
Investigators should follow the guidelines described below for the modification of sonidegib 
treatment.  Any plan to deviate from these guidelines in view of the patient safety must be 
previously discussed with Novartis unless there is an urgent need for action. 
 
All dose modifications should be based on the worst preceding toxicity. If study treatment is 
being held due to toxicity, scheduled visits and all assessments should continue to occur 
except the dosing of the study drug. 
 
A maximum of two dose reduction steps will be allowed (see Table below), after which the 
patient will be discontinued from study treatment if there is a need for further dose reduction.  
For patients who undergo dose interruptions (delays), if the same toxicity returns after re-
initiation of treatment, regardless of duration, the second re-initiation must resume at a lower 
dose. If the patient requires a dose interruption of > 21 days from the previous dose, then the 
patient must be discontinued from study treatment. Patients who discontinue the treatment 
due to an adverse event or an abnormal laboratory value must be followed until resolution or 
stabilization of the event. 
 
All dose changes or interruptions must be recorded in the dosage administration record CRF, 
as appropriately. 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
47 
 
Dose reduction steps for sonidegib 
Dose reduction* 
 
Starting dose level – 
0  
Dose level – 1 
Dose level -2 
Sonidegib dose (mg QD) 
600  
400  
200  
*Dose reduction should be based on the worst toxicity demonstrated.  
 
 
Recommended Dose Modifications and Dose Delays for suspected treatment-related 
toxicities  
Recommended dose modifications for sonidegib** 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Hematologic 
Neutropenia (ANC) 
Grade 1  
(ANC < LLN - 1500/mm3) 
Maintain dose level 
Grade 2  
(ANC < 1500 - 1000/mm3) 
Maintain dose level 
Grade 3 or 4  
(ANC < 1000 - 500/mm3  
or < 500/mm3) 
Omit dose until resolved to ≤ grade 1, then: 
 If resolved in ≤ 7 days, then maintain dose level 
 If resolved in > 7 days, then decrease dose by 1 step 
Thrombocytopenia (PLT) 
Grade 1 
(PLT < LLN - 75,000/mm3) 
Maintain dose level 
Grade 2  
(PLT < 75,000 - 50,000/mm3) 
Maintain dose level 
Grade 3 or 4  
(PLT < 50,000 - 25,000/mm3 or < 
25,000/mm3) 
Omit dose until resolved to ≤ grade 1, then: 
 If resolved in ≤ 7 days, then maintain dose level 
 If resolved in > 7 days, then decrease dose by 1 step 
Febrile Neutropenia 
Febrile neutropenia  
(ANC < 1.0 x 109/L, fever ≥ 38.5°C) 
Omit dose until resolved, then decrease dose by 1 step 
 
 
 
 
 
 
 
 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
48 
 
Recommended dose modifications for sonidegib** 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Muscle Toxicity 
Elevated creatine phosphokinase (CK) 
Asymptomatic CK elevation 
 
 
 
 
 
 
 
 
 
 
Grade 2 
[CK elevation >2.5 x ULN - 5 x 
ULN] 
 Continue treatment on the same dose and monitor CK levels weekly until 
resolution to baseline level. Check renal function (serum creatinine) 
regularly and ensure that patient is adequately hydrated. 
Symptomatic (new-onset or worsening of pre-existing muscle symptoms such as myalgia, myopathy, and/or spasms) 
CK elevation 
Grade 1 [CK elevation >ULN - 2.5 
x ULN)] 
Continue treatment at the same dose and monitor CK levels weekly until 
resolution to baseline level and then monthly thereafter. Monitor muscle 
symptoms for changes until resolution to baseline. Check renal function 
(serum creatinine) regularly and ensure that patient is adequately hydrated. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
49 
 
Recommended dose modifications for sonidegib** 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Grade 2 
[CK elevation >2.5 x ULN - 5 x 
ULN 
Interrupt treatment and monitor CK levels weekly until resolution to baseline 
level. Monitor muscle symptoms for changes until resolution to baseline. 
Upon resolution, resume treatment at the reduced dose level and measure CK 
monthly thereafter. Check renal function (serum creatinine) regularly and 
ensure that patient is adequately hydrated. 
 
 
 
 
 
 
 
Asymptomatic or Symptomatic CK elevation 
Grade 3 or 4 without renal 
impairment 
[Grade 3 (CK elevation >5 x ULN 
- 10 x ULN)] [or Grade 4 (CK 
elevation >10 x ULN)] 
 
Interrupt treatment and monitor CK levels weekly until resolution to 
baseline level. Monitor muscle symptoms for changes until 
resolution to baseline. 
   Check renal function (serum creatinine) regularly and ensure that patient is 
adequately hydrated. If renal function is not impaired (normal serum 
creatinine) and CK resolves to baseline level, consider resuming treatment at a 
reduced dose. CK levels should be measured weekly for 2 months after re-
administration of sonidegib and monthly thereafter. 
 
 
Grade 3 or 4 with renal 
impairment 
 
Interrupt treatment and monitor CK levels weekly until resolution to 
baseline level. Monitor muscle symptoms for changes until 
resolution to baseline. 
  If renal function is impaired (≥50% above the baseline level), interrupt 
treatment. Ensure patient is adequately hydrated and evaluate other secondary 
causes. Continue monitoring of CK and creatinine levels weekly. If CK levels 
return to baseline level and creatinine levels return to baseline, consider 
resuming treatment at the reduced dose otherwise discontinue treatment 
permanently. 
 
 
 
 
 
 
Muscle-related  
(muscle pain or cramps) 
 
If new-onset ≤ CTCAE grade 1 or 2 myalgia/muscle cramps without CK 
elevation or worsening of pre-existing myalgia/muscle cramps without 
CK elevation, continue treatment with sonidegib and consider 
symptomatic treatment. If associated with elevated CK, then it should be, 
managed as for symptomatic CK elevation (described above).    
 
If ≥ CTCAE grades 3, interrupt sonidegib dosing for up to 21 days and 
resume therapy at a reduced dose if resolution or improvement to CTCAE 
grade 1 occurs. Collect blood sample for PK and CK measurement at the 
time of dose interruption. If CK is elevated, manage as for symptomatic 
CK elevation. If muscle symptoms persist and CK is elevated, consider 
performing electromyography and muscle biopsy and monitor blood 
and/or urine myoglobin. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
50 
 
Recommended dose modifications for sonidegib** 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Renal 
Serum creatinine 
Serum creatinine <2 x ULN 
Maintain dose level 
Serum creatinine 2-3 x ULN 
Omit dose until resolved to ≤ grade 1, then: 
 
If resolved in ≤ 7 days, then maintain dose level 
 
If resolved in > 7 days, then decrease dose by 1 step 
Grade 3 
Serum creatinine > 3.0 - 6.0 x ULN 
Omit dose until resolved to ≤ grade 1, then decrease dose by 1 step 
Grade 4 
Serum creatinine > 6.0 x ULN  
Omit dose and discontinue patient from study 
Hepatic 
Bilirubin 
Total bilirubin <2 x ULN 
Maintain dose level 
Total bilirubin 2-3 x ULN 
Omit dose until resolved to ≤ grade 1, then: 
 
If resolved in ≤ 7 days, then maintain dose level 
 
If resolved in > 7 days, then decrease by 1 step 
Grade 3 
Total bilirubin > 3.0 - 10.0 x ULN  
Omit dose until resolved to ≤ grade 1, then decrease dose by 1 step 
Grade 4  
Total bilirubin > 10.0 x ULN  
Omit dose and discontinue patient from study 
AST or ALT 
Grade 1  
(> ULN - 2.5 x ULN) 
Maintain dose level 
Grade 2  
(> 2.5 - 5.0 x ULN) 
Maintain dose level 
Grade 3  
(> 5.0 - 20.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline then: 
 
If resolved in ≤ 7 days, then maintain dose level 
 
If resolved in > 7 days, then decrease dose by 1 step 
Grade 4  
(> 20.0 x ULN) 
Omit dose until resolved to ≤ grade 1 or baseline, then decrease dose by 1 step 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
51 
 
Recommended dose modifications for sonidegib** 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Cardiac 
Cardiac - prolonged QTc interval ≥ 
grade 3 (QTcF > 500 msec or >60 ms 
from baseline on at least 2 separate 
ECGs) 
First Occurrence: 
 
Omit dose 
 
Perform an analysis of serum potassium and magnesium, and if below 
lower limit of normal, correct with supplements to within normal limits. 
Concomitant medication usage must be reviewed. 
 
Perform a repeat ECG within one hour of the first QTcF of > 500 ms 
 
If QTcF remains > 500 ms, repeat ECG as clinically indicated but at least 
once a day until the QTcF returns to < 480 ms. 
 
Once QTcF prolongation has resolved, study treatment may be restarted 
at a reduced dose level 
 
Second Occurrence: 
 
discontinue patient from further study treatment 
Cardiac general 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose and discontinue patient from study 
Grade 4 
Omit dose and discontinue patient from study 
Other adverse events** 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Omit dose until resolved to ≤ grade 1, then decrease dose by 1 step 
Grade 4 
Omit dose and discontinue patient from study 
All dose modifications should be based on the worst preceding toxicity. 
If the dose-limiting toxicity recurs in a patient following 2 dose reductions, then further therapy with sonidegib will 
not be continued. 
If a patient requires a dose interruption of > 21 days from the intended day of the next scheduled dose because of an 
sonidegib-related toxicity, then the patient must be discontinued from the study.  
*Common Toxicity Criteria for Adverse Events (CTCAE Version 4.0). 
** If the investigator deems that a recommended dose reduction or the recommendation to maintain the same dose 
level is not in the best interest of the patient, this decision may be discussed with Novartis on a case-by-case basis. 
 
 
     5.2 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. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
52 
 
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 Levela 
 
Gemcitabine 
(mg/m2)a 
 
nab- Paclitaxel 
(mg/m2) 
 
 
 
Study Dose 
1000 
1000 
-1 
800 
800 
- 2 
600 
600 
aDose reductions may or may not be concomitant. Please refer to Tables 4-6 for specific 
recommendations regarding dose reductions 
 
 
If patients experience study drug-related toxicities that require a delay in scheduled 
gemcitabine dosing for ≥ 21 days will be discontinued from further participation in this 
study. 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 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) 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
53 
 
 
Non Hematologic Toxicity and/ or Dose Hold with Previous Cycle 
 
Toxicity/ dose held 
 
Gemcitabine 
dose this cycle 
Grade 0, 1 or 2 
Same as day 1 previous cycle 
Grade 3 toxicity 
Decrease gemcitabine to 800 mg/m2 
Grade 4 toxicity 
Off protocol treatment 
Dose held in 2 previous consecutive cycles 
Decrease gemcitabine to 800 mg/m2 
 
 
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. 
 
 
 
 
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*††† 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
54 
 
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* 
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 teatment 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  
 
 
 
Dose modifications may also be made for non-hematological toxicity within a cycle as 
specified in Table 6. 
 
 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
55 
 
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. 
 
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 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. 
 
 
 
 
 


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56 
 
6. 
SAFETY MONITORING AND REPORTING 
  
6.1 Adverse Events 
Definitions and reporting 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study drug (or therapy) 
even if the event is not considered to be related to study drug (or therapy). Study drug (or 
therapy) includes the drug (or therapy) under evaluation, and any reference or placebo drug (or 
therapy) given during any phase of the trial. 
 if it is unclear what study treatment includes, list all drug(s), other therapies, changes to 
existing therapy, diagnostic procedure, etc. that are specified by the protocol 
Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment (any procedures specified in the protocol). 
Adverse events occurring before starting study treatment but after signing the informed consent 
form are recorded. Abnormal laboratory values or test results constitute adverse events only if 
they induce clinical signs or symptoms or require therapy, and are recorded.  
Information about all serious adverse events will be collected and recorded on the FDA 
MedWatch 3500a form. To ensure patient safety each serious adverse event must also be 
reported to Novartis within 24 hours of learning of its occurrence. A serious adverse event is an 
undesirable sign, symptom or medical condition which: 
1. is fatal or life-threatening 
2. required or prolonged hospitalization 
3. results in persistent or significant disability/incapacity  
4. constitutes a congenital anomaly or a birth defect 
5. is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Events not considered to be serious adverse events are hospitalizations for the:  
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
 treatment, which was elective or pre-planned, for a pre-existing condition that did not worsen 
 treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions 
of serious given above and not resulting in hospital admission.  
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any birth 
defects or congenital abnormalities. 
Any serious adverse event occurring after the patient has provided informed consent, has started 
taking the study medication, and until 4 weeks after the patient has stopped study participation 
must be reported. This includes the period in which the study protocol interferes with the 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
57 
 
standard medical treatment given to a patient (e.g. treatment withdrawal during washout period, 
change in treatment to a fixed dose of concomitant medication). The period after discontinuing 
study drug may be extended if there is a strong suspicion that the drug has not yet been 
eliminated. 
For instructions about returning Serious Adverse Event Report Forms to Novartis refer to the 
protocol Section entitled Instructions for Rapid Notification of Serious Adverse Events. 
6.2 Instructions for rapid notification of serious adverse events 
6.2.1 Reporting responsibility 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, 
and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E) 
6.2.2 Reporting procedures 
The investigator must complete the FDA MedWatch 3500a form and Novartis SAE coversheet 
in English, assess the relationship to study treatment and send the initial completed MedWatch 
form and Novartis SAE coversheet by fax 1.888.299.4565 within 24 hours to the local Novartis 
Clinical Safety & Epidemiology (CS&E) Department.  The investigator must then ensure that the 
form and coversheet are accurately and fully completed with follow-up information and fax 
those to Novartis CS&E Department within 2 to 3 calendar days for deaths or life-threatening 
events and 5 calendar days for other serious adverse events. The original and the duplicate copies 
of the FDA MedWatch form, Novartis SAE coversheet, and the fax confirmation sheet must be 
kept with the case report forms at the study site.  
Follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, whether the blind was broken or not, and whether the patient continued or 
discontinued study participation. The MedWatch form, Novartis SAE coversheet, and fax 
confirmation sheet must be retained. Pregnancy follow-up should describe the outcome of the 
pregnancy, including any voluntary or spontaneous termination, details of the birth, and the 
presence or absence of any congenital abnormalities or birth defects. 
 
 
6.3 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. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
58 
 
 
 
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. 
 
6.4 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 (sonidegib and Gemcitabine) and can be expected. 
 
6.4.1 Adverse Event List(s) for Sonidegib 
 
Table  Adverse events suspected to be related with sonidegib, occurring in ≥5% of patients 
 
AE (preferred term) 
All 
N= 76 
 
All grades 
N (%) 
Grade 3/4 
N (%) 
Nausea 
21 (27.6) 
0 
Dysgeusia 
19 (25.0) 
0 
Muscle spasms 
18 (23.7) 
0 
Blood creatine phosphokinase increased 
17 (22.4) 
12* (15.8) 
Decreased appetite 
11 (14.5) 
0 
Fatigue 
11 (14.5) 
0 
Vomiting 
9 (11.8) 
0 
Myalgia 
8 (10.5) 
0 
Alopecia 
7 (9.2) 
0 
Weight decreased 
6 (7.9) 
0 
Diarrhea 
5 (6.6) 
0 
Headache 
5 (6.6) 
0 
Lethargy 
5 (6.6) 
0 
Aspartate amino transferase increased 
4 (5.3) 
2 (2.6) 
Asthenia 
4 (5.3) 
2 (2.6) 
Myositis 
4 (5.3) 
2 (2.6) 
Pain in extremity 
4 (5.3) 
0 
* An additional patient who experienced grade 4 CK elevation was not captured 
in this table because the investigator had indicated the event was not treatment-
related in the clinical database. However, the patient had high systemic sonidegib 
exposure, which was consistent with other patients who experienced DLTs. Also, 
the DLT of CK elevation at 1000 mg QD occurred after the database cut-off date 
on Oct 29, 2010. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
59 
 
6.4.2 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, 
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. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
60 
 
• 
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 
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).  
 
6.4.3 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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
61 
 
seen with Taxol. 
 
 
6.5 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. 
 
“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. 
 
Investigator Reporting of AEs and SAEs 
 
The Investigator or designee must completely and promptly record each adverse event 
using the CRF, 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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
62 
 
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 Case Report Forms.  
 
6.5.1 Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure 
patient safety each pregnancy must also be reported to Novartis within 24 hours of 
learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects, congenital abnormalities or maternal and newborn 
complications. 
 
 
6.5.2 Reporting Serious Adverse Events (SAEs) 
 
ALL Serious adverse events, regardless of causality, to ALL of the following: 
1. Novartis  
2. IRB 
3. FDA 
 
 
 
 
Timelines for reporting SAE’s 
 
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. Novartis - within 24 hrs of learning of a potential AE.   
Fax: to IMS at-1-888-299-4565 (toll-free) or-1-973-781-6794. If a fax machine is not 
available, AEs must be reported directly to IMS by calling 1-888-NOW-NOVA (1-888-
669-6682 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
63 
 
3. FDA- .  As per section 6.6 
 
Follow up on SAE reports should also be send to all the above agencies within two weeks of 
receipt of information at the site. 
 
6.6  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 sonidegib.  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 Novartis 
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 sonidegib.  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, 
Novartis Drug Safety, and all participating investigators within 15 calendar days of first 
learning 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: 
 
Novartis Drug Safety- within 24 hrs of learning of a potential AE.   


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64 
 
Fax: to IMS at-1-888-299-4565 (toll-free) or-1-973-781-6794. If a fax machine is not 
available, AEs must be reported directly to IMS by calling 1-888-NOW-NOVA (1-888-
669-6682 
For questions related to safety reporting, contact: 
 
Novartis Drug Safety:  1-888-NOW-NOVA (1-888-669-6682 
 
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 Novartis.  Copies of such reports 
should be faxed to: 
 
Novartis Drug Safety 
Fax: to IMS at-1-888-299-4565 (toll-free) or-1-973-781-6794. . 
6.7 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 
accordance with SKCCC guidelines.   
 
 
 
6.7.1     Internal review  
 
The PI 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 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: 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
65 
 
 
- 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.  
 
6.7.2  External review  
 
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.  
 
 
 
 
7. 
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. 
 
7.1 Sonidegib 
 
Route of Administration: 
Oral 
 
 
Mode of Action:  
Sonidegib is a potent antagonist of Hedgehog and 
Smoothened dependent signaling. 
 
 
Packaging and labeling:  
Medication will be labeled for Clinical Trial use and 
will include storage conditions for the drug and the 
medication number but no information about the 
patient. 
 
 
Packaging and labeling 
Study drugs 
Packaging 
Labeling (and dosing frequency) 
LDE-225 (sonidegib) 
 
Capsules in bottles (200 mg) 
 
Labeled as ”sonidegib” 
 


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66 
 
 
 
How Supplied:   
Sonidegib is supplied by Novartis as a 200-mg hard 
gelatin capsules for oral use, packaged in bottles, 
and will be administered on a flat scale of mg/day. 
 
Administration:   
Sonidegib should be taken as follows 
 Patients should be instructed to take their once-a 
day dose at approximately the same time each 
day 
 Each daily dose of sonidegib should be taken 
with a glass of water and consumed over as 
short a time as possible (e.g. 1 capsule every 2 
minutes) 
 Patients should be instructed to swallow 
capsules whole and to not chew or open them 
 Each daily dose of sonidegib should be taken 2 
hours after a light breakfast (e.g., consisting of 
juice, toast and jam). If breakfast was completed 
at 08:00 a.m., then study drug administration 
should occur at 10:00 a.m. Food intake should 
be avoided for at least 1 hour after study drug 
administration 
 Patients must avoid grapefruit, pomegranate, 
star fruit and Seville (sour) oranges during the 
entire study. The juices and products containing 
these fruits may also be avoided. 
 If vomiting occurs during the course of the 
treatment, then no re-dosing of the patient is 
allowed before the next scheduled dose 
 If the patient forgets to take his/her daily 
morning dose, then he/she should take sonidegib 
within 6 hours after the missed dose. If more 
than 6 hours have passed, then that day’s dose 
should be omitted and the patient should 
continue treatment with the next scheduled dose 
 Patients should inform the investigational site 
staff of any missed or delayed dose 
 
 
Supply, receipt and storage:   
 


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67 
 
 Study drug must be received by a designated 
person at the study site, handled and stored 
safely and properly, and kept in a secured 
location to which only the investigator and 
designated assistants have access. Upon receipt, 
sonidegib should be stored according to the 
instructions specified on the drug labels. Study 
medication will be dispensed by an authorized 
person at the investigator’s site.  
 Patients will be provided with adequate supply 
of sonidegib for self-administration at home 
until at least their next scheduled study visit. 
 
 
Drug Accountability:  
 
 Clinical drug supply must be accounted for and 
patients will be asked to return all unused study 
drug and packaging on a regular basis, at the 
end of the study or at the time of study drug 
discontinuation. 
 At the conclusion of the study, and, as 
appropriate during the course of the study, the 
Investigator will return all used and unused 
study drug, packaging, drug labels, and a copy 
of the completed drug accountability ledger to 
Novartis.  
Disposal and destruction:  
 
 The drug supply will be destroyed at a Novartis 
facility, Drug Supply group or third party, as 
appropriate. Study drug destruction at the 
investigational site will only be permitted if 
authorized by Novartis in a prior agreement and 
if permitted by local regulations. 
 
 
7.2 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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
68 
 
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 Study Drug:     
 
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: 
 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
69 
 
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 
 
7.3 
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 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.  


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70 
 
 
 
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 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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
71 
 
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. 
 
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. 


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72 
 
 
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:           Will be obtained by commercial means 
 
 
8. 
CORRELATIVE/SPECIAL STUDIES 
 
8.1 Laboratory Correlative Studies 
 
We will evaluate three sources of patient material (tumor biopsies, resected tumor and 
blood) in order to evaluate the effects of sonidegib. We will also evaluate the effects 
combination therapy on stromal compartment, intratumoral drug levels.  Tumor tissue 
(biopsies or resected tumor) and blood samples will be obtained pre- and mid-treatment 
in patients.  
 
Biopsies:  Pre-treatment biopsies will be done within 14 days before starting cycle 1. The 
second mid-treatment biopsy will occur after two cycles of chemotherapy with 
gemcitabine and the hedgehog inhibitor sonidegib. Resected tumors in patient who 
undergo resection will also be used for correlative studies. For patients with unresectable 
disease at the time of surgical exploration a core/wedge biopsy will be obtained intra-op 
for the correlative studies as a substitute to the resected specimen. 
 
 
8.1.1 Specimen collection techniques 
 
8.1.1.1. Core biopsy of tumor tissue 
 
8.1.1.1.1 Patient preparation instructions for 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: 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
73 
 
 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 small amounts of clear liquid only 
 
 
8.1.1.1.2. Biopsy Procedure 
Biopsies will be done by routine EUS. Biopsies will be done using a commercially 
available 22-gauge standard fine needle aspiration needle or ProCore needle will be used, 
and 2-4 samples will be obtained from the lesion.   
 
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 from primary tumor under EUS guided biopsy. 
 
8.1.1.1.3. Fine needle aspiration biopsy (FNAB) for core biopsy 
 
We will obtain a tumor core biopsy via ultrasound-guided FNA biopsy of the primary 
tumor. An FNAB will be performed using a standard technique using 22-gauge standard 
FNA needle or ProCore needle, per standard technique, including on-site microscopic 
evaluation by a cytopathologist, or a specially trained cytotechnologist. A maximum of 
ten “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 
gastroenterologist to the appropriate area of the lesion.   
 
8.1.1.2. Blood 
Blood samples for correlative biology and immunology evaluation will be collected up to 
14 days prior to initiation of therapy and following cycle 1 of treatment. We will collect 
approximately 220mL of blood (20mL of serum for banking in order to perform 
biomarker studies, and 200mL of PBMCs for circulating cancer cells.) 
 
 
8.1.2. Handling of specimens 
 
8.1.2.1. Core biopsy 
 


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74 
 
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).  Real time quantitative PCR (qRT-PCR) analysis will be 
performed for transcript levels of Gli1, Ptch in the samples, using SDHA as a 
housekeeping gene control. Further details on these assays are indicated in section 8.1.4. 
 
8.1.2.2. Blood 
PBMCs will be separated from whole blood using the Ficoll Hypaque density gradient 
centrifugation method, and used for flow cytometry for circulating cancer cells .  The 
residual serum will be stored at -800C. 
 
8.1.3. Evaluation of Specimens 
 
All samples collected for laboratory correlative studies will be taken to Anirban Maitra’s 
lab: 
 
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 
Ph 410 955 3511 / Fax 410 614 0671 
Email: amaitra1@jhmi.edu 
 
8.1.4 Specific laboratory assays  
 
8.1.4.1 Technique for Stroma evaluation 
 
Semiquantitative density of stroma by H&E using a scale of 1+, 2+ and 3+. Results will 
be correlated with the primary endpoint resection rate. 
 
8.1.4.2. Technique for Drug levels evaluation 
 
Using a genetic engineered mouse model, Tuveson and colleagues demonstrated 
decreased drug delivery of gemcitabine as one of the mechanisms for chemoresistance in 
PDA7. Subsequently, by co-administration of an Hh inhibitor as a stromal depleting 
agent, there was an increase in the intratumoral drug concentrations of the concomitant 
administered cytotoxic agent gemcitabine. We anticipate that co-administration of 
stromal modulating agents will result in increased drug levels of gemcitabine.  
 
We will analyze the intratumoral gemcitabine triphosphate concentrations in the mid 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
75 
 
treatment biopsy and the primary tumor of resected PDA. Gemcitabine triphosphate 
levels will be measured in the Johns Hopkins Analytical Pharmacology Laboratory by 
Michelle A. Rudek, Pharm.D., Ph.D. Concentrations will be quantitated by UPLC with 
tandem mass spectrometry. For gemcitabine triphosphate, tissue homogenates are 
prepared at a standardized concentration of 200 mg/mL in phosphate buffered saline 
which are then extracted by acetonitrile precipitation, dry down, and reconstitution.  
Gemcitabine triphosphate is quantitated over the range of 0.5-10 µg/mL (3-60 µg/g) 
which has been successfully utilized in preclinical models (Rudek, unpublished data).  
Results will be correlated with the primary endpoint of the phase 2 study, resection rate. 
The correlations are exploratory for hypothesis generation. 
8.1.4.3. 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 sonidegib.  
All of the qRT-PCR primers are routinely used in the Maitra laboratory.  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.   
 
8.1.4.4. Flow cytometric analysis for cancer stem cells (CSCs) in resected tumors 
In prior work we found that treatment with hedgehog pathway inhibitors leads to a 
reduction in the frequency of pancreatic CSCs (ALDH+ and CD44+CD24+ cells) 15,16.  
Additionally, aldehyde dehydrogenase (ALDH; a marker for pancreatic CSCs) expression 
in primary tumors correlates with worse survival in patients undergoing resection for 
early stage pancreatic adenocarcinoma 17.   The rationale for these studies, therefore, is to 
quantitatively compare the frequency of CSCs in resected tumors from patients receiving 
therapy with or without the Hh inhibitor sonidegib.  We will also correlate the frequency 
of CSCs in resected tumors with clinical outcomes (resection rate and overall survival).  
Tumors tissue (100-500 mm3) will be dissociated into a single cell suspension as 
previously described using mechanical and enzymatic dissociation and Ficol gradient 
centrifugation 17.  Cells will then be stained using antibodies against CD31, CD45, and 
glycophorin (to eliminate endothelial and hematopoietic cells) as well as the 
ALDEFLUOR reagent (to mark ALDH+ cells) and antibodies against CD44 and CD24, 
which are markers of pancreatic CSCs.  The percentage of ALDH+ and CD44+CD24+ 
cells in each tumor tissue will be analyzed and quantified using a FACSAria flow 
cytometer.   
 
8.1.4.5. Xenograft formation from resected tumors 
We have extensive experience with generating human pancreatic cancer xenografts in 
immunocompromised mice 18.  The ability of human tumors to form xenografts in mice is 
dependent on a number of factors, including the presence of CSCs that have long-term 
self-renewal potential and the capacity to differentiate.  In these studies we will study the 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
76 
 
effect of sonidegib on the ability of resected tumors to form xenografts.  If the sonidegib 
abrogates CSC function, then we expect those tumors to have a reduced capacity to form 
xenografts in immunocompromised mice.  We will correlate the ability of resected 
tumors to form xenografts with the frequency of CSCs in them (as described above) as 
well as with clinical outcomes (Progression free survival, time to relapse and overall 
survival).   Tumor tissue will be cut into 2x2x2 mm pieces and implanted subcutaneously 
into the right and left flanks of five athymic (nu+/nu+) mice.  Tumor formation and size 
will be measured weekly for 24 weeks.  To confirm that actual tumor tissue was 
implanted a separate 2x2x2 mm tumor piece will be fixed in formalin, sectioned, and 
stained for histologic analysis.  


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
77 
 
9. 
STUDY CALENDAR     
0       4        8       12     16       20      27     
C3
34      38
XRT
Rest
C2
C4
C1
Arm A:  Gem/ Nab-Paclitaxel/ LDE-225
S
U
R
G
E
R
Y
Phase I Stage
Neoadjuvant  Study of Borderline Resectable Pancreatic Cancer
Resectable?
Yes
OFF STUDY
No
Enrollment
Pre-Rx Biopsy
week
Mid treatment 
Biopsy
Optional biopsy
Restage
C5
C6
 
    
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
78 
 
0       4        8       12     16       20      27
C3
34      38
XRT
C5       C6 
Rest
C2
C4
C1
S
U
R
G
E
R
Y
Phase II Stage
Neoadjuvant  Study of Borderline Resectable Pancreatic Cancer
Resectable?
Yes
OFF STUDY
No
Enrollment
Pre-Rx Biopsy
week
Mid treatment 
Biopsy
Optional biopsy
Restage
Arm A:  Gem/ Nab-Paclitaxel/ LDE-225
Arm B:  Gem/Nab-Paclitaxel
 
 
 
 
 
 
 
 
 
 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
79 
 
CALENDAR FOR CHEMOTHERAPY 
  
 
Cycle 1-4 
Cycle 5-6 
   
 
Pre- 
Study 
 
Day 
1 
 
Day 
8 
 
Day 
15 
 
Cycle 3 
Day 1 
EOT 
 
 
Sonidegiba (daily, days 1-28) 
 
 
 
               X ---------------------------------------- X 
 
 
 
Gemcitabine and Nab-Paclitaxel 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical evaluation 
 
X 
 
At baseline and at the end of radiation 
 
 
 
Concurrent meds 
 
X 
 
               X ---------------------------------------- X 
 
 
X 
 
Concurrent procedures 
 
X 
 
               X ---------------------------------------- X 
 
 
X 
 
Adverse event evaluation 
 
 
 
               X ---------------------------------------- X 
 
 
X 
 
Physical exam 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Heightg and Weight 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
BSA calculation 
 
X 
 
X 
 
 
 
 
 
 
 
 
ECOG Performance 
 
X 
 
X 
 
 
 
 
 
 
 
X 
CBC w/diff, platelets, CKf 
 
X 
 
X 
 
X 
Xf 
 
 
 
X 
Comprehensive Metabolic panelf 
 
X 
 
X 
 
 
 
 
 
 
 
X 
PT, PTT, INRf 
 
X 
 
 
 
 
 
 
X 
 
 
Surgeryb 
 
X 
Four weeks after radiation 
 
 
 
EKG (as indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
Radiologic evaluation  
CT scan or MRIh 
 
X 
 
Imaging will be done at baseline, end of cycle 2, cycle 4, before 
radiation therapy, 4 weeks after radiation therapy and at the end of 
cycle 6. 
 
PET Scanh 
 
X 
 
PET scan at baseline and at the end of cycle 4 
 
 
Pregnancy Test 
Xc 
Xd 
 
 
 
Pre-Treatment Biopsy 
 
X 
 
 
 
 
 
 
 
 
 
 
Mid- treatment biopsy 
 
 
 
 
 
 
 
 
Xe 
 
Serum CA 19-9f  
 
 
 
X 
 
 
 
 
 
 
 
 
Sample for Cancer Stem Cells  
 
X 
 
At baseline and at the end of cycle 4 
 
a Only for patients in a treatment arm that includes sonidegib 
bAfter Surgery patients will have 4 weeks of recovery time before starting further treatment 
c Pregnancy test (women of childbearing potential) at screening and 24 hours prior to first dose of sonidegib  
d In women of childbearing potential. See next page for timings 
e Mid treatment biopsy at cycle three day 1 
f All blood tests will be done within +/- 3 days.  
g Height is required at baseline only.  
h All scans with a window of two weeks. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
80 
 
Baseline evaluations are to be conducted within 14 days 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. 
 
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 sonidegib (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.  A positive urine test must be confirmed by a serum 
pregnancy test.  Prior to dispensing sonidegib, 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 sonidegib. 
 
 
10. 
MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease 
will be assessed by standard criteria.  For the purposes of this study, patients should be re-
evaluated every 8 weeks.   
 
 
10.1 
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. 
 
 
 
10.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment with sonidegib. 
 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
81 
 
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.  
 
 
 
10.1.2 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). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or 
might not be considered measurable.  If the investigator thinks it appropriate to 
include them, the conditions under which such lesions should be considered must 
be defined in the protocol. 
 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
82 
 
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.  
 
 
 
10.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
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 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
83 
 
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 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.  Specific guidelines for 
both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
84 
 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
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. 
  
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. 
 
 
 
 
 
 
 
10.1.4 Response Criteria 


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85 
 
 
 
 
 
10.1.4.1 
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. 
 
 
 
 
10.1.4.2 
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. 
 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
86 
 
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). 
 
 
 
10.1.4.3 
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 
No 
PD 
Any 
Any 
Yes 
PD 
*  See RECIST 1.1 manuscript for further details on what is evidence 
of a new lesion. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
87 
 
**  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 
 
 
 
10.1.5 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.  
 
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.  
 
 
 
10.1.6 Response Review 
 
Response on imaging studies will be assessed by expert radiologists based on 
above RECIST 1.1 criteria.  
 
 


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88 
 
 
10.1.7 PET Response Review 
 
Response on PET will be assessed by expert radiologists based on PERCIST 
criteria  [ The Journal of Nuclear Medicine 2009 May;50 Suppl 1:122S-50S ].    
 
 
11. STATISTICAL CONSIDERATIONS 
 
 
11.1 
Study Design/Endpoints  
 
Study Design:  Open label, Phase 1/2 pilot trial. 
 
Endpoints:   
 
Primary endpoint for phase I component of the trial:  
 Safety Endpoints: Incidence, nature and severity of grade 3 and 4 toxicities that occur 
after Cycle 1, day 1. Grading according to National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI CTCAE; version 4.0). 
 
Primary endpoint for phase II component of the trial: 
 Resection rate as defined by the percent of patients that undergo resection after 
completion of neoadjuvant therapy. 
 
Secondary Endpoints: 
 Overall survival from day 1, cycle 1 
 Complete response, partial response, stable disease and progressive disease per 
RECIST criteria and PERCIST criteria 
 Post surgical pathologic findings including margin status, tumor differentiation and 
lymph node status after neoadjuvant therapy. 
 Toxicity rate, overall and stratified by grade and type. 
 
Correlative Endpoints: 
 Semiquantitative density of stroma. Results will be correlated with the primary 
endpoint resection rate. 
 Semi-quantitative measurement of Gli-1, SHH and PATCH on the biopsies and 
resected tumor.  
 Intratumoral gemcitabine triphosphate concentrations. Concentrations will be 
quantitated by UPLC with tandem mass spectrometry as previously done in 
preclinical models by our group 9. 
 
 
11.2 
Sample Size/Accrual Rate 
 
For the Phase 1 stage it is estimated that 6-12 patients will be enrolled. Phase II stage 
will recruit 40 patients (20 patients per arm). The estimated recruitment is 3-4 patients 
per month. 
 


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89 
 
 
11.3 
Analysis 
 
Phase I study.  A standard 3+3 design will be used to determine the MTD.  For a 
given dose level, if 0/3 toxicity are observed then the dose combination will be 
escalated.  If 1/3 toxicities are observed, then an additional 3 patients will be enrolled 
at the current dose level.  Escalation will continue if 1/6 toxicities are observed.  If > 
1/3 or > 1/6 toxicities are observed then escalation will be halted.  The MTD is 
defined as the highest dose level for which  0 or 1 out of 6 toxicities are observed.  
With 2 dose levels, we expect to enroll between 6-9 patients with an expected accrual 
rate of 3 patients per month. The phase I portion of the study will be completed 
during the first year of the study. We will tabulate the number, type and grade of 
toxicities for each treatment cycle. The six patients enrolled and treated with 
gemcitabine and sonidegib will not be included in the analysis. 
 
Phase II study.  The phase 2 study will be used to prospectively establish resection 
rates and initial efficacy outcome estimates for each of the treatment combinations to 
be used for designing larger phase 2 or 3 studies. We will enroll a total of 40 patients 
(20 patients per arm). Expected enrollment is 3 patients per month. Enrollment will 
occur during the first two years of the study. 
 
Summary statistics for continuous outcomes (mean, SD, median, range) and 
categorical outcomes (count, percentage) will be calculated.  The number and grade 
of toxicities will be tabulated.  Percent of patients that achieved resection will be 
described with exact Binomial 95% confidence intervals. Kaplan-Meier techniques 
will be used to summarize time-to-event outcomes (overall survival and disease free 
survival) graphically and to estimate the median and one and two-year survival 
outcomes with 95% confidence intervals.  Cox proportional hazards functions will be 
used to estimate the effect of risk factors (e.g. tumor grade, nodal status) on overall 
survival.      
 
Power calculations. With 20 patients in an arm, we have 81% power to detect an 
increase in the percentage of resectable patients from the null rate of 41% to 65% 
based upon a one-sample test of proportion with a one-sided type-1 error rate of 10%.  
This sample sizes allows us to estimate the proportion of resectable patients within  
23%.    
 
Correlative Studies: IHC analyses will be conducted using a semi-quantitative 
method.  Either hematoxylin and eosin staining for stroma, or specific IHC staining 
with the protein targeted antibody and will be scored from 1+ to 3+, resulting in three 
groups: low (1+), intermediate (2+), and high (3+).  We will correlate clinical 
outcomes (resection rate, tumor response and OS) with stroma density, SHH, Gli1 
and Patch expression. Logistic regression will be used to assess the association 
between stromal scoring and resection. Cox proportional hazards functions will be 
used to estimate the effect of risk factors (e.g. stromal grade) on overall survival.   
Comparisons of scoring between treatment arms and time periods will be evaluated 
using 2 tests (or Fisher’s exact test if appropriate) and with percent agreement and 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
90 
 
Kappa statistics, respectively.  Comparisons of expression across treatment groups 
and between time periods will be evaluated using t-tests (or Wilcoxon rank-sum 
tests) 
and 
paired 
t-tests 
(or 
Wilcoxon 
signed-rank 
tests), 
respectively. 
Pharmacokinetic (PK) data will be summarized using descriptive statistics. Logistic 
regression will be used to assess the association between drug concentrations and the 
clinical endpoint resection rate. 
 
 
 
11.4 
Futility Assessment and Toxicity Monitoring Guidelines 
 
A single interim futility analysis will be included to eliminate any arms that do not 
show activity.  The resection rate would have to be > 40% to be considered clinically 
significant. For each arm, if 0 out of the first 10 patients are eligible for resection then 
the arm will be dropped.  The upper boundary for the two sided 95% confidence 
interval for 0/10 is 26%, which is below the level of resection rate that would be 
considered clinically significant.  
 
Toxicity will be monitored throughout the course of the trial since only 6 patients will 
have received the combination therapy during phase 1.  Bayesian stopping guidelines 
have been developed.  The prior distribution was chosen to be a Beta(1.5, 5.5) to 
reflect the toxicity criteria from the phase 1 portion of the study.  As each patient 
completes 1 month of follow-up (the window initial for toxicity evaluation) or 
experiences an adverse event, the posterior probability that the toxicity exceeds 33% 
will be computed.  An initial 6 patients will be enrolled prior to initiation of 
monitoring.  Thereafter, if the probability that the toxicity level exceeds the target 
threshold (33%) is above 70%, then the study will be re-evaluated.  The table below 
lists the number of toxicities that would trigger a re-evaluation at each stage of 
enrollment.  Accrual will not be halted during the monitoring process unless 
excessive toxicity is encountered.  
 
 
Stopping guidelines for toxicity monitoring. 
 
Sample Size 
Number of toxicities 
3 
3 
4-6 
4 
7-9 
5 
10-12 
6 
13-14 
7 
15-17 
8 
18-20 
9 
 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
91 
 
Based upon 5000 simulated trials, applying these stopping guidelines would result in 
halting the trial early 29% of the time if the true level of toxicity were 33%. The table 
below gives the probability of stopping early under a number of different scenarios. 
 
Probability of early stopping based upon the guidelines described above. 
 
Underlying toxicity 
rate 
Probability of 
re-evaluation 
25% 
11.1% 
30% 
22.2% 
33% 
29.3% 
35% 
35.8% 
40% 
51.5% 
50% 
81.4% 
 
12 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE PROCEDURES 
 
12.1 Ethics and good clinical practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
3. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
4. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended 
Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms 
to. 
 
12.2 Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC/REB). A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. The name and occupation of the chairman and the members of 
the IRB/IEC/REB must be supplied to Novartis. Any amendments to the protocol, other than 
administrative ones, must be approved by this committee. 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
92 
 
12.3 Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval.  
 
12.4 Discontinuation of the study 
Novartis reserves the right to discontinue support for any study under the conditions specified in 
the clinical trial agreement. 
 
12.5 Amendments to the protocol 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Novartis and the investigator before implementation. Amendments significantly 
affecting the safety of subjects, the scope of the investigation or the scientific quality of the 
study, require additional approval by the IRB/IEC/REB. A copy of the written approval of the 
IRB/IEC/REB, must be sent to Novartis. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC/REB approval but the IRB/IEC/REB of each center must be kept 
informed of such administrative changes.  
 
12.6 Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and prior to any outside submission.  Novartis must receive copies of any 
intended communication in advance of publication (at least twenty-one working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the scientific 
content and conclusions of such publications or presentations.  Principal Investigation/Institution 
shall have the final authority to determine the scope and content of its publications, provided 
such authority shall be exercised with reasonable regard for the interests of Novartis and, in 
accord with the trial contract and shall not permit disclosure of Novartis confidential or 
proprietary information. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
93 
 
12.7 Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately to 
ensure their confidentiality. The information provided by Novartis to the investigator may not be 
disclosed to others without direct written authorization from Novartis, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the trial. 
 
12.8 Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 
or 
can 
be 
accessed 
via 
the 
website 
of 
the 
World 
Medical 
Association 
at 
http://www.wma.net/e/policy/17-c_e.html. 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
94 
 
13. REFERENCES 
 
1. 
Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin 
59:225-49, 2009 
 
2. 
van Geenen RC, ten Kate FJ, de Wit LT, et al: Segmental resection and wedge 
excision of the portal or superior mesenteric vein during pancreatoduodenectomy. Surgery 
129:158-63, 2001 
 
3. 
Curran T, Ng JM: Cancer: Hedgehog's other great trick. Nature 455:293-4, 2008 
 
4. 
Thayer SP, di Magliano MP, Heiser PW, et al: Hedgehog is an early and late 
mediator of pancreatic cancer tumorigenesis. Nature 425:851-6, 2003 
 
5. 
Tian H, Callahan CA, DuPree KJ, et al: Hedgehog signaling is restricted to the 
stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A 106:4254-9, 
2009 
 
6. 
Feldmann G, Habbe N, Dhara S, et al: Hedgehog inhibition prolongs survival in a 
genetically engineered mouse model of pancreatic cancer. Gut 57:1420-30, 2008 
 
7. 
Olive KP, Jacobetz MA, Davidson CJ, et al: Inhibition of Hedgehog signaling 
enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457-
61, 2009 
 
8. 
J. Rodon Ahnert JB, H. A. Tawbi, Y. Shou, C. Granvil, J. Dey, M. M. Mita, A. L. 
Thomas, D. D. Amakye, A. C. Mita: A phase I dose-escalation study of LDE225, a smoothened 
(Smo) antagonist, in patients with advanced solid tumors. J Clin Oncol 28:15s,  2010 (suppl; 
abstr 2500), 2010 
 
9. 
Veltkamp SA HM, Rosing H, Jansen RS, Wickremsinhe ER, Perkins EJ, 
Schellens JH, Beijnen JH. : Quantitative analysis of gemcitabine triphosphate in human 
peripheral blood mononuclear cells using weak anion-exchange liquid chromatography coupled 
with tandem mass spectrometry. J Mass Spectrom Dec;41(12):1633-42). 2006 
 
10. 
Jemal A, Siegel R, Xu J, et al: Cancer Statistics, 2010. CA Cancer J Clin  
 
11. 
Abrams RA, Lowy AM, O'Reilly EM, et al: Combined modality treatment of 
resectable and borderline resectable pancreas cancer: expert consensus statement. Ann Surg 
Oncol 16:1751-6, 2009 
 
12. 
Katz MH, Pisters PW, Evans DB, et al: Borderline resectable pancreatic cancer: 
the importance of this emerging stage of disease. J Am Coll Surg 206:833-46; discussion 846-8, 
2008 
 
13. 
Miyamoto H, Murakami T, Tsuchida K, et al: Tumor-stroma interaction of human 
pancreatic cancer: acquired resistance to anticancer drugs and proliferation regulation is 
dependent on extracellular matrix proteins. Pancreas 28:38-44, 2004 
 
14. 
Erkan M, Michalski CW, Rieder S, et al: The activated stroma index is a novel 
and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin Gastroenterol 
Hepatol 6:1155-61, 2008 
 
15. 
Jimeno A, Feldmann G, Suarez-Gauthier A, et al: A direct pancreatic cancer 
xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther 
8:310-4, 2009 
 
16. 
Feldmann G, Dhara S, Fendrich V, et al: Blockade of Hedgehog Signaling 
Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy 
in Solid Cancers. Cancer Res 67:2187-2196, 2007 
 
17. 
Rasheed ZA, Yang J, Wang Q, et al: Prognostic significance of tumorigenic cells 
with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 102:340-51, 2010 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
95 
 
 
18. 
Rubio-Viqueira B, Jimeno A, Cusatis G, et al: An in vivo platform for 
translational drug development in pancreatic cancer. Clin Cancer Res 12:4652-61, 2006 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
96 
 
 
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. 
 
 
 
 
 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
97 
 
 
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, during their participation in the study and 
for 20 months following discontinuation of sonidegib. 
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) 
The following are acceptable forms of secondary contraception, when used with a barrier 
method: 
 Tubal ligation  
 Partner’s vasectomy 
 Intrauterine device (non–progesterone T) 
 Vaginal sponge (containing spermicide) 
In addition, 100% commitment to abstinence is considered an acceptable form of 
contraception. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
0 
 
The following are unacceptable forms of contraception for women of childbearing potential: 
 Hormonal contraception including birth control pills, patches, rings, or injections  
 IUD progesterone T  
 Progesterone-only “minipill” 
 Female condom 
 Natural family planning (rhythm method) or breastfeeding 
 Fertility awareness 
 Withdrawal 
 Cervical shield 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
1 
 
APPENDIX C 
 
 
 
 
 
 
 
 
 
 
 
 
An eligibility form must be completed for every subject 
and must be kept in the research chart. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
2 
 
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 BORDERLINE  
                                           RESECTABLE adenocarcinoma of the pancreas.  Patients who have not  
                                        undergone biopsy but have highly suspected adenocarcinoma of the  
                                        pancreas with borderline resectable features on imaging study may also  
                                        be eligible for study and undergo the pretreatment biopsy as per  
                                        protocol. The biopsy must confirm adenocarcinoma of the pancreas to  
                                        continue on study. Borderline resectable disease is defined by one of the  
                                        following criteria:                       
(1)  Tumor associated deformity of the superior mesenteric vein (SMV) or portal 
vein (PV)  
(2)  Abutment of the SMV or PV < 1800  
(3)  Short-segment occlusion of the SMV or PV amenable to resection and venous 
reconstruction  
(4)  Short-segment involvement of the hepatic artery or its branches amenable to 
resection and reconstruction or  
(5)  Abutment of the superior mesenteric artery (SMA) < 1800 
 
 
 
 
_____ ____     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, surgical resection,      
                                     chemotherapy or   investigational drug therapy for pancreatic adenocarcinoma.  
 
_____     _____ 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 
-     plasma creatinine phosphokinase (CK)   < 1.5 x ULN 
- 
creatinine  
 
 
 
 
within normal institutional limits 
OR 
- 
creatinine clearance  
 
Creatinine clearance >50 mL/min/1.73 m2 for 
patients. Serum creatinine < 2 mg/mL 
 
Instructions: This eligibility checklist must be completed in its entirety.   
  
Yes        No                  ELIGIBILITY CRITERIA: (All answers must be YES)_____    ____ 8             


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
3 
 
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 
 
_____   _____ 10        For sexually active females:  Patient has agreed to practice effective  
contraceptive measures throughout  the study and for 20 months after last  
dose of study drug. 
                                     
                                 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 6    
months after stopping sonidegib. Males should not donate sperm during treatment,  
and for up to six months after last dose.                                                                                                
  
_____     ____ 12.         Patient agrees NOT to donate blood products for 12 months after stopping  
                                      sonidegib 
 
_____     ____ 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 is willing to have two biopsies while on treatment 
 
 
____ ____    16.           Patient has NO history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to sonidegib 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®). 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
4 
 
Instructions: This eligibility checklist must be completed in its entirety.   
 
Yes       No                  ELIGIBILITY CRITERIA: (All answers must be YES) 
 
____ ____    18.             Patients is NOT taking medications known to be moderate  and strong  
                                     inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or  
                                     CYP2C9 that have narrow therapeutic index, and that cannot be  
                                     discontinued before starting treatment with sonidegib. Medications that 
are  
                                     strong CYP3A4/5 inhibitors should be discontinued at least 7 days and  
                                     strong CYP3A/5 inducers for at least 2 weeks prior to starting treatment  
                                     with sonidegib. 
             
 
____ ____    19.             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. 
 
____ ____    20.             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)  
 
____ ____   21.         Patient does NOT have 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 
 
____ ____   22.         Patient does NOT have history neuromuscular disorders (e.g. inflammatory   
                                Myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal  
                                muscular atrophy)  or is on concomitant treatment with drugs that are 
                                recognized to cause  rhabdomyolysis, such as HMG CoA inhibitors (statins), 
                                clofibrate and gemfibrozil, and that cannot be discontinued at least 2 weeks 
                                prior to starting sonidegib treatment.  If it is essential that the patient  
 
 
 
 
        stays on a statin to control hyperlididemia, only pravastatin may be used with 
                                caution. b)  Patient is NOT planning on embarking on a new strenuous  
                                exercise regimen after initiation of study treatment. NB: Muscular activities,  
                                such as strenuous exercise, that can result in significant increases in plasma 
                               CK levels should be avoided whie on sonidegib treatment. 
                                
                        
 
 
                                                   
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
5 
 
____ ____   23.        Impaired cardiac function or clinically significant heart disease, including any 
one of the following: 
 Angina pectoris within 3 months 
 Acute myocardial infarction within 3 months 
 QTcF > 450 msec for males and > 470 msec for females on the screening ECG 
 A past medical history of clinically significant ECG abnormalities or a family history 
of prolonged QT-interval syndrome 
 Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled 
hypertension, history of labile hypertension, or history of poor compliance with an 
antihypertensive regimen) 
  
 
 
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:  ____________________________ 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
6 
 
APPENDIX D 
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.  
 
 
 
 
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.) 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
7 
 
 
APPENDIX E: 
 
 
 PROTOCOL SIGNATURE PAGE 
 
 
 Protocol Number: J1130, NA_00047491 
 
 
Protocol Title: Phase 1/2 Safety and Feasibility of Gemcitabine and Nab-Paclitaxel in 
combination with LDE-225 (Sonidegib) as Neoadjuvant Therapy in Patients with 
Borderline Resectable PancreaticAdenocarcinoma. 
 
 
Protocol Amendment 3.4, date August 13, 2014 
 
IND Number: 112289 
 
 
Sponsor: Investigator Initiated 
 
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:  
Ana De Jesus-Acosta MD 
 
Title:   
Assistant Professor  
 
Address:    
The Sidney Kimmel Comprehensive  
                  
 Cancer Center at Johns Hopkins 
                  
 1650 Orleans Street, CRBI, Room4M08,  
                   
Baltimore, MD 21231-1000 
 
 
PI Signature: _____________________ 
 
 
Date:  
_________________        
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
8 
 
APPENDIX F: AMENDMENT SUMMARIES 
 
 
Amendment # 1, Feb 21, 2012 
 
1. On page 27, modified the sentence for “Mid Treatment Biopsy” section as “A window of 3 
days after the treatment will be allowed.” 
2. On page 66, Calendar for Chemotherapy section- 
a) Moved Mid-treatment Biopsy from Day 28 to Cycle 3 Day 1;  
b) Added PT/PTT/INR on Cycle 3 Day 1. 
c) Added “All blood tests will be done within +/- 3 days” to the notation section. 
 
3. In the head section, changed the version and the date of the protocol Amend 1. 
4. On the first page, deleted John Cameron, MD and Marcia Irene Canto, MD from the study. 
5. Added Appendix E: Protocol  Signature Page 
6. Added Appendix F: Amendment Summaries  
 
Amendment # 2, August 29, 2012 
 
1. Header section with new amendment date was added 
2. Page 2: Removed H. Cai from study. Added T. Brown as data manager / coordinator.  
3. Section 3.1.8, Inclusion Criteria, page 22: Removed “unless liver metastases are clearly present, 
then <5X ULN is allowed”. 
4. Section 4.1.7, page 31: End of Therapy evaluation was added 
5. Section 4.6, page 41: Specified schedule for follow up for progression/recurrence and overall 
survival. 
6. Section 8.1, page 62: Added language “For patients found with unresectable disease at the time 
of surgical exploration a core/wedge biopsy will be obtained intra-op for the correlative studies 
as a substitute to the resected specimen.” 
7. Section 9, page 68: Study calendar section modified to reflect EOT evaluation and follow up 
schedule. Footnotes updated. Window of two weeks is added for all scans.  
8. Consent form updated to JHM IRB template 13 and modified to reflect end of treatment visit.  
 
Amendment # 3, April 25, 2013 
 
1. Title: added Nab-Paclitaxel 
2. Responsible research nurse information updated: Sheila Linden 
3. Header section with new amendment date was added 
4. Primary objective: added nab-Paclitaxel. Section 1.1 
5. Section 2.3 Rationale for adding nab-Paclitaxel included 
6. Section 2.4 Rationale moving radiation to pre-surgery included 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
9 
 
7. Section 2.5: Other drugs nab-Paclitaxel added 
8. Section 4.1.5 (Surgery) moved to after radiation 
9. Radiation section now 4.1.5 and timing from chemotherapy within 4 weeks included 
10. Section 4.2 added nab-Paclitaxel to agent administration, regimen description and dose 
escalation cohorts. Dose of nab-Paclitaxel is fixed as per phase II and III studies. 
11. Nab-Paclitaxel added to phase 2 study 
12. Section 4.2.3 Premedication description for nab-Paclitaxel 
13. Section 5.2 modified to include dose modifications for nab-Paclitaxel on day 1 of each cycle and 
during treatment cycles. Also includes management for non-hematological toxicities. 
14. Section 6.4.3 added adverse even list for nab-Paclitaxel 
15. Section 6.3 was added with drug information for nab-Paclitaxel 
16. Section 7.3 added: Pharmacy information for nab-Paclitaxel 
17. Study calendar diagrams to reflect changes and addition of nab-Paclitaxel were modified. 
18. Section 11.3 specifies that the six patients enrolled at this point will not be included in final 
analysis. 
 
Amendment # 3.1, MAY 31, 2013 
Protocol:  
1. Section 3.1.10: “12” months changed to “6” months 
2. Section 3.1.11: “3” months changed to “6” months 
3. Appendix B: “12” months changed to “6” months 
4. Eligibility form, near end of protocol, Item # 11: “12” months changed to “6” months 
Consent:  
5. Section 5: “12” months changed to “6” months (two times) 
6. Section 5: “3” months changed to “6” months 
7. Section 12: added 
a. “and governmental agencies in foreign countries)” 
b. “, the drug supplier (Novartis) and its authorized agents,” 
c. “During the study, you may not have access to some of your medical information 
obtained or created as part of this study.  You will be allowed to access this information 
once the study is finished.” 
d. “If the results of this study are published or presented in a meeting, you will not be 
named and nobody will be able to tell that you were in the study from the publication or 
presentation.” 
 
 
 
 
 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
10 
 
Amendment # 3.2, NOV 27, 2013 
Protocol:  
1. Section 3.1.4: Added “for pancreatic adenocarcinoma” 
2. Section 3.2.1: Added/reworded: “Patients who have had previous radiotherapy, surgical 
resection, chemotherapy or investigational drug therapy for pancreatic adenocarcinoma.” 
3. Appendix C: Added “for pancreatic adenocarcinoma” to item # 3.  
 
 
Amendment #3.3, JUNE 26, 2014 
 
Protocol:  
1. Header: Updated version number and date to Version # 3.3, JUNE 26, 2014. 
2. All applicable sections: Changed LDE-225 to sonidegib. 
3. Section 3.2.12, page 26: added “Impaired cardiac function or clinically significant heart disease” 
as exclusion. 
4. Section 4.4.3, pages 43-44:  
a. “Hormonal” removed from section title. 
b. Added clarification of contraceptive methods. 
5. Section 5.1, page 47-49: updated recommended dose modifications for sonidegib . 
6. APPENDIX B, page 96: 
a. Page 96: Changed number of months women of child bearing potential must use 
contraception from 6 months post-last dose of study drug to 20 months post-last dose 
of study drug.  
b. Page 96: Removed hormonal contraceptive as acceptable method for this study. 
7. Appendix C:  
a. Females must use birth control for 20 months after taking last dose. 
b. Added “Impaired cardiac function or clinically significant heart disease” as exclusion.  
 
Consent:  
1. Removed line for subject initials at bottom of each page, since not IRB required. 
2. Section 3, Cycles 5-6: clarified language about addition of nab-paclitaxel. 
3. Section 4, LDE225 risks:  
a. Added: instructions for females and males (females must use birth control for 20 
months post last dose, and males must use condom during intercourse). 
b. Changed: 700 to 1000. 
c. Added: “including patients”. 
d. Moved: risks of upper abdominal pain, back pain, and cough from less common to 
common side effects section. 
4. Section 5, Pregnancy risks:  
a. Added “while receiving sonidegib, and for 20 months after taking the last dose”. 


J1130, Neoadjuvant Protocol Amendment 3.4: August 13, 2014 
 
11 
 
b. Changed: 6 months to 20 months. 
5. Section 15, added “Novartis will not provide financial assistance or compensation for injury, 
medical expenses, lost wages or any other damages or losses as a result of participation in this 
research study.” 
 
Amendment # 3.4, AUGUST 13, 2014 
Protocol: 
1. Header: updated version to 3.4, August 13, 2014. 
2. Title page: added Amy Ryan, CRNP as co-investigator. 
3. Table of contents: updated page numbers for tracked and clean versions. 
4. Section 3.1.11, Eligibility: changed three to six. “Males should not donate sperm during 
treatment, and for up to six months after last dose.” 
5. Appendix C # 11, Eligibility: added “Males should not donate sperm during treatment, and for up 
to six months after last dose.” 
Consent: 
1. Section 3, page 7: deleted “(initial and date)” since initials are sufficient, and the subject dates 
the final page of the consent form.  
2. Section 5, page 15: added “Women of childbearing potential are required to have a negative 
serum pregnancy test within 10-14 days and within 24 hours prior to the first dose of sonidegib 
(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.  A 
positive urine test must be confirmed by a serum pregnancy test.” 
3. Section 5, page 16: added “Males should not donate sperm during treatment, and for up to six 
months after last dose.”