Conditions: Prostate Cancer
Keywords: LDE225 High risk localized prostate cancer Pre-surgical
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: no

Brief summary:
This trial is designed as a randomized two-arm (LDE225 vs. observation groups) open-label prospective clinical trial in men with localized high-risk prostate cancer undergoing radical prostatectomy.

The investigators propose to determine the effects of LDE225 on neoplastic prostate tissue from men at high risk of systemic disease progression, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested at the time of prostatectomy.

Detailed description:
High-risk patients will be identified based on their core-needle biopsy features, PSA levels, and clinical stage. After obtaining baseline laboratory and clinical values (including an ECG, PSA, hematologic, and renal and hepatic panels), men will receive oral LDE225 800 mg/day or observation daily for 4 weeks (±3 days) prior to prostatectomy. Patients will have a clinical visit and an ECG and laboratory testing will be performed at 2 weeks and then again at 4 weeks, including a 4-week pre-prostatectomy measurement of PSA and a blood sample to determine plasma LDE225 levels. Men will undergo radical prostatectomy (with bilateral pelvic lymphadenectomy as appropriate), at which point two 250-mg biopsies of prostate tissue will be obtained, frozen and stored for analysis.

Arms:
arm 1: Treatment arm (Arm 1) will receive LDE225 by mouth 800 mg daily for 4 weeks (+/- 3 days) arm 2: Observation Arm (Arm2) will receive no treatment prior to prostatectomy.

Interventions: intervention 1: LDE225
Intervention descriptions: intervention 1: Sonidegib was given as an oral drug at 800mg daily for 28 days prior to prostetoctomy

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version 3: October 6, 2015 
Page 1 of 37 
 
 
A pharmacodynamic pre-surgical study of Hedgehog pathway 
inhibition with LDE225 in men with high-risk localized prostate 
cancer 
 
Novartis Study #:  LDE225XUS13T 
Institutional Study #:  J1402 
Investigational New Drug (IND) #:  119644 
Version #:  3 (10/06/2015) 
 
 
Principal Investigator 
Emmanuel Antonarakis, MD 
Johns Hopkins Kimmel Cancer Center 
Email: eantona1@jhmi.edu 
Phone: 443-287-0553 
Fax: 410-614-8397 
 
Co-investigator 
Ashley Ross, MD PhD 
Email: aross2@jhmi.edu 
 
Project Manager 
Ting Wang, MS, MHS 
Johns Hopkins Kimmel Cancer Center 
Email: twang2@jhmi.edu 
 
Lead Study Coordinator: 
Rana Harb, MS 
Johns Hopkins Kimmel Cancer Center 
Email: rharb1@jhmi.edu 
 
 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Protocol Version 3: October 6, 2015 
Page 2 of 37 
Table of Contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 4 
Glossary of terms ................................................................................................................. 6 
1 
Background .......................................................................................................................... 7 
1.1 
Overview of Prostate Cancer ................................................................................... 7 
1.2 
Overview of the Hedgehog (Hh) pathway and its role in cancer ............................ 7 
1.2.1 
Inhibition of Hh pathway by small molecules ........................................ 7 
1.3 
Overview of LDE225 and Nonclinical studies ........................................................ 8 
1.3.1 
Pharmacodynamics ................................................................................. 8 
1.3.2 
Nonclinical pharmacokinetics and metabolism ...................................... 8 
1.3.3 
Nonclinical toxicity and safety studies ................................................... 9 
1.4 
Clinical Experience with LDE225 ........................................................................... 9 
1.4.1 
Clinical safety and efficacy ..................................................................... 9 
1.4.2 
Clinical pharmacokinetics and pharmacodynamics .............................. 11 
1.5 
Study purpose and rationale................................................................................... 12 
2 
Objectives and Endpoints .................................................................................................. 13 
Primary Objective .............................................................................................................. 13 
Secondary Objectives ........................................................................................................ 13 
3 
Investigational Plan ........................................................................................................... 15 
3.1 
Overview and study design .................................................................................... 15 
3.1.1 
Investigational treatment ....................................................................... 16 
3.1.2 
Treatment arms ...................................................................................... 16 
3.1.3 
Treatment duration ................................................................................ 16 
3.1.4 
Treatment assignment/randomization ................................................... 17 
3.2 
Rationale for the study design ............................................................................... 17 
4 
Population and Eligibility Criteria ..................................................................................... 17 
4.1 
Inclusion criteria .................................................................................................... 17 
4.2 
Exclusion criteria ................................................................................................... 18 
5 
Treatment ........................................................................................................................... 19 
5.1 
Treating the patient ................................................................................................ 19 
5.1.1 
Administration....................................................................................... 19 
5.1.2 
Dosing and treatment schedule ............................................................. 19 
5.1.3 
Dose modification and dose delay ........................................................ 20 
5.1.4         Protocol Stopping Rules…………………………………………24 
5.1.5 
Permitted concomitant therapy ............................................................. 23 
5.1.6 
Permitted concomitant therapy requiring caution and/or action ........... 24 


Protocol Version 3: October 6, 2015 
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5.1.7 
Prohibited concomitant therapy ............................................................ 24 
5.2 
Study drug (LDE225) ............................................................................................ 26 
5.2.1 
Packaging and labeling ......................................................................... 26 
5.2.2 
Supply, receipt and storage ................................................................... 27 
5.2.3 
Drug compliance and accountability ..................................................... 27 
5.2.4 
Disposal and destruction ....................................................................... 27 
6 
Schedule and Assessments ................................................................................................ 28 
6.1 
Study flow and visit schedule ................................................................................ 28 
6.1.1 
Screening Evaluation ............................................................................ 29 
6.2 
Assessments ........................................................................................................... 29 
6.2.1 
Efficacy assessments ............................................................................. 29 
6.2.2 
Safety assessments ................................................................................ 29 
6.2.3 
Pharmacokinetics .................................................................................. 29 
6.2.4 
Biomarkers ............................................................................................ 29 
7 
Safety Monitoring and Reporting ...................................................................................... 30 
7.1 
Adverse Events ...................................................................................................... 30 
7.1.1 
Definitions and reporting ...................................................................... 30 
7.2 
Instructions for rapid notification of serious adverse events ................................. 31 
7.2.1 
Reporting responsibility ........................................................................ 31 
7.2.2 
Reporting procedures ............................................................................ 31 
7.3 
Pregnancies ............................................................................................................ 32 
8 
Statistical Methods and Data Analysis .............................................................................. 32 
8.1 
Sample size considerations, and analysis of the primary endpoint ....................... 32 
8.2 
Analysis of the secondary endpoints ..................................................................... 32 
8.3 
Analysis of the exploratory endpoints ................................................................... 33 
9 
Ethical Considerations ....................................................................................................... 33 
9.1 
Ethics and good clinical practice ........................................................................... 33 
9.2 
Institutional review board / Independent ethics committee ................................... 33 
9.3 
Informed consent ................................................................................................... 33 
9.4 
Discontinuation of the study .................................................................................. 34 
9.5 
Amendments to the protocol .................................................................................. 34 
9.5.1 
Publication of results ............................................................................. 34 
9.5.2 
Disclosure and confidentiality............................................................... 34 
9.5.3 
Declaration of Helsinki ......................................................................... 35 
10 References ......................................................................................................................... 35 
 


Protocol Version 3: October 6, 2015 
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List of abbreviations 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse Event 
ALT 
Alanine aminotransferase (glutamic pyruvic transaminase/SGPT) 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase (glutamic oxaloacetic transaminase/SGOT) 
AUC 
Area under the curve 
BCC 
Basal Cell Cancer 
BCNS 
Basal Cell Nevoid Syndrome 
BCRP 
Breast Cancer Resistance Protein 
BID 
bis in diem/twice a day 
CK 
Creatine Phosphokinase 
Cmax 
Maximum (peak) concentration of drug 
Cmin 
Minimum (peak) concentration of drug 
CML 
Chronic Myeloid Leukemia 
CR 
Complete Response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper  
CRO 
Contract Research Organization 
CSP 
Clinical Study Protocol 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria Adverse Events 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of tumor Response 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety and Epidemiology 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
GPCR 
G protein-couple receptor 
Hgb 
Hemoglobin 
Hh 
Hedgehog 
H&N35 
Head and Neck cancer module 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
IHC 
International Conference of Harmonization 
Immunohistochemistry 
IEC 
Independent Ethics Committee 
IMS 
Integrated Medical Safety 


Protocol Version 3: October 6, 2015 
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IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
Lactate Dehyrogenase 
LLOQ 
Lower limit of quantification 
MB 
Medulloblastoma 
MRI 
Magnetic Resonance Imaging 
MRP2 
multi-resistance protein 2 
NBCCS 
Nevoid basal cell carcinoma syndrome 
NMSC 
Non-melanoma skin cancers 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamics 
PFS 
Progression Free Survival 
Pgp 
P-glycoprotein 
PHI 
Patient Health information 
PK 
Pharmacokinetics 
PMR 
Partial Metabolic Response 
PPS 
Per-Protocol Set 
PR 
Partial Response 
PTCH 
Patched 
QD 
Quaque die/ once a day 
QLQ-C30 
RP 
Quality of Life Questionnaire 
Radical Prostatectomy 
RAP 
Report and Analysis Plan (RAP) 
REB 
Research Ethics Board 
RECIST 
Response Criteria in Solid Tumors 
RT 
RT-PCR 
Radiotherapy 
Real time PCR 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum glutamic oxaloacetic transaminase (aspartate aminotransferase; AST) 
SGPT 
Serum glutamic pyruvic transaminase (alanine aminotransferase; ALT) 
Smo 
Smoothened 
SSC 
Study Steering Committee 
TK 
Toxicokinetics 
TTR 
Time to tumor response 
Vss 
Volume of distribution 
WBC 
White Blood cells 
WHO 
World Health Organization 


Protocol Version 3: October 6, 2015 
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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being testing in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study.  
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/healthy volunteer 
who enrolls in the study 
Phase 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival 
Randomization number 
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered 
to the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment  for any 
reason; may or may not also be the point/time of premature patient 
withdrawal 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points 


Protocol Version 3: October 6, 2015 
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1 
Background  
1.1 
Overview of Prostate Cancer 
 
Despite advances in the detection and treatment of prostate cancer, it remains the second most 
common cause of cancer-related deaths in the United States, killing approximately 30,000 
men per year. Men with high-risk localized prostate cancer (Gleason sum 8-10, PSA >20 
ng/mL, clinical stage ≥T3) account for the highest density of prostate cancer deaths and many 
succumb to their disease despite optimal local and systemic treatments (including surgery, 
adjuvant radiation therapy, androgen deprivation therapy, and chemotherapy), highlighting the 
need for novel prostate cancer therapies for these patients.   
 
1.2 
Overview of the Hedgehog (Hh) pathway and its role in cancer  
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 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, ovarian cancer and prostate 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).   
1.2.1 
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.  
Vismodegib (GDC0449; Roche)  has 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, advanced breast cancer, advanced esophageal 
junction and SCLC. Vismodegib is now FDA-approved for use in patients with BCC. XL-139 
(Bristol Myers-Squibb) 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 


Protocol Version 3: October 6, 2015 
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JR ESMO 2010, Rudin et al ESMO 2010) and in superficial BCC in patients with Gorlin 
syndrome (De Rie et al 2010). Vismodegib is now FDA-approved for patients with BCC 
including Gorlin syndrome. 
 
1.3 
Overview of LDE225 and Nonclinical studies 
LDE225 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 multiple types of cancer. 
1.3.1 
Pharmacodynamics 
LDE225 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 LDE225 resulted in >90% 
inhibition Gli1 mRNA expression in tumor samples that was sustained for over 24 hrs. Daily 
multiple doses of LDE225 (20 mg/kg QD) caused >90% tumor regression in genetically 
defined in vivo MB xenograft models characterized by heterozygous deletion of PTCH.  
1.3.2 
Nonclinical pharmacokinetics and metabolism 
LDE225 was well absorbed with good oral bioavailability, ranging from 68 to 100% in the 
mouse, rat, dog, and monkey after PO 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. LDE225 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 (1.9-7.0 L/kg). LDE225 exhibited high protein 
binding (approximately 98% in mouse, rat, dog and human plasma), independent of 
concentration. In rats, ~85% of LDE225 related radioactivity was eliminated into the feces, 
and renal excretion was minor, accounting for <3.0% of the administered dose.  
Clearance of LDE225 is primarily hepatic by CYP3A4. LDE225 was extensively 
metabolized, with the major metabolic pathway being via mono- or di-oxygenation, 
demethylation, and oxidation leading to carboxylic acid formation, dealkylation, and 
dehydrogenation monohydroxylation. The elimination of metabolites is mainly through bile. 
Studies with human liver microsomes demonstrated that LDE225 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 major CYP450 enzymes was 
observed. LDE225 is neither a substrate nor an inhibitor of P-glycoprotein (P-gp) or multi-
resistance protein 2 (MRP2); but it has shown inhibitory effects on breast cancer resistance 
protein (BCRP), with an estimated IC50 value of 1.5 µM. The potential of LDE225 and its 
metabolites to undergo covalent binding to cellular macromolecules was found to be low. 
The results of toxicokinetics (TK) studies with LDE225 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 


Protocol Version 3: October 6, 2015 
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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 LDE225. 
1.3.3 
Nonclinical toxicity and safety studies 
The majority of adverse effects observed in toxicity studies in growing rats and dogs can be 
attributed to the pharmacologic action of LDE225, and the effects in both species were 
similar.  The most striking effects of LDE225, 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. Gli-Luc 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 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 LDE225. 
 
1.4 
Clinical Experience with LDE225 
1.4.1 
Clinical safety and efficacy 
  
LDE225 has been evaluated in a first-in-human, phase I, multicenter open-label dose-
escalation study [CLDE225X2101] in patients with advanced solid tumors including 
medulloblastoma that have progressed despite standard treatments or have no existing 
therapies. The primary objective was to assess the safety, tolerability, PK, PD and potential 
efficacy of continuous once daily oral administration. The MTD for once daily administration 
of LDE225 was 800 mg. Data provided here are obtained from an active clinical trial 
database; therefore, they are preliminary and may be subject to change upon final QC review. 
As of October, 2012, data were available on 103 patients with cancer who have been treated 
with LDE225 at dose levels of 100, 200, 400, 800, 1000, 1500, and 3000 mg once daily (QD) 
and 250, 400 and 750 mg twice daily (BID). Based on the available data, the recommended 
phase II dose of LDE225 in adults is 800 mg once daily. 
DLTs that are characterized by CTCAE grade-3 or -4 increases in plasma creatinine 
phosphokinase (CK) were observed at once daily doses ≥800 mg and twice daily doses ≥250 


Protocol Version 3: October 6, 2015 
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mg (Table 1-1). The majority of the dose-limiting toxicity (DLT) events occurred during the 
initial 4-6 weeks of treatment with LDE225, except for three events that were observed after 6 
weeks. None of the patients experienced impairment of renal function as a result of this 
toxicity. The DLTs resolved following discontinuation of LDE225 therapy.  
Table 1-1 
Incidence of dose limiting toxicities in Study CLDE225X2101 
Dose of LDE225 
No. of patients 
treated 
Elevated plasma CK 
No. patients with 
CTCAE grade-3 
No. patients with 
CTCAE grade-4 
Total (CTCAE 
grades 3 or 4) 
100 mg QD  
6 
0 
0 
0 
200 mg QD  
6 
0 
0 
0 
400 mg QD  
5 
0 
0 
0 
800 mg QD 
26 
1 
1 
2 
1000 mg QD 
11 
1 
1 
2 
1500 mg QD 
9 
0 
3 
3 
3000 mg QD  
10 
0 
3 
3 
250 mg BID 
14 
1 
1 
2 
400 mg BID  
8 
1 
1 
2 
750 mg BID  
8 
0 
5 
5 
Total 
103 
4 
15 
19 
Across all the doses studied, commonly reported CTCAE grade-1 or -2 (in >10% of patients) 
that are suspected to be treatment-related include: nausea, vomiting, dysgeusia, decreased 
appetite, myalgia, muscle spasms, increased blood CK, alopecia, asthenia 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 LDE225 Investigator’s Brochure for further details. 
Table 1-2 
Adverse events suspected to be related with LDE225, occurring in ≥5% of 
patients in Study CLDE225X2101 as of October 2012 
  
800 mg QD* (n=26) 
All doses**  
(n=103) 
 
Grade 1/2 (%) 
Grade 3/4 (%) 
Grade 1/2 (%) 
Grade 3/4 (%) 
Nausea 
3 (11.5) 
 
26 (25.2) 
 
Dysgeusia 
5 (19.2) 
 
29 (28.2) 
 
Weight decrease 
4 (15.4) 
 
10 (9.7) 
 
Decreased appetite 
4 (15.4) 
 
18 (17.5) 
 
Vomiting 
2 (7.7) 
 
13 (12.6) 
 
Diarrhea 
2 (7.7) 
 
7 (6.8) 
 
Constipation 
1 (3.8) 
 
6 (5.8) 
 
Muscle spasms 
9 (34.6) 
 
31 (30.1) 
 
Myalgia 
5 (19.2) 
 
18 (17.5) 
1 (1.0) 
Blood CK increased 
6 (23.1) 
2 (7.7) 
30 (29.1) 
19 (18.4) 
AST increased 
1 (3.8) 
 
8 (7.8) 
3 (2.9) 
ALT increased 
1 (3.8) 
 
7 (6.8) 
3 (2.9) 
Fatigue 
1 (3.8) 
 
15 (14.6) 
 
Asthenia 
5 (19.2) 
1 (3.8) 
11 (10.7) 
2 (1.9) 
Alopecia 
3 (11.5) 
 
11 (10.7) 
 
Lethargy 
3 (11.5) 
 
7 (6.8) 
 
   * Recommended phase II dose in adults             ** All doses, including BID and QD schedule 


Protocol Version 3: October 6, 2015 
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1.4.1.1 
Clinical efficacy 
Preliminary antitumor activity and evidence of disease stabilization has been observed with 
LDE225 treatment. Nine (9) adult patients with recurrent MB have been treated in the phase I 
study CLDE225X2101. Of these, three (3) patients achieved confirmed partial tumor 
responses at 200 mg QD (by RECIST), 800 mg QD (by RECIST) and 1500 mg QD (by FDG-
PET) and remained on treatment for approximately 6, 8 and 10 months, respectively. The 
remaining patients progressed after 1 to 4 months on study therapy (see Table 1-3).  
Table 1-3 
Antitumor activity in adult patients with recurrent medulloblastoma 
Patient  
Dose 
Overall Best 
Response 
Time on Study* 
(months) 
0502-00103 
100 mg QD 
PD 
1.0 
0001-00103 
200 mg QD 
PR 
6.0 
0502-00104 
200 mg QD  
PD 
2.0 
0502-00121 
800 mg QD 
SD 
4.0 
0010-00111 
800 mg QD 
PR 
9.0 
0001-00134 
800 mg QD 
PD 
2.5 
0501-00113 
1500 mg QD 
PD 
2.0 
0001-00113 
1500 mg QD 
PMR 
10 .0 
0502-00125 
250 mg BID 
PD 
2 .0 
PD, disease progression; PMR partial metabolic response; PR, partial response; SD, stable disease 
* Time from trial entry until documented disease progression. All the MB patients are off study 
A total of 16 patients with locally advanced/metastatic BCC were enrolled. Table 1-4 shows 
the antitumor activity observed in 10 patients who received LDE225 therapy for >2 months.  
Table 1-4 
Antitumor activity in patients with BCC 
Patient 
Dose 
Overall best  
response 
Approximate time on 
study in (months) 
502-0102 
100 mg QD 
SD 
32* 
001-0127 
800 mg QD 
SD 
9 
001-0131 
800 mg QD 
SD 
6 
001-0137 
800 mg QD 
PR 
7* 
020-0103 
800 mg QD 
PR 
7 
502-0119 
800 mg QD 
PR 
17* 
020-0110 
1000 mg QD 
PR 
15* 
020-0112 
250 mg BID 
SD 
7 
001-0139 
250 mg BID 
PR 
7* 
001-0119 
400 mg BID 
CR 
15 
CR, complete response; PR, partial response; SD, stable disease; PD, disease progression 
* Patients still on therapy 
1.4.2 
Clinical pharmacokinetics and pharmacodynamics 
The preliminary pharmacokinetics (PK) data from the ongoing phase 1 study in patients with 
advanced solid tumors [CLDE225X2101] showed that the median time of Cmax (Tmax) occurs 
2-13 hours (range: 1-48 hours) after oral dosing. Plasma exposure to LDE225 (Cmax and 


Protocol Version 3: October 6, 2015 
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AUC0-168h) after single dose administration increased dose proportionally from 100 to 400 mg 
and less than dose-proportionally above 400 mg. After repeated once-daily (QD) dosing from 
100 mg to 3000 mg, Cmax and AUC0-24h on Cycle 1 Day 15 increased approximately dose-
proportionally up to 400 mg and less than dose proportionally above 400 mg. After twice-
daily (BID) administration of LDE225 from 250 mg to 750 mg, Cmax and AUC0-12h on Cycle 
1 Day 15 also increased approximately dose-proportionally in this dose range. BID dosing 
results in higher systemic exposures compared with the equivalent once daily regimen. The 7-
day PK run-in phase implemented in this phase 1 study was not long enough to allow for 
accurate estimation of the half-life using non-compartmental methods. Based on available 
data as of December 8, 2011, steady-state was achieved in a limited number of patients, after 
2 weeks to 6 cycles of repeated dosing with an accumulation ratio of 6- to 90-fold based on 
Cmin. The estimated effective half-life, calculated based on the Cmin accumulation from these 
patients, ranged from 4 days to 62 days (median 19 days). The inter-subject coefficient of 
variation for Day 15 AUC and Cmax is 33 to 106% and 39 to 113%, respectively, across the 
dose range of 100 mg to 3000 mg/day. At the recommended phase II dose of 800 mg QD, the 
inter-subject coefficient of variation for Day 15 AUC0-24h and Cmax is 50.0% and 54.5%, in 18 
and 20 subjects, respectively. Exploratory analyses suggested that the incidence of CK DLT 
increased with both AUC and Cmax on day 15.  
Analyses of skin punch biopsies taken at baseline and at the end of the first treatment cycle 
have shown evidence of potent target modulation, as measured by Gli1 mRNA, in a dose- and 
exposure (Cmin)-dependent manner. The available data shows that LDE225 caused ≥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 750 
mg BID (see Table 1-5).  
Table 1-5 
Inhibition of Gli1 mRNA expression in skin 
Dose 
N 
Mean Fold change 
95 % CI (Lower, Upper) 
Mean % Inhibition 
100 mg QD 
4 
-1.7 
-6.4, 4.9 
39.6% 
200 mg QD 
4 
-4.1 
-11.4, 1.1 
75.6% 
400 mg QD 
3 
-9.2 
-53.5, -1.0 
89.1% 
800 mg QD 
20 
-3.8 
-6.6, -2.2 
73.5% 
1000 mg QD 
6 
-5.7 
-20.8, -1.5 
82.3% 
1500 mg QD 
5 
-17.5 
-30.4, -8.2 
94.3% 
3000 mg QD 
4 
-13.9 
-27.0, -6.0 
92.8% 
250 mg BID 
7 
-7.4 
-12.7, -4.3 
86.5 % 
400 mg BID 
7 
-6.4 
-11.2, -3.7 
84.4% 
750 mg BID 
6 
-26.5 
-45.7, -15.3 
96.2% 
1.5 
Study purpose and rationale 
 
Discrepancies between preclinical data and clinical observations highlights the need to carry 
out pharmacodynamic studies of promising cellular pathway inhibitors before conducting 
large-scale clinical trials for efficacy.  While pre-clinical data suggests a role for LDE225 in 
the inhibition of prostate cancer progression, no clinical study exists which confirms the 
ability of LDE225 to suppress the Hedgehog pathway in prostate cancer cells (or benign 
prostate tissue). 
 


Protocol Version 3: October 6, 2015 
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From a tissue acquisition perspective, the presurgical setting is ideal for the study of novel 
drug effects on both normal and neoplastic prostate tissues.  In addition, our data (and that of 
other investigators) suggest that the Hedgehog pathway is active in men with high-risk 
localized prostate cancer and thus this cohort represents an appropriate population for study of 
Hh pathway inhibitors.  Specifically, previous work has suggested that pathways 
characteristic of metastatic disease might be active in high-grade localized tumors (Ross et al. 
2011). Expanding on this work, we characterized gene expression profiles from tumors of 
clinically and pathologically matched men with localized high-grade disease who had no 
preoperative treatment and either experienced rapid metastasis following extirpative surgery 
or no metastases for a 5-year period. Analysis of functional annotation of differentially 
expressed genes in these two groups demonstrated enrichment for embryonic stem cell 
pathways among the localized tumors of men who would experience metastasis (adjusted 
P<0.0001) and a 3.7-fold increase in Sonic Hh expression in these tumors (adjusted P<0.035).  
These data and that of others suggest up-regulation of Hh signaling in localized prostate 
cancer with metastatic potential (Tzelepi et al. 2011, Chen et al. 2010, Kim et al. 2011). 
 
We believe that completion of this pharmacodynamic (pre-surgical) trial will guide future use 
of LDE225 in prostate cancer.  Furthermore, knowledge of molecular responses to Hedgehog 
signaling inhibition in prostate cancer could help better select patients and the timing for 
treatment with LDE225 or with combination therapies.  
 
2 
Objectives and Endpoints 
 
We propose to determine the effects of LDE225 on neoplastic prostate tissue from men at 
high risk of systemic disease progression, by comparing pre-surgical core-biopsy specimens 
to tumor tissue harvested at the time of prostatectomy.  In addition to assaying drug-related 
on-target effects (i.e. GLI expression changes) we propose to determine the effects of Smo 
inhibition on the prostate cancer transcriptome.  
Primary Objective 
 
(1) To determine the pharmacodynamic (PD) effects of LDE225 on resected prostate 
tissue from men undergoing radical prostatectomy for high-risk localized prostate 
cancer (as measured by reductions in Gli1 mRNA expression). 
Secondary Objectives 
 
(1) To determine whether presurgical treatment with LDE225 can exert a pathological 
effect on high-risk tumors (i.e. increase apoptosis, decrease proliferation).  
 
(2) To evaluate whether presurgical treatment with LDE225 diminishes the risk of PSA 
recurrence following prostatectomy. 
 
(3) To evaluate the safety and tolerability of LDE225 in the presurgical setting. 
Exploratory Objectives 
(1) To evaluate genome-wide mRNA expression changes in prostate cancer induced by 
LDE225 exposure. 
The objectives and related endpoints are summarized in the Table below. 


Protocol Version 3: October 6, 2015 
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Objective 
Endpoint 
Analysis 
Primary 
Pharmacodynamic effect 
of LDE225 on prostate 
tissue 
50% reduction in Gli1 
mRNA expression 
comparing pre-operative 
prostate biopsies to 
radical prostatectomy 
specimens  
qRT-PCR performed on 
pre-operative tumor 
biopsy specimens and 
tumor from RP 
specimens.  Comparison 
performed within and 
between treated and 
untreated groups.  
Correlation of Gli1 
levels to pre-operative 
Gli1 expression. 
Secondary 
-Pathological effect on 
localized high-risk 
cancer 
 
 
 
 
 
-To determine whether 
pre-surgical treatment 
with LDE225 
diminishes the risk of 
PSA recurrence 
following prostatectomy 
 
-To evaluate drug-
related toxicities 
including peri-operative 
complications 
-Assessment of tumor 
stage and grade 
(predicted versus actual) 
and changes in 
proliferation and 
apoptosis 
 
 
 
-PSA >0.2 ng/ml at 3 
months following 
prostatectomy 
 
 
 
-Length of surgery, 
intraoperative blood 
loss, length of hospital 
stay, rates of post-
operative complications 
(infection, wound 
breakdown, deep vein 
thrombosis, within 90 
days from surgery) 
-Routine pathologic 
analysis.  Additionally, 
semi-quantitative IHC 
for Ki-67 and cleaved 
caspase-3.  Comparison 
performed within and 
between treated and 
untreated groups. 
 
-Routine serum ELISA 
for PSA 
 
 
 
 
-Comparison of 
routinely collected 
intraoperative and post-
operative data between 
treated and untreated 
groups 
Exploratory 
Evaluate genome-wide 
mRNA expression 
changes in prostate 
cancer induced by 
LDE225 exposure 
Gene expression 
analysis on biopsy and 
prostatectomy tissue 
using the Affymetrix 
GeneChip Human Exon 
1.0ST Array 
Differential gene 
expression analysis and 
analysis of functional 
annotation comparing 
biopsy and 
prostatectomy 
specimens both between 
and within groups 


Protocol Version 3: October 6, 2015 
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3 
Investigational Plan 
3.1 
Overview and study design 
 
This pharmacodynamic/phase 0 trial is designed as a randomized two-arm (LDE225 vs. 
observation groups) open-label prospective clinical trial in men with localized high-risk 
prostate cancer undergoing radical prostatectomy.   
 
Activation of the Hedgehog pathway is most reliably indicated by increased expression of the 
GLI1 transcription factor.  Quantitiative RT-PCR (qRT-PCR) provides the most reliable 
means to assess changes in GLI1 expression upon exposure to drug and will be used as our 
primary readout. Our intent will be to examine the fold change in GLI1 expression in each 
man following exposure to drug (comparing pre-operative needle biopsy tissue to surgical 
tissue obtained from the same man’s prostatectomy specimen).  Because the effects of surgery 
and fluctuations in hedgehog signaling in the prostate are unknown, GLI1 expression will also 
be compared between biopsies and prostatectomy specimens for men without drug exposure.  
As treatment with LDE225 may alter the gene expression of other Hedgehog pathway 
members and affect separate signaling pathways, as an exploratory goal, we will perform 
genome-wide expression analysis using the GeneChip Human Exon 1.0ST Array 
(Affymetrix) and will confirm fluctuations in selected genes of interest.  
 
High-risk patients will be identified based on their core-needle biopsy features, PSA levels, 
and clinical stage. Eligible men (NCCN high-risk (Gleason sum >8, or PSA >20 or clinical 
stage >T3 with no evidence of metastatic disease) will undergo a repeat prostate biopsy at 
Johns Hopkins with multiple (up to 12) cores taken from the area of their primary lesion. This 
tissue will be frozen fresh and used for analysis of Gli1 mRNA expression and array analysis 
as well as mounted for pathological analysis and IHC analysis of proliferation (Ki-67) and 
apoptosis (cleaved caspase-3) markers. 
 
After obtaining baseline laboratory and clinical values (including an ECG, PSA, hematologic, 
and renal and hepatic panels), men will receive oral LDE225 800 mg/day or observation daily 
for 4 weeks (±3 days) prior to prostatectomy. Patients will have a clinical visit and an ECG 
and laboratory testing will be performed at 2 weeks and then again at 4 weeks, including a 4-
week pre-prostatectomy measurement of PSA and a blood sample to determine plasma 
LDE225 levels by LC-MS/MS. Previous studies using other oral Hedgehog inhibitors indicate 
that 4 weeks will allow time for steady-state levels of drug in the plasma and for inhibition of 
Gli1 expression (LoRusso et al. 2011). 
Men will undergo radical prostatectomy (with bilateral pelvic lymphadenectomy as 
appropriate), at which point two 250-mg biopsies of prostate tissue will be obtained, frozen 
and stored for analysis (including Gli1 expression, genome-wide expression analysis, intra-
prostatic LDE225 levels, Ki-67, and cleaved caspase-3) with the remainder of the prostate 
tissue then being formalin-fixed paraffin-embedded (FFPE) and cross-sectioned for analysis 
as per our standard institutional procedures. 
 
Relative fold-changes in mRNA expression of Gli1 will be determined by first normalizing 
input amounts of the preoperative biopsy and prostatectomy biopsies to the housekeeping 
gene HPRT1. IHC comparisons between diagnostic biopsy specimens and prostatectomy 
specimens will be made by calculating immunoreactivity scores (staining intensity × 
percentage cell involvement).  
 


Protocol Version 3: October 6, 2015 
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All men will receive routine post-operative care, and in addition will have ultrasensitive PSA 
testing at 1 and 2 months post-op followed by standard PSA testing at the 3 month visit. 
 
Study Schema  
3.1.1 
Investigational treatment 
The investigational study drug used in this trial is LDE225, which is supplied as oral capsules. 
3.1.2 
Treatment arms 
This will be a randomized 2-arm trial.  Arm 1 will receive LDE225 by mouth 800 mg daily 
for 4 weeks (+ 3 days);  Arm 2 will receive no treatment (observation) prior to prostatectomy. 
3.1.3 
Treatment duration 
Patients will continue on LDE225 therapy for 4 weeks (±3 days) in Arm 1, or until they 
experience a treatment toxicity requiring discontinuation. 


Protocol Version 3: October 6, 2015 
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3.1.4 
Treatment assignment/randomization 
Patients will be randomized (1:1) to treatment with LDE225 or observation, with a total 
sample size of 22 patients (i.e. 11 per group). 
 
3.2 
Rationale for the study design 
 
Discrepancies between preclinical data and clinical observations highlight the need to carry 
out pharmacodynamic studies of promising cellular pathway inhibitors before conducting 
large-scale clinical trials for efficacy.  While pre-clinical data suggests a role for LDE225 in 
the inhibition of prostate cancer progression, no clinical study exists which confirms the 
ability of LDE225 to suppress the Hedgehog pathway in prostate cancer.  For this reason, we 
believe that a phase 0 (pharmacodynamic) trial would be instrumental in determining whether 
further larger clinical studies should be carried out with LDE225 in prostate cancer.   
 
From a tissue acquisition perspective, a pre-surgical trial involving biopsy tissue collection 
and tissue at prostatectomy would be ideal for determining whether LDE225 has effects on its 
in vivo target and additionally to measure genome-wide alterations caused by drug exposure.  
 
Based on our pre-clinical data (and that of other groups) we believe that men with NCCN high 
risk prostate cancer are the best candidates for this trial due to relative enrichment in baseline 
Hedgehog pathway activation in this subgroup (Ross et al. 2011, Tzelepi et al. 2011, Chen et 
al. 2010, Kim et al. 2011).  Because the temporal variability of Hedgehog pathway activity 
and the effects of surgical treatment on pathway activation are largely unknown, we believe 
that a control/observation arm is critical to the study. 
 
4 
Population and Eligibility Criteria 
Target Population. This study will include men age 18 or older diagnosed with NCCN high-
risk (Gleason sum >8, or PSA >20, or clinical stage >T3) prostate cancer who are candidates 
for radical retropubic prostatectomy. 
4.1 
Inclusion criteria 
Patients must meet all of the following criteria: 
1. Provide written informed consent prior to any screening procedures. 
2. Age 18 years or older. 
3. Histologically-documented prostatic adenocarcinoma in ≥2 cores 
4. ECOG performance status ≤2 
5. Localized prostate cancer with at least one of the following NCCN high-risk features: 
• Gleason sum >8 
• PSA >20 ng/mL 
• Clinical stage >T3 
6. Must be a candidate for radical prostatectomy 
7. No evidence of known metastatic disease (M0 or Mx allowed) 
8. Adequate bone marrow, liver and renal function as specified below: 


Protocol Version 3: October 6, 2015 
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• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
• Hemoglobin (Hgb) ≥ 9.0 g/dL 
• Platelets ≥ 100 x 109/L 
• Serum total bilirubin ≤ 1.5 x ULN (upper limit of normal) 
• AST and ALT ≤ 2.5 x ULN 
• Plasma creatine phosphokinase (CK) < 1.5 x ULN, if known 
• Serum creatinine ≤ 1.5 x ULN [or 24-hour creatinine clearance ≥ 50ml/min] 
9. Patient is able to swallow and retain oral medications 
4.2 
Exclusion criteria 
Patients must not meet any of the following criteria: 
1. Patients who have had major surgery within 4 weeks of enrollment. 
2. Patients with concurrent uncontrolled medical conditions that may interfere with their 
participation in the study. 
3. Patients unable to take oral drugs (e.g. lack of physical integrity of the upper GI tract or 
known malabsorption syndromes). 
4. Patients who have previously been treated with LDE225 or other Hh pathway inhibitors. 
5. Patients who have neuromuscular or muscular disorders (e.g. inflammatory myopathies, 
muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on 
concomitant treatment with drugs that are known to cause rhabdomyolysis (such as statins 
and fibrates), and that cannot be discontinued at least 2 weeks prior to starting LDE225.  If 
it is essential that the patient stays on a statin for hyperlipidemia, only pravastatin may be 
used with extra caution. Patients should not plan to embark 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 LDE225 treatment).  
6. Patients who have taken part in an experimental drug study within 4 weeks or 5 half-lives 
(whichever is longer) of initiating treatment with LDE225. 
7. Patients who are receiving other anti-neoplastic therapy (e.g. chemotherapy, targeted 
therapy or radiotherapy) concurrently or within 2 weeks of starting LDE225. 
8. Patients taking moderate/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 LDE225. Medications that are strong 
CYP3A4/5 inhibitors should be discontinued for at least 7 days and strong CYP3A/5 
inducers for at least 2 weeks prior to starting treatment with LDE225.  
9. No concurrent use of statins (except for pravastatin, if absolutely necessary) 
10. No concurrent warfarin or Coumadin-derivatives 
11. Impaired cardiac function or significant heart disease, including any one of the following: 
• Angina pectoris within 3 months 
• Acute myocardial infarction within 3 months 
• QTc >450 msec on the screening ECG 
• A past medical history of clinically significant ECG abnormalities or a family 
history of prolonged QT-interval syndrome 


Protocol Version 3: October 6, 2015 
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• Other clinically significant heart disease (e.g. heart failure, uncontrolled/labile 
hypertension, or history of poor compliance with an antihypertensive regimen) 
12. Patients who are not willing to apply highly effective contraception during the study and 
through the duration of LDE225 treatment. 
• Male patients 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 last 
dose of the study drug. A condom is also required to be used 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 must be willing to use a condom 
during intercourse while taking the study drug and for 6 months after stopping 
investigational medications and agree not to father a child during this period.  
13. Patients unwilling or unable to comply with the research protocol. 
 
5 
Treatment 
5.1 
Treating the patient 
The treating 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 appropriate. 
5.1.1 
Administration 
Table  
 
Treatment and schedule 
Study treatments 
Pharmaceutical form and route of 
administration 
Dose 
Frequency and/or 
regimen 
LDE225 
Capsules (200 mg) for oral use 
800 mg 
Daily 
LDE225 will be administered orally, on a continuous once-daily schedule, at a dose of 800 
mg. Participating patients will receive flat doses on mg/day basis and not according to their 
body weight or body surface area. LDE225 is supplied as 200-mg hard gelatin capsules in 
bottles and must be stored at 2-8°C/ 35.6-46.3°F. Patients will receive 4 capsules of LDE225 
daily (= 800 mg/day). 
5.1.2 
Dosing and treatment schedule 
 
Patients will be dosed at 800 mg of LDE225 daily. Hard gelatin capsules at 200 mg are 
available (4 capsules will be taken all at one time). Dose escalation will not be allowed. 
LDE225 should be taken as follows: 
• Men should be instructed to take their daily dose at approximately the same time each day 
• On days where PK samples need to be collected prior to taking study drug, that day’s dose 
should be taken in the clinic (study site) 
• Each daily dose of LDE225 should be taken with a glass of water and consumed over as 
short a time as possible (e.g. 1 capsule every 2 minutes) 


Protocol Version 3: October 6, 2015 
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• Patients should be instructed to swallow capsules whole and to not chew or open capsules 
• Each daily dose of LDE225 (including days which involve PK blood sampling) should be 
taken 2 hours after a light breakfast (e.g., consisting of juice, toast and jam). 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 the following day 
• If the patient forgets to take his daily morning dose, then he should take LDE225 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 doses 
5.1.3 
Dose modification and dose delay 
 
Investigators should follow the guidelines described below for the modification of LDE225 
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.  Treatment related toxicities are adverse events that are 
possibly, probably or definitely related to the study drug. 
 
Any grade 3 or grade 4 toxicities will result in discontinuation of the study drug.  Men with 
prolonged grade 2 toxicity will receive a reduced dose of the study drug at 400mg.  If the 
grade 2 toxicitiy continues on the reduced dose then the dose level will be reduced again to 
200mg.  A maximum of two dose-reduction steps will be allowed (see Table below), after 
which the patient will be discontinued from study treatment.  
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 >7 days from the previous dose, then the 
patient must be discontinued from study treatment although he may still undergo 
prostatectomy. 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 appropriate. 
Table  
Dose reductions for LDE225 
Dose reduction* 
 
Starting dose level  
Dose level -1 
Dose level -2 
LDE225 dose (mg QD) 
800  
400  
200  
*Dose reduction should be based on the worst toxicity demonstrated.  
 
 


Protocol Version 3: October 6, 2015 
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Detailed indications and instructions for dose-modifications are shown below in Table 5-3. 
Different dose modifications are dependent on the type and severity of the toxicity, as shown 
in Table 5-3. 
Table 5-1 
Recommended Dose Modifications and Dose Delays for suspected 
treatment-related toxicities  
Recommended dose modifications for LDE225** 
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) 
Reduce dose to 400mg.  If resolved in < 7 days then maintain dose 
level.  If not resolved in < then decrease level to 200mg 
Grade 3 or 4  
(ANC < 1000 - 500/mm3  
or < 500/mm3) 
• Discontinuation of study drug 
Thrombocytopenia (PLT) 
Grade 1 
(PLT < LLN - 75,000/mm3) 
Maintain dose level 
Grade 2  
(PLT < 75,000 - 50,000/mm3) 
Reduce dose to 400mg.  If resolved in < 7 days then maintain dose 
level.  If not resolved in < then decrease level to 200mg 
Grade 3 or 4  
(PLT < 50,000 - 25,000/mm3 or 
< 25,000/mm3) 
• Discontinuation of study drug 
Febrile Neutropenia 
Febrile neutropenia  
(ANC < 1.0 x 109/L, fever ≥ 
38.5°C) 
Omit dose until resolved, then decrease dose by 1 step 
Muscle Toxicity 
Elevated creatine phosphokinase (CK) 
Asymptomatic (no new-onset 
muscle pain/spasm or 
worsening of pre-existing 
muscle pain/spasm)  
CTCAE grade 1 or 2 CK 
elevation 
• For CTCAE grade 1 CK elevation, continue treatment on same 
dose and continue monitoring as per schedule of assessments 
• For sites in France: For treatment-emergent CTCAE grade 1 CK 
elevation, continue treatment on same dose. CK should be 
measured weekly until CK returns to normal for baseline value. 
• For CTCAE grade 2 CK elevation, collect blood sample for PK 
and consider performing a muscle biopsy; continue on same 
dose level of LDE225.  CK should be measured weekly until 
resolution to ≤ grade 1. 
Symptomatic (new-onset or 
worsening of pre-existing 
muscle pain/spasm) with 
CTCAE grade 1 or 2 CK 
elevation 
• For CTCAE grade 1 CK with muscle pain/spasm ≥ CTCAE grade 
1, continue treatment at same dose and measure CK weekly 
until CK returns to normal or baseline value or muscle 
pain/spasm resolves 
• For CTCAE grade 2 CK with muscle pain/spasm ≥ CTCAE grade 
1, collect blood sample for PK and continue treatment at same 
dose level of LDE225.  CK should be measured weekly until CK 
is ≤ CTCAE grade 1 


Protocol Version 3: October 6, 2015 
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Recommended dose modifications for LDE225** 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
CTCAE grade 3 or 4 CK 
elevation (with or without muscle 
pain/spasm) 
• 
Discontinuation of study drug 
Muscle pain/spasm (new onset 
or worsening of pre-existing 
muscle pain/spasm) 
• 
For CTCAE grade 1 muscle pain/spasm, continue treatment on 
the same dose and planned assessments 
• 
For CTCAE ≥ grade 2 muscle pain/spasm, measure CK weekly 
until muscle pain resolves to ≤ grade 1.  If CK is elevated, follow 
guidance for CK elevation as described above. Continue 
treatment with LDE225 
• 
For new-onset CTCAE grade 3 muscle pain/spasm, study drug 
will be discontinued 
Renal 
Serum creatinine 
Serum creatinine <1.5 x ULN 
Maintain dose level 
Serum creatinine 1.5-3 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 (consider 
checking serum CK, if not already done) 
Grade 3 
Serum creatinine > 3.0 - 6.0 x 
ULN 
Discontinuation of study drug 
Grade 4 
Serum creatinine > 6.0 x ULN  
Discontinuation of study drug 
Hepatic 
Bilirubin 
Total bilirubin <1.5 x ULN 
Maintain dose level 
Total bilirubin 1.5-3 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  
Discontinuation of study drug 
Grade 4  
Total bilirubin > 10.0 x ULN  
Discontinuation of study drug 
AST or ALT 
Grade 1  
(> ULN - 3.0 x ULN) 
Maintain dose level 
Grade 2  
(> 3.0 - 5.0 x ULN) 
Maintain dose level 
Grade 3  
(> 5.0 - 20.0 x ULN) 
• 
Discontinuation of study drug 
Grade 4  
(> 20.0 x ULN) 
Discontinuation of study drug 


Protocol Version 3: October 6, 2015 
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Recommended dose modifications for LDE225** 
Worst toxicity 
CTCAE grade* (value) 
During a cycle of therapy 
Cardiac 
Cardiac - prolonged QTc interval 
≥ grade 3 (QTc >500 msec or 
>60 ms from baseline on at least 
2 separate ECGs taken within 1 
hour) 
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 QTc >500 ms 
• 
If QTc remains > 500 ms, repeat ECG as clinically indicated but 
at least once a day until the QTc returns to <480 ms. 
• 
Once QTc 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 
Discontinuation of study drug 
Grade 4 
Discontinuation of study drug 
Other adverse events** 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Discontinuation of study drug 
Grade 4 
Discontinuation of study drug 
All dose modifications should be based on the worst preceding toxicity.  Treatment related toxicities are 
adverse events that are possibly, probably or definitely related to the study drug. 
If the dose-limiting toxicity recurs in a patient following 2 dose reductions, then further therapy with 
LDE225 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 LDE225-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. 
5.1.4 
Protocol Stopping Rules 
The study will be closed if >3 patients experience a delay in surgery by more than 2 weeks 
due to drug related toxicities.  In other words, if 4 or more patients in the experimental arm 
have their prostatectomy delayed by more than 2 weeks, we will close the study.  In addition, 
the study will close if we observe >3 patients who experience a grade 3 or grade 4 adverse 
event that is possibly, probably or definitely related to the study drug.  In other words, if 4 or 
more patients in the experimental arm experience a grade 3 or grade 4 drug-related toxicity 
the study will be closed. 


Protocol Version 3: October 6, 2015 
Page 24 of 37 
5.1.5 
Permitted concomitant therapy 
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. 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. 
5.1.6 
Permitted concomitant therapy requiring caution and/or action  
LDE225 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 statins is 
generally prohibited during this study (except for pravastatin). 
In vitro drug metabolism studies reveal that the metabolism of LDE225 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 LDE225 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 LDE225 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 LDE225 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. 
5.1.7 
Prohibited concomitant therapy 
5.1.7.1 
Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. Anticancer 
therapy (chemotherapy, immunotherapy, 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. 
5.1.7.2 
Strong CYP3A inhibitors and inducers 
No clinical studies have been performed to confirm if LDE225 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. 
This 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 


Protocol Version 3: October 6, 2015 
Page 25 of 37 
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 LDE225 treatment throughout the study due to 
potential CYP3A4/5 inhibition. The other drugs without an asterisk should be carefully used 
as concomitant therapy. 
Table  
 
Medications that are CYP3A4/5 inducers or inhibitors 
Medications 
 
Inhibitors 
HIV antivirals: indinavir, nelfinavir, ritonavir*, saquinavir 
 
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 2-5–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 dose.  
** - Known strong inducers of CYP3A4/5 (AUC decrease by 50-80%) 
5.1.7.3 
CYP2B6 and CYP2C9 substrates (narrow therapeutic index) 
LDE225 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. 
Table  
 
 
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 


Protocol Version 3: October 6, 2015 
Page 26 of 37 
 
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 LDE225, as it is primarily 
transformed in the liver cytosol by sulfonation, not by CYP2C9 or CYP3A4. (Evans et al. 2002) 
5.1.7.4 
Warfarin and coumadin derivatives 
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumadin-derivative 
anticoagulants are not permitted since LDE225 is a competitive inhibitor of CYP2C9 based 
on the in vitro data. An alternative, therapeutic anticoagulation may be accomplished using 
low-molecular weight heparin. 
5.1.7.5 
 Drugs that may increase risk of rhabdomyolysis  
Selected drugs that may increase risk of myopathy and rhabdomyolysis when used 
concomitantly with LDE225 should be avoided. Such drugs should be discontinued for at 
least 2 weeks prior to initiation of LDE225 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 LDE225 through inhibitory effects on CYP3A4 (enzyme 
metabolized  LDE225) or the inhibitory effect on CYP2C9 by LDE225 of drugs that may 
induced rhabdomyolysis. 
 
• Azoles:   Itraconazole, ketoconazole,  fluconazole,  voriconazole 
• Macrolides:   Azithromycin,  clarithromycin,  erythromycin,  telitromycin 
• Fibrates: Gemfibrozil, fenofibrate 
• HMG CoA reductase inhibitors* (“statins”): Atovastatin, Fluvastatin, Fluvastatin, 
Lovastatin, 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 treatment with LDE225. 
5.2 
Study drug (LDE225) 
5.2.1 
Packaging and labeling 
LDE225 capsules will be supplied by Novartis as 200-mg hard gelatin capsules for oral use, 
packaged in bottles, and will be administered on a flat scale of 800 mg/day for all patients.  


Protocol Version 3: October 6, 2015 
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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. 
Table  
 
Packaging and labeling 
Study drugs 
Packaging 
Labeling (and dosing frequency) 
LDE225 
 
Capsules in bottles (200 mg) 
 
Labeled as ”LDE225” 
 
5.2.2 
Supply, receipt and storage 
Study drug must be received by a designated person at the study site (usually the site 
pharmacist), handled and stored safely and properly, and kept in a secured location to which 
only the investigator and designated assistants have access. Upon receipt, LDE225 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 (usually the pharmacist).  
Patients will be provided with adequate supply of LDE225 for self-administration at home 
until at least their next scheduled study visit (i.e. at least a 4-week period).  Patients should be 
instructed to store LDE225 capsules in the refrigerator. 
5.2.3 
Drug compliance and accountability 
5.2.3.1 
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.  
5.2.4 
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. 
 
 
 
 
 


Protocol Version 3: October 6, 2015 
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6 
Schedule and Assessments 
6.1 
Study flow and visit schedule 
 
 
Screening 
Evaluation 
Repeat 
Biopsy a 
Day 
1 
Day 
14 
Prostatectomy, 
Day 28 (±3) 
Follow-
up, 
1 mo 
Post-Op 
Follow-
up, 
2 mo 
Post-Op 
Follow-
up,  3 mo 
Post-Op j 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
X 
X 
 
 
 
Medication review 
X 
 
 
X 
X 
 
 
 
Physical exam 
X 
 
 
X 
X 
 
 
X 
Vital signs 
X 
 
 
X 
X 
 
 
X 
Height and weight 
X 
 
 
X 
X 
 
 
 
Performance status 
X 
 
 
X 
X 
 
 
X 
ECG 
X 
 
 
X 
X 
 
 
 
CT and bone scan b 
X 
 
 
 
 
 
 
 
Heme labs, Coags c 
X 
 
 
X 
X 
 
 
X 
Chemistries, incl. CK d 
X 
 
 
X 
X 
 
 
X 
PSA (standard) e 
X 
 
 
 
X 
 
 
X 
PSA (ultrasensitive) e 
 
 
 
 
 
X 
X 
 
Plasma for PKs f 
X 
 
 
 
X 
 
 
 
LDE225 dose g (Arm 1) 
 
 
X---------------------------X 
 
 
 
Observation g (Arm 2) 
 
 
X---------------------------X 
 
 
 
Toxicity assessment   
 
X-----------------------------------------------------------------X 
Prostatectomy 
specimen h 
 
 
 
 
X 
 
Pathologic review i 
X 
X 
 
 
X 
 
a: 
A repeat 12-core (pre-treatment) prostate biopsy should be conducted within 4 weeks (±4 days) of starting protocol therapy. Tissue 
will be subject to mRNA analysis.  
b: 
Staging CT (if allergic to CT scan contrast, obtain MRI with contrast); CT and Bone scan must be performed within 2 months of starting 
protocol therapy 
c: 
Hematology laboratories include hemoglobin, hematocrit, white blood cell count with differential, and platelets. In addition, PT/INR 
and APTT should be collected. 
d: 
Chemistry laboratories include sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, glucose, calcium, albumin, total 
protein, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase. In addition, creatine 
kinase (CK) should be measured at baseline, and then only for patients receiving LDE225..  Samples drawn for CK levels will be taken 
from both arms. 
e: 
Serum PSA should be obtained pre-treatment and on the day of surgery, and at 1, 2 and 3 months post operatively.  Ultrasensitive PSA 
testing should be run at the 1 and 2 month post-op time points. 
f: 
Blood samples will be collected at baseline and on the day of prostatectomy for measurement of plasma LDE225 levels. 
g: 
LDE225 800 mg by mouth once daily (for 4 weeks, ±3 days) OR observation. Patients randomized to the observation arm are not 
required to have the C1D14 visit. 
h: 
Radical prostatectomy specimens to be processed at Johns Hopkins according to standard procedures, with additional 250-mg biopsies 
of prostate tissue frozen for analysis of mRNA expression and tissue LDE225 levels. 
i: 
Pathological review of outside biopsy slides at the Johns Hopkins Hospital are required to confirm Gleason grade of disease at 
screening. Pathologic evaluation will also occur with frozen tissue from repeat biopsies and with tissue from radical prostatectomy. 
j: 
The post-operative evaluation at 1 and 2 months after prostatectomy may take place over the telephone or in person, but patients are 
required to have labs collected as indicated above. The 3-month follow-up should involve an office visit. After the 3-month visit, PSA 
will continue to be collected according to the treating physician’s standard practice (usually once every 3 months). 


Protocol Version 3: October 6, 2015 
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6.1.1 
Screening Evaluation 
The screening examination must start with the Informed Consent procedure. The investigator 
is obliged to give the patient thorough information about the study and the study related 
assessments, and the patient should be given ample time to consider his or her participation. 
The investigator must not start any study related procedure before ICF is signed and dated by 
both patient (and impartial witness, if applicable) and investigator.  
6.2 
Assessments 
6.2.1 
Efficacy assessments 
The primary measures of efficacy in this trial are pharmacodynamic measured by the change 
in Gli1 expression by qRT-PCR.  In addition, efficacy will also be evaluated in secondary 
endpoints which will compare tumor stage, grade, surgical margin rates and tumor 
proliferation / apoptosis between treatment and observation arms.  The proportion of patients 
with undetectable PSAs at three months will also be assessed in the two groups. 
6.2.2 
Safety assessments 
Safety assessments will consist of monitoring and recording all adverse events (AEs), 
including serious adverse events, the monitoring of hematology, blood chemistry, ECG and 
the regular monitoring of vital signs, and physical condition as shown in corresponding tables.  
All patients will receive CK level monitoring at baseline, day 14 and day 28 with additional 
levels drawn in patients report symptoms of rhabdomyolysis during the study.  For details on 
AE collection and reporting, refer to the Safety section in the protocol.   
In addition, we will pay particular attention to peri-operative adverse events (intraoperative 
bleeding, increased operative time, increased hospital length of stay, increased postoperative 
infections, wound breakdowns, etc.).  These will be monitored by review of in hospital 
records and post-operative clinic notes. 
6.2.3 
Pharmacokinetics 
Plasma LDE225 trough levels (PK) will be measured at baseline and on the day of 
prostatectomy using LC-MS/MS. 
6.2.4 
Biomarkers 
For analysis of Gli1 expression, RNA will be purified using the RNeasy Minikit (Qiagen) and 
then cDNA will be synthesized according to standard procedures.  Quantitative PCR will then 
be performed using the Taqman system with primers for Gli1 and the reference gene HPRT1.  
Applied Biosystems software will be used to calculate threshold cycle values (and thus 
relative expression levels). Normalized changes in Gli1 expression between each patient pre- 
and post-operatively and between each group (observation versus treatment arm) will be made 
with 2-sided pairwise comparisons considering P < 0.05 to be statistically significant.     
Genome-wide mRNA expression data will also be collected with comparisons made both 
within and between treatment groups.  This analysis will look for expression based indications 
of molecular pathway alterations upon exposure to LDE225 and will do so in an unbiased 


Protocol Version 3: October 6, 2015 
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way. For each array, data will be processed for statistical analysis using packages from 
R/Bioconductor with a mixed-effects model used to fit for each gene and to estimate 
expression differences between groups and an empirical Bayesian approach used to moderate 
log2 fold change standard errors. Functional themes will be obtained from Gene Ontology, 
Kyoto Encyclopedia of Genes and Genomes, the Humna Protein Reference Databases and 
Molecular Signature Databases and used to perform enrichment analysis using Wilcoxon 
tests.  Multiple testing corrections will be performed using the Benjamini-Hochberg method.   
7 
Safety Monitoring and Reporting 
7.1 
Adverse Events 
7.1.1 
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 AEs 
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.  


Protocol Version 3: October 6, 2015 
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Pregnancy, although not itself an SAE, should also be reported on an SAE form or pregnancy 
form and be followed up to determine outcome, including spontaneous/voluntary termination, 
details of birth, and the presence or absence of any birth defects or congenital abnormalities. 
Any SAE 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 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. 
This is a DSMP Level II study under the SKCCC Data Safety Monitoring Plan (12/6/2012). 
Data Monitoring of this protocol will occur on a regular basis with the frequency dependent 
on the rate of subject accrual and the progress of the study. The protocol will be monitored 
internally at SKCCC by the Principal Investigator and 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. 
7.2 
Instructions for rapid notification of serious adverse events 
7.2.1 
Reporting responsibility 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology Department (DS&E) 
7.2.2 
Reporting procedures 
All SAEs are reported to the FDA by the trial’s IND Sponsor-Investigator (Dr. Antonarakis) 
via the IND annual report per 21 CFR 312.33. All SAEs deemed unexpected and related to the 
investigational product qualify for expedited reporting and must be submitted to the FDA by 
the IND Sponsor-Investigator per 21 CFR 312.32 as shown immediately below. The IND 
Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the Sponsor-Investigator to be possibly related to the 
use of LDE225 within 7 calendar-days of first learning of the event. An unexpected adverse 
event deemed possibly related to the use of an investigational study drug is defined as any 
adverse drug experience of which the specificity or severity is not consistent with the current 
investigator brochure, the general investigational plan, or elsewhere in the current application, 
as amended. Such reports are to be telephoned or faxed to the FDA within 7 calendar-days of 
first learning of the event. The IND Sponsor-Investigator is required to notify the FDA in a 
written IND Safety Report, of any serious, unexpected adverse event considered by the 
Sponsor-Investigator to be possibly related to the use of LDE225 within 15 calendar-days of 
first learning of the event. 
In addition to the above, 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 Drug Safety & Epidemiology (DS&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 DS&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 


Protocol Version 3: October 6, 2015 
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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. 
7.3 
Pregnancies 
Each pregnancy occurring for a female partner of a male study participant must be reported 
while the patient is on study treatment and for up to 6 months after the patient’s last dose.  
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. 
8 
Statistical Methods and Data Analysis 
In general terms, we wish to determine if there is a statistically significant reduction in Gli1 
expression in prostate tissue after a 4-week exposure to LDE225. We expect to see significant 
down-regulation of Gli1 in the treatment arm compared to the observational arm.   
8.1 
Sample size considerations, and analysis of the primary endpoint 
 
The primary endpoint is a ≥50% reduction in Gli1 mRNA (or protein) expression following 
treatment with LDE225. This study will compare prostatectomy Gli1 expression levels to 
presurgical biopsy Gli1 expression levels in the same patients (i.e. intra-patient changes). In 
the control group (observation), we expect <10% of patients to show a ≥50% Gli1 
downregulation (null hypothesis), while in the LDE225 group we would hypothesize that 
>50% of patients would demonstrate a ≥70% Gli1 downregulation (alternative hypothesis). 
Using a 2-sided alpha (α) of 0.10 and a beta (β) of 0.20 (power = 80%), a sample size of 11 
men/arm (total = 22men) would be required to observe a difference in the primary endpoint 
from <10% (in the control arm) to ≥70% (in the LDE225 arm). 
8.2 
Analysis of the secondary endpoints 
 
• Apoptotic markers. Caspase 3 staining (and/or TUNEL assay results) will be expressed 
as the mean staining percentage in tumor samples, and reported separately for each treatment 
group. Standard deviations, 95% confidence intervals, and ranges will also be reported where 
appropriate. Means will be compared across treatment arms using two-way ANOVA. 
 
• Proliferation markers. Ki-67 staining will be expressed as the mean staining percentage 
in tumor samples, reported separately for each treatment arm. Standard deviations, 95% 
confidence intervals, and ranges will also be reported where appropriate. Means will be 
compared across treatment arms using two-way ANOVA. 
 
• Pathological complete responses (pCR). This will be defined as an absence of tumor 
identification on standard histological analysis of the resected prostate specimens. The 
proportion of patients achieving a pCR will be compared between treatment arms using the 
Mantel-Haenszel test. 


Protocol Version 3: October 6, 2015 
Page 33 of 37 
 
• PSA response rates. This will be defined as an undetectable PSA (<0.1 ng/mL) at 3 
months after prostatectomy. The proportion of patients achieving a PSA response will be 
compared between treatment arms using the Mantel-Haenszel test. 
8.3 
Analysis of the exploratory endpoints 
 
Genome-wide mRNA expression data will also be collected with comparisons made both 
within and between treatment groups.  This analysis will look for expression based indications 
of molecular pathway alterations upon exposure to LDE225 and will do so in an unbiased 
way. For each array, data will be processed for statistical analysis using packages from 
R/Bioconductor with a mixed-effects model used to fit for each gene and to estimate 
expression differences between groups and an empirical Bayesian approach used to moderate 
log2 fold change standard errors. Functional themes will be obtained from Gene Ontology, 
Kyoto Encyclopedia of Genes and Genomes, the Humna Protein Reference Databases and 
Molecular Signature Databases and used to perform enrichment analysis using Wilcoxon 
tests.  Multiple testing corrections will be performed using the Benjamini-Hochberg method. 
9 
Ethical Considerations 
9.1 
Ethics and good clinical practice 
This study must be carried out in compliance with the protocol and GCP, as described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. 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 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. 
9.2 
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. 
9.3 
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 may withdraw from the study at any time 


Protocol Version 3: October 6, 2015 
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and that withdrawal of consent will not affect his 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 
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.  
Fertile men should be informed that taking the study medication may involve unknown risks 
to a conceived fetus if pregnancy were to occur during the study and agree that in order to 
participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they should not be 
entered in the study. 
9.4 
Discontinuation of the study 
Novartis reserves the right to discontinue support for any study under the conditions specified 
in the clinical trial agreement. 
9.5 
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.  
9.5.1 
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 
Investigator/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. 
9.5.2 
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' 


Protocol Version 3: October 6, 2015 
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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. 
9.5.3 
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. 
 
10 
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