An Open-label, Multi-center, Single-arm Study to Evaluate the Efficacy of Nilotinib in Adult Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line Treatment
Phase: PHASE4
Conditions: Gastrointestinal Stromal Tumors
Sponsor: Novartis Pharmaceuticals



Novartis 
Confidential 
Page 2 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Signature page for Novartis 
 
Compound name: AMN107 (Nilotinib) 
Protocol number: CAMN107DDE06 
 
Approved by the following: 
 
Dr. 
 
(Principal Investigator) 
Signature 
 
Date 
 
Dr. 
 
(
, Novartis) 
Signature 
 
Date 
 
 
(Study Lead, Novartis) 
Signature 
 
Date 
 
 
(Study Statistician, Novartis) 
Signature 
 
Date 

Novartis 
Confidential 
Page 3 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Signature page for investigators 
 
Compound name: AMN107 (Nilotinib) 
Protocol number: CAMN107DDE06 
 
I have read this protocol and agree to conduct this trial in full accordance with the 
protocol and the Declaration of Helsinki. 
I have read and I understand the information in the Investigators’ Brochures or Package 
Inserts, including the potential risks and side effects of the products under investigation, 
and will ensure that all associates, colleagues, and employees assisting in the conduct 
of the study are informed about the obligations incurred by their contribution to the 
study. 
 
 
Name of investigator 
Signature  
 
Date 
 

Novartis 
Confidential 
Page 4 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Table of contents 
Table of contents .................................................................................................. 4 
List of tables .......................................................................................................... 6 
List of abbreviations .............................................................................................. 7 
Amendment 5 ........................................................................................................ 9 
1. Background ......................................................................................................... 12 
1.1 
Overview of Gastrointestinal stromal tumors (GIST) ................................ 12 
1.2 
Overview of nilotinib ................................................................................. 13 
1.2.1 
Clinical experiences with nilotinib .............................................. 15 
1.2.2 
Adverse reactions from clinical studies ...................................... 17 
2 
Study rationale/purpose ...................................................................................... 21 
3 
Objectives ........................................................................................................... 22 
3.1 
Primary objective ...................................................................................... 22 
3.2 
Secondary objectives ............................................................................... 22 
 
 23 
4 
Study design ....................................................................................................... 23 
4.1 
Study drug treatment ................................................................................ 24 
4.2 
Follow-Up ................................................................................................. 25 
5 
Population ........................................................................................................... 25 
5.1 
Inclusion criteria ........................................................................................ 25 
5.2 
Exclusion criteria ...................................................................................... 26 
5.3 
Eligibility criteria for patients from studies CAMN107G2301 or 
CAMN107DDE05 ..................................................................................... 27 
6 
Treatment ............................................................................................................ 29 
6.1 
Patient numbering .................................................................................... 29 
6.2 
Investigational drug .................................................................................. 29 
6.2.1 
Instructions for prescribing and taking the study drug ................ 29 
6.2.2 
Study drug ................................................................................. 30 
6.2.3 
Treatment .................................................................................. 30 
6.3 
Treatment arms ........................................................................................ 30 
6.4 
Treatment assignment .............................................................................. 30 
6.5 
Treatment blinding .................................................................................... 30 
6.6 
Treating the patient ................................................................................... 30 
6.6.1 
Study drug administration .......................................................... 31 
6.6.2 
Permitted study drug adjustments ............................................. 31 
6.6.3 
Other concomitant medications ................................................. 36 

Novartis 
Confidential 
Page 5 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
6.6.4 
End of treatment and study drug discontinuation ....................... 37 
7 
Visit schedule and assessments ......................................................................... 38 
7.1 
Information to be collected on screening failures...................................... 42 
7.2 
Patient demographics/other baseline characteristics ................................ 42 
7.3 
Treatments ............................................................................................... 42 
7.4 
Efficacy ..................................................................................................... 42 
7.5 
Safety ....................................................................................................... 43 
7.5.1 
Adverse events .......................................................................... 43 
7.5.2 
Physical examination, weight, height ......................................... 45 
7.5.3 
Vital signs .................................................................................. 45 
7.5.4 
Performance status .................................................................... 45 
7.5.5 
Laboratory evaluations .............................................................. 45 
7.5.6 
Cardiac assessments ................................................................ 46 
7.5.7 
Tumor characterizations ............................................................ 46 
8 
Safety monitoring ................................................................................................ 47 
8.1 
Serious adverse event reporting ............................................................... 47 
8.2 
Pregnancies ............................................................................................. 48 
8.3 
Data Monitoring Board .............................................................................. 48 
9 
Data review and data management .................................................................... 49 
9.1 
Site monitoring .......................................................................................... 49 
9.2 
Data collection .......................................................................................... 49 
9.3 
Database management and quality control .............................................. 49 
10 Statistical methods and data analysis ................................................................. 50 
10.1 Populations for analysis ............................................................................ 50 
10.2 Patient demographics/other baseline characteristics ................................ 51 
10.3 Treatments (study drug, concomitant therapies, compliance) .................. 51 
10.4 Primary objective ...................................................................................... 51 
10.4.1 
Variable ..................................................................................... 51 
10.4.2 
Statistical hypothesis, model, and method of analysis ............... 52 
10.4.3 
Handling of missing values/censoring/discontinuations ............. 52 
10.4.4 
Supportive analyses .................................................................. 52 
10.5 Secondary objectives ............................................................................... 52 
10.5.1 
Population and grouping for the analyses .................................. 52 
10.5.2 
Secondary efficacy variables and analyses ............................... 52 
10.5.3 
Safety parameters and analyses ............................................... 53 
10.5.4 
Biomarkers................................................................................. 54 

Novartis 
Confidential 
Page 6 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
10.6 Sample size calculation ............................................................................ 54 
10.7 Power for analysis of critical secondary variables .................................... 54 
11 References .......................................................................................................... 55 
Appendix 1: Administrative procedures ............................................................... 58 
Post-text supplement 1: ECOG Performance Status Scale ................................ 60 
Post-text supplement 2: Medication that may prolong the QT interval ................ 60 
Post-text supplement 3: Response Evaluation Criteria in Solid Tumors 
(RECIST) .................................................................................................. 61 
Post-text supplement 4: Substrates of cytochrom P450 isoenzym ..................... 67 
 
List of tables 
 
Table 1-1  
Adverse reactions from clinical studies ...................................... 18 
Table 6-1 
Summary of dose reduction guidelines for study drug-related 
non-hematologic toxicity – nilotinib ............................................ 31 
Table 6-2 
Summary of dose reduction guidelines for study drug-related 
related-hematologic toxicity – nilotinib ....................................... 35 
Table 7-1 
Visit evaluation schedule ........................................................... 40 
Table 10-1 
Design features for exact binomial single-stage design ............. 54 
Table 11-1 
Response criteria for target lesions ........................................... 63 
Table 11-2 
Response criteria for non-target lesions .................................... 64 
Table 11-3 
Overall lesion response at each assessment ............................ 64 
Table 11-4 
Medications that can induce CYP3A4 ........................................ 67 
Table 11-5 
Medications that can inhibit CYP3A4 ......................................... 68 
Table 11-6 
CYP3A4 substrates: Narrow therapeutic index, sensitive, and 
others ......................................................................................... 69 
 

Novartis 
Confidential 
Page 7 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
List of abbreviations 
AE 
Adverse event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT 
ANC 
Absolute neutrophil count 
AP 
Acute phase 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT 
ATP 
Adenosine triphosphate 
AUC 
Area under the curve 
bid 
bis in diem/twice a day 
BCR 
Breakpoint cluster region gene 
Bcr-Abl 
A fusion gene of the BCR and ABL genes 
BC 
Blastic crisis 
BUN 
Blood urea nitrogen 
CCyR 
Complete cytogenetic response  
CBC 
Complete blood count 
CHR 
Complete hematologic response 
CML 
Chronic Myelogenous Leukemia 
CP 
Chronic phase 
CR 
Complete response 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CTCAE 
NCI common terminology criteria for adverse events 
CYP 
Cytochrome P450 
DNA 
Deoxyribose nucleic acid 
ECG 
Electrocardiogram 
CRF 
Case report form 
EDC 
Electronic data capture 
EDM 
Electronic data management 
ECG 
Electrocardiogram 
EOS 
End of study  
FDA 
Food and drug administration 
FDG-PET  
[18F]-flourodeoxyglucose-positron emission tomography 
GI 
Gastrointestinal 
GIST 
Gastrointestinal Stromal Tumor 
GLP 
Good laboratory practice 
HES 
Hypereosinophilic syndrome 
Hgb 
Hemoglobin 
HPLC 
High pressure (performance) liquid chromatography 
IC50 
Concentration that inhibits function by 50% 
IEC 
Independent Ethics Committee 

Novartis 
Confidential 
Page 8 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
IMS 
Integrated Medical Safety 
IRB 
Institutional Review Board 
LC-MS/MS Liquid chromatography – tandem mass spectrometry 
LLN 
Lower limit of normal 
LVEF 
Left ventricular ejection fraction 
mg/m2 
Milligrams per square meter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multiple uptake gated acquisition scan 
PET/CT 
Combination PET and CT scanner 
PDGFR 
Platelet derived growth factor receptor  
PFS 
Progression free survival 
PG 
Pharmacogenetic 
PI3-kinase 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetic 
PR 
Partial response/ remission 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SCF 
Stem cell factor 
SD 
Stable disease 
SM 
Systemic mastocytosis 
SC 
Steering committee 
SOP 
Standard Operating Procedure 
SST 
Serum separator tube 
SUV 
Standardized Uptake Value 
TK 
Tyrosine kinase 
TNF 
Tumor necrosis factor 
TTP 
Time to tumor progression 
ULN 
Upper limit of normal 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
WOCBP 
Women of child bearing potential 
WHO 
World Health Organization 
WNL 
Within normal limits 
 
 
 

Novartis 
Confidential 
Page 11 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
month and to specify EoT procedure and safety follow up following the last study 
drug intake. 
Section 7.4 
• Specification that imaging will be done according to the visit schedule during the 
Follow up phase. 
Section 7.5.5 
• Clarification on protocol. 
Section 7.5.7 
• Deleted Section: Pharmacokinetics  
• Update of address for pathological review. 
Section 10.5.4 
• Deleted section: Pharmacokinetics 
Reference section: 
• Update of the protocol references. 
Appendix 1: 
• Deleted section: Preparation & Shipping of Pharmacokinetic Samples 
Post-text supplement 2:  
• Insertion of a new link as reference for medications that may prolong QT interval. 
Post-text supplement 4:  
• Deleted post-text supplement 4: Choi criteria and Table 11-4 Response criteria 
• Update of the lists of CYP3A4 inducers and inhibitors and added a list of CYP3A4 
substrates. 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/ 
Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and 
submit for approval a revised Informed Consent that takes into account the changes 
described in this protocol amendment. 
 

Novartis 
Confidential 
Page 12 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
1. 
Background 
1.1 
Overview of Gastrointestinal stromal tumors (GIST) 
Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms that are thought 
to arise from the interstitial cells of Cajal or their mesenchymal stem cell precursor. 
GISTs are positive for the CD117 antigen, an epitope of the KIT receptor tyrosine 
kinase (TK), in almost 100% of cases (Corless et al 2004). KIT is a 145-kD 
transmembrane glycoprotein with tyrosine kinase activity that serves as a receptor for 
the stem cell factor (SCF). Binding of SCF to KIT results in receptor homodimerization, 
activation of tyrosine kinase activity and phosphorylation of a variety of substrates 
involved in intracellular signal transduction pathways (Tosoni et al 2004). GISTs are 
most commonly found in the stomach (52%), followed by the small intestine (25%), 
large intestine (11%) and esophagus (5%). A small percentage (7%) of tumors arise 
from the omentum, mesentery and peritoneum. The clinical presentation of GIST varies, 
ranging from small silent lesions found during surgery to larger lesions causing 
abdominal pain and acute hemorrhage from tumor rupture, bowel obstruction and/or 
perforation. Several observations indicate some differences in the biology of GISTs 
depending on their site of origin, however, the actual clinical course is difficult to predict, 
and even small lesions (< 2 cm in diameter) have an unpredictable malignant potential. 
Many authors have accepted tumor size and mitotic rate as morphologic criteria for 
predicting tumor behavior. Efforts are currently directed to define more objective 
prognostic parameters including genetic biomarkers (Singer 2002, Heinrich 2003a, 
Tosoni 2004). 
Activating mutations of KIT are the characteristic pathogenic feature of these tumors, 
being present in up to 92% of GISTs (Heinrich et al 2002). Recent studies have 
reported a small subgroup of KIT-negative GISTs (Tosoni 2004, Corless 2004). Among 
the GISTs without KIT mutations, a subgroup has mutations in the platelet-derived 
growth factor receptor A (PDGFRA) and another subgroup lack identified mutations. 
KIT Exon 11 mutations, in the form of frame deletions, missense mutations, and 
internal tandem duplication have been found in 57-77% of cases. In 3-18% of cases, 
mutations, mainly duplications, have been found in KIT exon 9. Point mutations in 
exons 13 and 17 are very rare (2-4% of all GISTs). Heinrich et al (2003b) have recently 
reported activating mutations in the PDGFRA (exons 12 and 18) in 35% of GISTs 
without KIT mutations. PDGFRA mutations were absent in tumors harboring known 
KIT mutations and KIT mutant tumors lacked PDGFRA mutations suggesting that 
PDGFRA and KIT mutations give rise to alternative and mutually exclusive oncogenic 
mechanisms in GISTs. Moreover, the same activated signal transduction pathways 
were present in KIT and PDGFRA-mutant tumors further confirming that both genes 
play an important role in the development of GISTs.  
The mainstay of therapy for GISTs is surgical resection, however, recurrence is almost 
inevitable in high-risk tumors and secondary surgery or other salvage therapy has 
yielded poor outcome. The median survival for patients with unresectable or metastatic 
GIST is approximately 20 months, and for patients with local recurrence it is 9 to 12 
months. Responses to chemotherapy have been at best 5%. The introduction of 

Novartis 
Confidential 
Page 13 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
imatinib has dramatically changed the prognosis of these patients yielding response 
rates between 41% and 71% and an overall clinical benefit (tumor responses plus 
stable disease) ranging between 73% and 90% (Demetri 2002, van Oosterom 2002, 
Benjamin 2003, Verweij 2003, Verweij 2004). Imatinib is the first-line therapy for 
metastatic GIST with a median progression free survival 
(PFS) reported between 18 months (Phase III) and 29 months (Phase II) and a median 
overall survival of 57 months (Verweij 2004, Blanke 2008a, Blanke 2008b, Bertucci 
2012). 
During the consensus conference on GIST management (Blay et al 2006), the 
recommended option in patients progressing on imatinib 400 mg daily was to increase 
the dose of imatinib. Dose escalation of imatinib from 400 mg to 600 mg and 800 mg 
for patients who progress during therapy with imatinib 400 mg has been approved in 
Europe. Two very similar, large Phase III studies (Verweij 2003, Rankin 2004), 
comparing imatinib 400 mg daily and 800 mg daily, showed similar response rates with 
the two imatinib doses. Both trials reported superior progression free survival (PFS) in 
the 800 mg arm, one of them reaching statistical significance (median PFS of 22 
months versus median PFS not reached, p=0.02) (Verweij et al 2003), while, the other 
was not statistically significant (median PFS of 22 months versus 27 months, p=0.13) 
(Rankin et al 2004). In both of these studies, patients initially randomized to receive 
imatinib 400 mg daily could cross-over to 800 mg daily upon disease progression. In 
the European trial, 133 out of 247 patients who had progressive disease crossed-over 
to imatinib 800 mg daily (Zalcberg et al 2005). Three patients achieved a partial 
response (2.3%) and 36 patients had stable disease (27%). The median PFS after 
cross-over was 81 days. Similar results were observed in the US study in which 84 out 
of 164 patients treated with 400 mg imatinib and having progressive disease crossed-
over to the 800 mg arm (Rankin et al 2004). Five of these patients achieved a partial 
response (7%) and 20 patients had stable disease (29%). Median progression-free 
survival and overall survival for patients who crossed over were 4 months and 19 
months, respectively. Imatinib was well tolerated across all studies up to a dose of 800 
mg daily with the main adverse effects being nausea, vomiting, edema and skin rash. 
An adverse event observed particularly in GISTs patients was gastrointestinal 
hemorrhage, potentially related to tumor necrosis induced by imatinib. 
 
1.2 
Overview of nilotinib  
Nilotinib is a second generation inhibitor of the Bcr-Abl tyrosine kinase which, like 
imatinib, targets the causative abnormality of chronic myelogenous leukemia (CML). 
Nilotinib is an ATP-competitive inhibitor of the protein tyrosine kinase activity of Bcr-
Abl, which prevents the activation of Bcr-Abl dependent mitogenic and anti-apoptotic 
pathways (e.g. PI-3 kinase and STAT5), leading to the death of the Bcr-Abl phenotype. 
In addition, nilotinib inhibits the PDGF-receptor tyrosine kinases including FIP1L1-
PDGFRα tyrosine kinase, which is often associated with HES and chronic eosinophilic 
leukemia (CEL), and TEL-PDGFRβ which causes chronic myelomonocytic leukemia 

Novartis 
Confidential 
Page 14 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
(CMML), as well as the stem cell factor receptor c-Kit tyrosine kinase, which is often 
associated with GIST and SM. 
The activity of nilotinib on c-Kit autophosphorylation has been investigated using 
GIST882 cells, a human cell line expressing constitutively activated c-Kit (CD117) 
derived from a patient with GIST, and in Ba/F3 cells engineered to express the D816Y 
and D816V mutant forms of KIT. Nilotinib potently reduced c-Kit autophosphorylation 
in GIST cells with a mean IC50 of 202 nM, similar to that of imatinib. The compound 
was less potent against D816Y and D816V mutant autophosphorylation in Ba/F3 cells, 
with mean IC50 values of 480 and 2500 nM respectively. Experiments conducted in 
GIST cell lines carrying mutations sensitive and resistant to imatinib (GIST882, 
GIST430 and GIST48) have shown that nilotinib inhibits proliferation of these cell lines 
more potently than imatinib (Dileo et al 2006). Moreover, studies investigating the 
cellular uptake of nilotinib in comparison with imatinib have revealed that nilotinib 
intracellular concentrations are 7- and 10- fold higher that those of imatinib in GIST882 
and GIST GDG1 cell lines respectively (Prenen et al 2006). 
In in vitro assays, nilotinib has been shown to interact with CYP2C9, CYP2C8, CYP2D6, 
and CYP3A4. Because of the inherent risk of either reduced activity or enhanced 
toxicity of the concomitant medication and/or nilotinib, medications known to interact 
with these cytochrome P450 isoenzymes should be used with caution (Post-text 
supplement 5). In particular concomitant use of CYP3A4 inhibitors should be avoided 
if at all possible. 
 
Clinical Pharmacokinetics 
Nilotinib is metabolized by the liver, primarily via CYP3A4. Thus strong inhibitors or 
inducers of CYP3A4 can significantly alter the pharmacokinetics and systemic 
exposure of nilotinib in humans. In addition, nilotinib exhibits moderate inhibitory effect 
on CYP3A4, which may increase the exposure of sensitive CYP3A4 substrates. 
Unchanged nilotinib represents the predominant systemic circulating component 
(approximately 88% of the total drug-related serum exposure). The terminal elimination 
half-life of nilotinib was estimated to be approximately 17 hours.  
Race was assessed as a covariate on the bioavailability or clearance of nilotinib in the 
population pharmacokinetic analysis which included a total of 550 patients. No 
significant differences were observed in nilotinib pharmacokinetics across various race 
groups, e.g. Caucasian (n=348 patients), Black (n=23 patients), Asian (n=138 patients) 
and other races (n=41 patients) [Modeling report CAMN107A2303]. These findings are 
consistent with the previous observations in patients with imatinib resistant or intolerant 
CML [Study CAMN107A2101 PopPK] and the ethnic insensitivity analysis conducted 
for the original Tasigna® submission. Population pharmacokinetics (PK) analysis also 
suggested that male patients had an approximately 10% lower bioavailability or 10% 
lower systemic exposure than female Patients. However, since the observed extent of 
the difference is relatively small, such a sex effect is unlikely to be clinically meaningful 
for nilotinib therapy. Other demographic variables, such as age and body weight did 

Novartis 
Confidential 
Page 15 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
not significantly affect nilotinib PK. Thus, patient demographics are not a clinically 
important factor contributing to interpatient variability in nilotinib PK and exposure.  
Impaired renal function is not expected to influence nilotinib PK, since neither nilotinib 
nor its metabolites are renally excreted. 
Compared to healthy subjects with normal hepatic function, nilotinib AUC0-∞ was 
increased by 35% in both the mild (Child-Pugh class A, score 5-6) and moderate (Child-
Pugh class B, score 7-9) impairment groups, and by 19% in the severe impairment 
group. The mean T1/2 of nilotinib was similar between the mild hepatic impairment and 
non-impaired control groups (approximately 15.1 and 16.0 hours, respectively), but 
was prolonged in the moderate and severe hepatic impairment groups (to 21.6 hours 
and 32.4 hours, respectively) (Yin 2009). 
Bioavailability of nilotinib is reduced following gastrectomy. Population PK analysis 
from [CAMN107A2201] estimated that the relative bioavailability of nilotinib was 
reduced by approximately 48% and 22% in patients who had undergone total or partial 
gastrectomy, respectively. The extent of decrease in nilotinib absorption due to partial 
gastrectomy is small, and thus its impact on nilotinib therapy is expected to be minor. 
For additional nilotinib clinical pharmacokinetics information, please refer to the latest 
nilotinib [Investigator’s Brochure]. 
 
1.2.1 
Clinical experiences with nilotinib 
A Phase I/II study of nilotinib (CAMN107A2101), is currently taking place in adult 
patients with imatinib-resistant CML in CP (chronic phase), AP (accelerated phase) or 
BC (blastic crisis), relapsed/refractory Ph+ ALL, and other hematological malignancies.  
 
A total of 321 CML-CP patients (70.4% imatinib-resistant, 29.6% were imatinib-
intolerant) in the Phase II study [CAMN107A2101E2] were evaluated for efficacy. 
Patients were treated with nilotinib 400 mg BID (total daily dose of 800 mg). 
At 24 months data cut-off, 124 (38.6%) patients were ongoing and 197 (61.4%) had 
discontinued treatment. The reasons for discontinuation were mainly due to AEs (61 
patients, 19.0%) and disease progression (88 patients, 27.4%). For additional safety 
data, please refer to the IB version 9. Nilotinib induced a major and complete 
cytogenetic response in 51.4% and 36.8% of patients, respectively. These responses 
were durable: an estimated 77% and 85% of patients with MCyR and CCyR, 
respectively, maintained response at 24 months. 
A Phase I study of nilotinib alone and in combination with imatinib [CAMN107A2103] 
was performed in adult patients with imatinib-resistant GIST.  The study showed that 
nilotinib alone or in combination with imatinib was well tolerated and showed clinical 
activity in the studied patient population. 
The efficacy of nilotinib in patients with newly diagnosed Ph+ CML-CP has been 
evaluated 
in 
a 
phase 
III 
multi-center 
open 
label, 
randomized 
study 

Novartis 
Confidential 
Page 16 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
(CAMN107A2303/ENESTnd) comparing nilotinib to imatinib in adult patients with 
newly diagnosed CML-CP. This study is ongoing and showed continuing superiority of 
nilotinib vs. imatinib at 12, 24, 36, and 48 months follow-up in terms of cytogenetic and 
molecular responses, as well as in reduction of progression to AP/BC. A total of 846 
newly diagnosed CML-CP patients were randomized into the study of which 643 
patients were still receiving treatment as of the 48 month cut-off date (162 patients 
(57.2%) in the imatinib arm, 186 patients (66.0%) in the nilotinib 300 mg b.i.d arm and 
195 patients (69.4%) in the nilotinib 400 mg b.i.d arm). 
At the time of the 48 month cut-off date, the time on treatment was comparable 
between the treatment groups, with a median of about 48 months in all groups. Most 
patients (>98%) experienced at least one adverse event (AE). The most frequently 
affected system organ class (SOC) in the nilotinib groups, were skin and subcutaneous 
tissue disorders and GI disorders. 
In the imatinib group, the most frequently affected SOCs were GI disorders and 
musculoskeletal and connective tissue disorders. The highest incidence of combined 
AEs/abnormal laboratory values leading to study discontinuation was observed in the 
nilotinib 400 mg b.i.d. arm (46 patients, 16.4%), followed by the imatinib arm (33 
patients, 11.7%) and the nilotinib 300 mg bid arm (28 patients, 9.9%). 
A Phase III study of nilotinib vs. best supportive care (with or without imatinib or 
sunitinib) was performed [CAMN107A2201].  
A total of 248 patients with third-line unresectable and/or metastatic gastrointestinal 
stromal tumors (GIST) were randomized in a 2:1 ratio to the nilotinib arm (165 patients) 
or to the control arm (83 patients). The control arm included three treatment options 
(to be selected by investigators): best supportive care (BSC) only, BSC plus imatinib 
(BSC+I), and BSC plus sunitinib (BSC+S). 
Patients whose tumors had not progressed at the completion of the core study (i.e., 
after 174 events had occurred) were eligible for roll-over to the extension study. All 
patients continued to be treated as per their assigned treatment arm until they 
experienced disease progression. 
Therefore, patients entering the extension study on the control arm were permitted to 
cross over to nilotinib only upon documented disease progression according to 
RECIST criteria based on investigators assessment. 
This study was completed on June 20, 2011. Median duration of exposure to nilotinib 
treatment was 127 days for nilotinib and 82 days for the control arm. Among nilotinib 
patients, 63 (38%) were treated for > 6 months, including 43 (26%) patients for > 9 
months. 
Median duration of exposure for patients crossing over to nilotinib in the extension 
study was 89 days. The majority of patients (82%) were treated with nilotinib after 
crossover for less than 6 months. The duration of nilotinib exposure after crossover 
ranges from 1 to 1273 days. 
In the core study result, for the primary efficacy variable of PFS based on blinded 
central radiology review, there was no significant difference between the arms in the 

Novartis 
Confidential 
Page 17 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
distribution of time to PFS event (median 109 and 111 days, respectively; log-rank test 
p=0.5555). Based on the local review, there was a highly significant difference in PFS 
based on local radiology assessments in favor of nilotinib. Median PFS was 119 days 
in the nilotinib arm vs. 70 days in the control arm (p=0.0007, log-rank test). Since the 
primary endpoint for the PFS evaluation was based on the independent radiological 
review and no additional independent radiological review was conducted after the cut-
off date reported in the Core study CSR (27-Jun-2008), there was no further update on 
the PFS for the Core study. 
OS was not statistically significant between the two treatment arms (p=0.3547, log-
rank test). 
A total of 217 deaths were reported: 142 (86.1%) in the nilotinib arm and 75 (90.4%) in 
the control arm. The median OS was 361 days in the nilotinib arm vs. 300 days in the 
control arm. 
The OS rate at 12 months was 49.0% for nilotinib arm vs. 43.9% for control arm. 
In study [CAMN107G2301] patients with unresectable and/or metastatic GIST who 
have either not received prior therapy with a TKI or who have recurrent GIST after 
stopping adjuvant therapy, were randomized to either nilotinib or imatinib therapy 
(Table 5-3). The primary objective of this study is to compare PFS of nilotinib and 
imatinib when used as initial therapy in this patient population. 
Based on data as of November 11, 2010, a planned interim analysis for futility was 
conducted. 
The results were reviewed by an independent Data Monitoring Committee (DMC) on 
April 4, 2011. The DMC observed that the futility boundary had been exceeded and 
therefore concluded that the study was highly unlikely to meet its primary endpoint. 
DMC’s recommendation was therefore to stop recruitment. Accrual was stopped on 
April 8, 2011. As a result, the development program of nilotinib in GIST was closed.  
Nilotinib is currently approved for the treatment of adult patients with Philadelphia 
chromosome positive (Ph+) chronic myeloid leukemia in chronic phase and 
accelerated phase resistant to or intolerant to at least one prior therapy including 
imatinib and for the treatment of adult patients with newly diagnosed Ph+ CML in CP. 
Tasigna is indicated for the treatment of adult patients with newly diagnosed 
Philadelphia chromosome positive chronic myelogenous leukaemia (CML) in the 
chronic phase. 
 
1.2.2 
Adverse reactions from clinical studies 
Adverse reactions reported as more than an isolated case are listed by system organ 
class and by frequency in Table 1-1. Frequency categories are defined using the 
following CIOMS III frequency convention: very common (≥1/10), common (≥1/100 to 
<1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare 

Novartis 
Confidential 
Page 18 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
(<1/10,000) and not known (cannot be estimated from the available data). Information 
in tables below was taken from the Investigator’s Brochure v. 9.0. 
In general, the safety profile in GIST patients was similar to that in CML patients, with 
the exception of a lower incidence of hematological toxicity in GIST patients.  
 
Table 1-1 Adverse reactions from clinical studies 
Most frequent drug-related adverse events (more than 5%) at 24-months in CML-AP 
and -CP patients (Study 2101 E1 and E2) 
___________________________________________________________________________ 
2101E11  
 
2101E21 
All grades 
 
All grades  
CML-AP  
 
CML-CP 
N=137  
 
N=321 
Preferred Term  
 
 
 
 
n (%) 
 
 
n (%) 
______________________________________________________________ 
_____________ 
Any event  
 
 
 
 
 
120 (87.6)  
 
304 (94.7) 
_______________________________________________________ 
____________________ 
Thrombocytopenia  
 
 
 
 
52 (38.0)  
 
90 (28.0) 
Neutropenia  
 
 
 
 
 
31 (22.6)  
 
48 (15.0) 
Rash  
 
 
 
 
 
 
29 (21.2)  
 
99 (30.8) 
Anemia   
 
 
 
 
 
24 (17.5)  
 
42 (13.1) 
Pruritus   
 
 
 
 
 
24 (17.5)  
 
84 (26.2 
Lipase increased   
 
 
 
 
18 (13.1)  
 
41 (12.8) 
Fatigue   
 
 
 
 
 
14 (10.2)  
 
65 (20.2) 
Constipation  
 
 
 
 
 
13 (9.5)   
 
43 (13.4) 
Diarrhea  
 
 
 
 
 
13 (9.5)   
 
39 (12.1) 
Leukopenia  
 
 
 
 
 
13 (9.5)   
 
13 (4.0) 
Muscle spasms   
 
 
 
 
13 (9.5)   
 
24 (7.5) 
Nausea   
 
 
 
 
 
13 (9.5)   
 
79 (24.6) 
Alopecia  
 
 
 
 
 
12 (8.8)   
 
27 (8.4) 
Myalgia   
 
 
 
 
 
12 (8.8)   
 
33 (10.3) 
Blood bilirubin increased   
 
 
 
11 (8.0)   
 
22 (6.9) 
Headache  
 
 
 
 
 
11 (8.0)   
 
57 (17.8) 
Hyperbilirubinemia  
 
 
 
 
11 (8.0)   
 
23 (7.2) 
Abdominal pain   
 
 
 
 
10 (7.3)   
 
17 (5.3) 
Pyrexia   
 
 
 
 
 
9 (6.6)   
 
13 (4.0) 
Anorexia  
 
 
 
 
 
8 (5.8)   
 
23 (7.2) 
Pain in extremity   
 
 
 
 
8 (5.8)   
 
17 (5.3) 
Arthralgia  
 
 
 
 
 
7 (5.1)   
 
24 (7.5) 
Hypophosphatemia  
 
 
 
 
7 (5.1)   
 
8 (2.5) 
Peripheral edema  
 
 
 
 
7 (5.1)   
 
20 (6.2) 
Vomiting  
 
 
 
 
 
5 (3.6)   
 
41 (12.8) 
Alanine aminotransferase increase   
 
 
5 (3.6)   
 
34 (10.6) 
Bone pain  
 
 
 
 
 
5 (3.6)   
 
24 (7.5) 
Erythema  
 
 
 
 
 
2 (1.5)   
 
23 (7.2) 
Asthenia  
 
 
 
 
 
5 (3.6)   
 
21 (6.5) 
Aspartate aminotransferase increase  
 
 
4 (2.9)   
 
20 (6.2) 

Novartis 
Confidential 
Page 19 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Dry skin   
 
 
 
 
 
5 (3.6)   
 
20 (6.2) 
Dyspnea  
 
 
 
 
 
0 (0.0)   
 
17 (5.3) 
Weight decreased  
 
 
 
 
3 (2.2)   
 
17 (5.3) 
___________________________________________________________________ 
________ 
AP = accelerated phase, CML = chronic myeloid leukemia, CP = chronic phase, 
1 The source used for 24-month 2101E1 data (cut-off 29-Aug-2008) and 24-month 2101E2 data (cut-off 20-Apr-
2008) 
Source: [CAMN107A2101E1] and [CAMN107A2101E2 CSR]. 
 
 
1.2.2.1 
Ischemic Vascular and Ischemic Cardiovascular Events Reported for 
CAMN107A2303 (ENESTnd Study) 
Newly-diagnosed or worsened Ischemic Vascular and Ischemic Cardiovascular Events 
such as Ischemic Heart Disease (IHD), Ischemic Cerebrovascular Events (ICVE) or 
Peripheral Artery Occlusive Disease (PAOD) have occurred in a relatively small 
number of CML-CP patients while on study medication. However, such events have 
been reported with higher frequency on the nilotinib treatment arms compared with the 
imatinib treatment arm. Up to the data cut-off for the 60 Month analysis (30-Sep-2013), 
the number of patients reported with events is as follows: 
- Nilotinib 300 mg BID: IHD, 11 (3.9%); ICVE, 4 (1.4%); PAOD, 7 (2.5%) 
- Nilotinib 400 mg BID: IHD, 24 (8.7%); ICVE, 9 (3.2%); PAOD, 7 (2.5%) 
- Imatinib 400 mg QD: IHD, 5 (1.8%); ICVE, 1 (0.4%); PAOD, 0 (0.0%) 
The majority of reported ischemic vascular and ischemic cardiovascular events were 
in patients with associated risks (e.g., advanced age, hypertension, hyperlipidemia, 
hypercholesterolemia, smoking, diabetes mellitus, pre-existing peripheral vascular 
disease). 
1.2.2.2 
ECG QT prolongation 
Nilotinib has an IC50 value of 0.13 µM in the hERG channel assay indicating the 
potential for QT prolongation of nilotinib.In the Phase III study in newly diagnosed Ph+ 
CML-CP patients the change from baseline in mean time-averaged QTcF interval at 
steady-state observed in the nilotinib 300 mg BID group was 6 ms. At the 
recommended dose of 300 mg BID no patient had an absolute QTcF of >480 ms and 
no events of Torsade de Pointes were observed. 
In the Phase II study in imatinib-resistant or intolerant CML patients in chronic and 
accelerated phase, treated with nilotinib 400 mg BID, the change from baseline in mean 
time-averaged QTcF interval at steady-state was 5 and 8 ms, respectively. QTcF 
of >500 ms was observed in 4 patients (<1% of these patients). 
In a healthy volunteer study with exposures that were comparable to the exposures 
observed in patients, the time-averaged mean placebo-subtracted QTcF change from 
baseline was 7 ms (CI ± 4 ms). No subject had a QTcF >450 ms. In addition, no 

Novartis 
Confidential 
Page 20 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
clinically relevant arrhythmias were observed during the conduct of the trial. In 
particular, no episodes of torsade de pointes (either transient or sustained) were 
observed. 
Clinically meaningful prolongation of the QT interval may occur when nilotinib is 
inappropriately taken with food, and/or strong CYP3A4 inhibitors and/or medicinal 
products with a known potential to prolong QT. Therefore, co-administration with food 
must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal 
products with a known potential to prolong QT should be avoided. The presence of 
hypokalemia and hypomagnesemia may place patients at risk of developing QT 
prolongation. 
Known risk factors for QT prolongation are bradycardia, left ventricular failure, 
electrolyte abnormalities (hypokalemia, hypocalcemia), congenital long QT syndrome, 
heart disease, female gender, genetic variants, drug interactions (concomitant use of 
2 drugs that prolong QTc interval). 
1.2.2.3 
Sudden deaths 
In clinical trials, uncommon cases (0.1 to 1%) of sudden death have been reported in 
patients in patients with imatinib-resistant or intolerant CML in chronic and accelerated 
phase receiving nilotinib with a past medical history of cardiac disease or significant 
cardiac risk factors. Comorbidities in addition to the underlying malignancy were also 
frequently present as were concomitant medications. Ventricular repolarization 
abnormalities may have been contributory factors. Based on post-marketing exposure 
in patient-years, the estimated reporting rate for spontaneous reports of sudden death 
is 0.01% per patient-year. No cases of sudden deaths have been reported in the newly 
diagnosed Ph+ CML-CP Phase III study [CAMN107A2303].Safety in GIST patients 
In general, the safety profile in GIST patients was similar to that in CML patients, with 
the exception of a lower incidence of hematologic toxicity. 
1.2.2.4 
Safety in Study CAMN107A2201 
In the phase III study [CAMN107A2201], the median (mean) dose intensity was 800 
mg/day (749.6 mg/day) for nilotinib, 800 mg/day (625.8 mg/day) for imatinib and 
30.1mg/day (33.2 mg/day) for sunitinib. 
Adverse events were reported in 242 patients (97.6%). Adverse events reported most 
frequently affected the gastrointestinal system (197 patients, 79.4%), with an incidence 
similar between the nilotinib arm (129 patients, 78.2%) and the control arm (68 patients, 
81.9%). 
Study drug-related AEs were reported in a total of 177 (71.4%) patients: 126 (76.4%) 
in the nilotinib arm and 51 (61.4%) in the control arm. The most commonly reported 
study drug related AEs were asthenia, nausea and fatigue in the nilotinib arm and 
nausea, peripheral edema and vomiting in the control arm. Overall 43 (17.3%) patients 
reported Grade 3 or 4 study drug-related AEs: 32 (19.4%) in the nilotinib arm and 11 
(13.3%) in the control arm. Asthenia (5 patients, 3.0%) and lipase increase (4 patients, 
2.4%) were the most frequently reported Grade 3 or 4 study drug-related AEs in the 

Novartis 
Confidential 
Page 21 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
nilotinib arm and anemia (4 patients, 4.8%) and neutropenia (3 patients, 3.6%) was the 
most frequently reported Grade 3 or 4 study drug-related AE in the control arm. All 
other Grade 3 or 4 study drug-related AEs occurred with a frequency of less than 2% 
in the nilotinib or control arms. The pattern and incidence of AEs, SAEs, other clinically 
significant AEs and deaths, was as expected in the population studied. Overall adverse 
events and SAEs most commonly affected the gastrointestinal system. Nearly all 
deaths were due to disease progression. The percentage of patients with AE, study 
drug-related SAEs, Grade 3 or 4 AEs, SAEs, study drug-related SAEs and AEs 
associated with discontinuation was slightly higher in the nilotinib arm compared to the 
control arm. 
1.2.2.5 
Summary of safety 
The currently approved dose of nilotinib is 400 mg BID for imatinib-resistant/-intolerant 
Ph+ CML patients and 300 mg BID for newly diagnosed Ph+ CML patients.  
While AEs are common in CML, they are generally mild to moderate, reversible, and 
manageable with dose interruption and/or dose reduction. The most common grade ¾ 
toxicities are hematologic, which are not unexpected in the CML population, and are 
generally manageable. Hematotoxicity is more frequent in patients with imatinib-
resistant or -intolerant CML and in particular in patients with CML-AP and CML-BC. 
The most commonly reported non-hematologic adverse reactions in patients with 
newly diagnosed Ph+ CML-CP, resistant or intolerant Ph+ CML-CP, or resistant or 
intolerant Ph+ CML-AP are rash, pruritus, headache, nausea, fatigue, myalgia, 
nasopharyngitis, constipation, diarrhea, abdominal pain, vomiting, arthralgia, pyrexia, 
upper urinary tract infection, back pain, cough, and asthenia. Hematologic adverse 
drug reactions include myelosuppression: thrombocytopenia, neutropenia and anemia. 
In comparison to 1st line patients, Grade 3/4 adverse events were more frequently 
observed in CML patients resistant or intolerant to prior therapy including imatinib. 
Other significant drug effects reported with nilotinib include modest QTc prolongation, 
elevations of blood glucose, bilirubin, lipase, and transaminases, which are 
manageable with dose interruptions and reductions. 
In general, the safety profile in GIST patients was similar to that in CML patients, with 
the exception of a lower incidence of hematologic toxicity in GIST patients. GI related 
adverse events were more frequently reported as expected in this patient population. 
However, given that two phase III studies designed to demonstrate the superiority of 
nilotinib over imatinib for the treatment of patients with GIST (one study in patients who 
had failed prior therapy with imatinib and sunitinib and the other in newly diagnosed 
untreated patients) failed to meet their primary endpoints, development of nilotinib for 
the treatment of GIST patients has been discontinued. 
2 
Study rationale/purpose 
Nilotinib inhibits the tyrosine kinase activities of PDGFRA and KIT and affects the 
viability of the GIST cell line GIST882 with similar potency as imatinib. In vitro data in 
GIST cell lines expressing different mutations of KIT indicate that nilotinib has 

Novartis 
Confidential 
Page 22 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
antiproliferative activity against certain imatinib-sensitive and -resistant forms of KIT. 
Moreover, studies investigating the cellular uptake of nilotinib in comparison with 
imatinib have revealed that nilotinib intracellular concentrations are 7- and 10-fold 
higher than those of imatinib in GIST882 and GIST GDG1 cell lines respectively. 
Preliminary data from an ongoing Phase I study [CAMN107A2103] indicate that 
nilotinib is well tolerated and has clinical benefit in patients with imatinib-resistant GIST 
who have failed other second line targeted therapies.  
Further investigation of the potential efficacy of nilotinib in a larger number of GIST 
patients who have failed other second line therapies are ongoing in a Phase III study 
[CAMN107A2201]. The study includes adult patients with unresectable or metastatic 
GIST showing progression of disease on both imatinib and sunitinib, or demonstrating 
intolerance to imatinib and/or sunitinib. In this multi-national trial a total of 44 patients 
from approximately 5 countries were recruited. 
Further investigation of the potential efficacy of nilotinib in an earlier stage of the 
disease with a potential overall benefit for GIST patients is indicated based upon the 
experimental data indicating that nilotinib inhibits the proliferation of imatinib-resistant 
GIST cell lines, evidence that nilotinib is well tolerated and has clinical benefit in GIST 
patients. 
Data from Phase II and Phase III clinical trials investigating the relationship between 
KIT and PDGFR mutations and response to imatinib have indicated that GISTs with 
different kinase genotypes differ in their clinical response. In particular, higher 
response rates and longer TTP have been observed for GISTs carrying KIT exon 11 
mutation (Heinrich 2005, Blanke 2006). There are not such data with nilotinib and 
efforts will be made to perform KIT/PDGFR mutational analysis in tumor samples as 
part of the proposed study. 
In the current trial we propose to investigate nilotinib in patients with a first line 
treatment. The promising efficacy data [CAMN107A2103] in combination with the 
safety profile of nilotinib which is comparable to imatinib allow to investigate the drug 
in the 1st line treatment of metastatic and/or unresectable GIST patients.  
3 
Objectives 
3.1 
Primary objective 
• To evaluate the efficacy of Nilotinib in patients with unresectable or metastatic 
gastrointestinal stromal tumors. Efficacy is defined as the proportion of patients 
showing stable disease (SD), partial response (PR) or complete response (CR) 
during the first 6 months according to RECIST criteria. 
3.2 
Secondary objectives 
• To evaluate the objective tumor response rate based on RECIST criteria 
(complete response (CR) and partial response PR) 
• To evaluate time to overall response (PR or CR) 
• To evaluate duration of response 

Novartis 
Confidential 
Page 24 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
principles of pharmacovigilance within clinical trials and GCP and to inadequacy of the 
protocol to evaluate the safety of an IMP in agreement with the level of current scientific 
knowledge, two patients currently benefiting from the nilotinib treatment within the 
CAMN107G2301 trial in Germany will be without an alternative drug re-supply at the 
closure of the CAMN107G2301trial. 
The CAMN107DDE05 close-out plan included the access to nilotinib for ongoing 
German patients until disease progression. As of today there are only two patients with 
metastatic GIST currently benefiting of the nilotinib treatment within the 
CAMN107DDE05 trial in Germany. Considering that these two patients are benefiting 
from nilotinib treatment and might continue receiving the experimental drug for a 
prolonged time, they will be moved to study CAM107DDE06 to allow the closure of 
study CAMN107DDE05.  
Screening 
At Visit 1 patients will be assessed for eligibility for study participation. Tumor 
measurements will be reported in the CRF and the images (original or copy) should be 
kept as part of the source documentation. 
Patients will be advised that formal study entry cannot be fully determined until the 
completion of screening, when all inclusion/exclusion criteria have been finally 
assessed. 
Patients 
moving 
from 
CAMN107G2301 
and 
CAMN107DDE05 
studies 
to 
CAMN107DDE06 study in Germany will be assessed for eligibility at Visit 1. 
Patients from CAMN107G2301 and CAMN107DDE05 studies will start the treatment 
in study CAMN107DDE06 depending on the date of the last patient last visit in the 
previous study. 
Tumor measurements assessed at baseline before starting treatment with nilotinib in 
studies CAMN107G2301 or CAMN107DDE05 and before starting treatment in study 
CAMN107DDE06 will be reported in the CRF and the images (original or copy) should 
be kept as part of the source documentation. 
4.1 
Study drug treatment 
At Visit 2 (Day 1) eligible patients will start study treatment with Nilotinib 400 mg bid. 
From May 5, 2011 on, patients still receiving nilotinib should be offered the opportunity 
to discontinue study drug prematurely to receive standard treatment with imatinib. 
Patients who are receiving nilotinib and considered by the investigators to be deriving 
benefit have the option to remain on medication. Those patients will be treated with 
nilotinib until disease progression is determined by the local radiologist/oncologist 
(RECIST criteria), unacceptable toxicity, death, discontinuation from the study for 
another reason or to the end of the study. 

Novartis 
Confidential 
Page 25 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Patients 
moving 
from 
CAMN107G2301 
or 
CAMN107DDE05 
studies 
to 
CAMN107DDE06 study in Germany will continue receiving nilotinib treatment at the 
dosage ongoing in studies CAMN107G2301 or CAMN107DDE05. 
4.2 
Follow-Up 
Patients who finished the study after 6 months without progression have the option to 
remain on medication. Those patients may continue to be treated with nilotinib as 
foreseen by the protocol until disease progression by entering the follow-up or may 
discontinue trial participation to receive nilotinib according to a local transition plan. If 
required by specific health authorities (e.g. Afssaps-French Health Authority), all 
nilotinib patients will have to discontinue trial participation to receive imatinib according 
to local prescription practice. 
Follow-up will continue until the patient has documented disease progression or starts 
another cancer therapy. The investigator/designee will document data till change of 
treatment. 
Patients 
moving 
from 
CAMN107G2301 
or 
CAMN107DDE05 
studies 
to 
CAMN107DDE06 study will enter directly in the follow-up phase of study 
CAMN107DDE06. They will be treated with nilotinib until patient is no longer benefiting 
from the treatment, unacceptable toxicity, consent withdrawal, investigator decision or 
patient’s death, whichever comes first. 
The start of treatment date for patients included in CAMN107DDE06 study will be 
based on the date of the last patient last visits in CAMN107G2301 and CAM107DDE05 
trials. 
5 
Population 
The study population will consist of adult patients with unresectable or metastatic GIST 
showing progression of disease. In this multi-national trial a total of 44 patients from 
approximately 5 countries recruited.  
The investigator or his/her designee must ensure that all patients who meet the 
following inclusion and exclusion criteria are offered enrollment in the study, with the 
exception of patients moving from studies CAMN107G2301 or CAMN107DDE05. Ad 
hoc criteria applies for these patients (Section 5.3). 
5.1 
Inclusion criteria 
• Age ≥18 years 
• Histologically confirmed diagnosis of GIST that is unresectable and/or metastatic 
and therefore not amenable to surgery or combined modality with curative intent 
prior to or at Visit 1 
• At least one measurable site of disease on CT/MRI scan at Visit 1, as defined by 
RECIST criteria (see Post Text Suppl 3 for details) The scans should be at 
maximum 2 weeks old. New scans are only required as baseline scans if they are 
older than approx. 2 weeks. 

Novartis 
Confidential 
Page 26 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
• WHO Performance Status of 0, 1 or 2  
• Patients must have the following laboratory values (≥ LLN (lower limit of normal) 
or corrected to within normal limits with supplements prior to the first dose of study 
medication.): 
1. Potassium ≥ LLN, 
2. Magnesium ≥ LLN, 
3. Phosphorus ≥ LLN, 
4. Total calcium (corrected for serum albumin) ≥ LLN 
• Patients must have normal organ, electrolyte, and marrow function as defined 
below: 
1. Absolute Neutrophil Count (ANC) ≥ 1.5x 109/L; 
2. Platelets ≥ 100 x 109/L; 
3. ALT and AST ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if considered 
due to tumor; 
4. Alkaline phosphatase ≤ 2.5 x ULN unless considered due to tumor; 
5. Serum bilirubin ≤ 1.5 x ULN; 
6. Serum lipase and amylase ≤ 1.5 x ULN; 
7. Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min. 
(calculated creatinine clearance using Cockroft formula is acceptable) 
• Ability to understand and willingness to sign a written informed consent 
5.2 
Exclusion criteria 
• Prior treatment with nilotinib  
• Treatment with any cytotoxic and/or investigational cytotoxic drug ≤ 4 weeks (6 
weeks for nitrosurea or mitomycin C) prior to Visit 1 with the exception of imatinib 
targeted therapy as an adjuvant therapy or imatinib in first line treatment for 
maximum of 4 weeks. 
• Prior or concomitant malignancies requiring active treatment other than GIST with 
the exception of previous or concomitant basal cell skin cancer, previous cervical 
carcinoma in situ 
• Impaired cardiac function at including any one of the following: 
1. LVEF < 45% or below the institutional LLN range (whichever is higher) as 
determined by echocardiogram at Visit 1 
2. Complete left bundle branch block 
3. Use of a ventricular paced cardiac pacemaker 
4. Congenital long QT syndrome or family history of long QT syndrome 
5. History of or presence of significant ventricular or atrial tachyarrhythmias 
6. Clinically significant resting bradycardia (< 50 beats per minute) 
7. QTc > 450 msec on screening ECG (using the QTcF formula). If QTc > 450 
msec and electrolytes are not within normal ranges (electrolytes should be 
corrected and then the patient rescreened for QTc. 

Novartis 
Confidential 
Page 27 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
8. Right bundle branch block plus left anterior hemiblock, bifascicular block 
9. Myocardial infarction within 12 months prior to Visit 1 
10. Other clinically significant heart disease (e.g., unstable angina, congestive 
heart failure or uncontrolled hypertension,) 
• Patients with severe and/or uncontrolled concurrent medical disease that in the 
opinion of the investigator could cause unacceptable safety risks or compromise 
compliance with the protocol e.g. impairment of gastrointestinal (GI) function, or 
GI disease that may significantly alter the absorption of the study drugs, 
uncontrolled diabetes 
• Use of therapeutic coumarin derivatives (i.e. warfarin, acenoucumarol, 
phenprocoumon) 
• Use of any medications that prolong the QT interval and CYP3A4 inhibitors if the 
treatment cannot be either safely discontinued or switched to a different 
medication prior to starting study drug administration. Please see 
www.qtdrugs.org for a comprehensive list of agents that prolong the QT interval 
as well as [Post-Text Supplement 2]. 
• Patients who have undergone major surgery ≤ 2 weeks prior to Visit 1 or who 
have not recovered from side effects of such surgery 
• Patients who have received wide field radiotherapy ≤ 4 weeks or limited field 
radiation for palliation < 2 weeks prior to Visit 1 or who have not recovered from 
side effects of such therapy 
• A history of noncompliance to medical regimens or inability or unwillingness to 
return for scheduled visits 
• Patients who are pregnant, breast feeding or women of childbearing potential 
(WOCBP). Post-menopausal women must be amenorrheic for at least 12 months 
to be considered of non-childbearing potential Women of reproductive potential, to 
include female partners of heterosexual or bisexual patients, must agree to use an 
effective method of contraception during the study and for up to three months 
following termination of the study.  
• Patients unwilling or unable to comply with the protocol 
5.3 
Eligibility criteria for patients from studies CAMN107G2301 or 
CAMN107DDE05 
Patients currently participating in the Novartis-sponsored studies CAMN107G2301 or 
CAMN107DDE05 and benefiting from the nilotinib treatment according to the 
investigator will be offered the possibility to continue treatment with nilotinib in study 
CAMN107DDE06. 
They will be included in study CAMN107DDE06 if the following criteria are fulfilled: 
• Patient has an histologically confirmed diagnosis of GIST that is unresectable 
and/or metastatic 
• Patient is currently enrolled in the studies CAMN107G2301 or CAMN107DDE05 
in Germany and is on treatment with nilotinib  

Novartis 
Confidential 
Page 28 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
• Patient is currently benefiting from the treatment with nilotinib, as determined by 
the investigator 
• Patient has demonstrated compliance, as assessed by the investigator, within the 
CAMN107G2301 or CAMN107DDE05 protocols requirements 
• Patient has willingness and ability to comply with scheduled visits, treatment plans 
and any other study procedures 
• Written informed consent obtained prior to enrollment in the study 
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test. 
• Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of 
contraception during dosing and for 30 days of study medication. Highly effective 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of 
the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects 
on the study the vasectomized male partner should be the sole partner for 
that subject. 
• Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or 
other 
forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal 
suppository 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the 

Novartis 
Confidential 
Page 29 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
• Sexually active males unless they use a condom during intercourse while taking 
drug and for 30 days after stopping study medication and should not father a child 
in this period. A condom is required to be used also by vasectomized men in order 
to prevent delivery of the drug via seminal fluid. 
6 
Treatment 
6.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center 
number and patient number. The center number is assigned by the sponsor to the 
investigative site. Upon signing the informed consent form, the patient is assigned a 
patient number by the investigator. At each site the first patient is assigned patient 
number 1, and subsequent patients are assigned consecutive numbers (e.g. the 
second patient is assigned patient number 2, the third patient is assigned patient 
number 3). Once assigned to a patient, a patient number will not be reused. If the 
patient fails to be started on treatment for any reason, the reason for not being treated 
will be entered on the Screening Log, and the Demography CRF should also be 
completed. No other data will be entered into the clinical data base for screen failure 
patients. 
Informed consent must be obtained before any study procedures are carried out; this 
includes any procedures to determine a patient’s eligibility.  
6.2 
Investigational drug 
6.2.1 
Instructions for prescribing and taking the study drug 
Nilotinib is available as a hard gelatin capsule and will be dosed on a flat scale of 
mg/day and not by weight or body surface area. It will be provided by Novartis as global 
clinical study supply or as local commercial packs and sourced in the country. It will be 
supplied to the investigator/hospital pharmacy as open-label medication and packed 
and labeled under the responsibility of Novartis Drug supply management. Nilotinib will 
be delivered as dose strength of 200 mg and supplied in blisters. 
Medication labels or booklets, if used, will comply with the legal requirements of each 
country and be printed in the local language. They will supply no information about the 
patient. The patient number will be added to the label by the site personnel. The 
storage conditions for study drug will be described on the medication label or leaflet (in 
case of local commercial packs). 
 
 

Novartis 
Confidential 
Page 30 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
6.2.2 
Study drug 
Each study site will be supplied by Novartis with nilotinib in identically-appearing 
packaging. For global study supply, one component of the packaging has a 2-part label. 
Each part of this label will give the name and dose of the drug. There will also be a 
blank space that needs to be completed with the patient ID number. Immediately before 
dispensing study drug to the patient, investigator staff will detach the outer part of the 
label from the packaging and affix it to the source document (Drug Label Form) 
containing that patient’s unique patient number. For local commercial packs, name and 
dose of the drug, batch number and patient ID number will be noted in the respective 
Drug Label Form before dispensing. 
6.2.3 
Treatment 
The dose of nilotinib will be 400 mg bid which is the current Phase II dose as 
established in study CAMN107A2101. 
For patients moving from the CAMN107G2301 or CAMN107DDE05 studies to 
CAMN107DDE06 study the starting dose of nilotinib should be the current dose used 
while on treatment in the CAMN107G2301 or CAMN107DDE05 study. 
6.3 
Treatment arms 
Not applicable. This is a single arm study. 
6.4 
Treatment assignment 
This is a single arm study. Please see Section 6.1. 
6.5 
Treatment blinding 
This is an open-label study and blinding is not applicable. 
6.6 
Treating the patient 
General 
Patients will be asked to take their daily medication doses at approximately the same 
time each day and to swallow the tablets/capsules whole and not chew them. Patients 
will also be advised to avoid grapefruit or grapefruit juice, Seville oranges, and star fruit 
and star fruit juice during the entire study as this can enhance and prolong their 
exposure to the study drugs. 
The investigator should instruct the patient to take the study drug exactly as prescribed 
(promote compliance). All dosages prescribed and dispensed to the patient and all 
dose changes during the study must be recorded on the Dosage Administration Record 
CRF. 

Novartis 
Confidential 
Page 31 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
6.6.1 
Study drug administration 
Patients should take nilotinib twice daily approximately 12 hours apart and it should not 
be taken with food. The capsules should be swallowed whole with water. No food 
should be consumed for 2 hours before the dose is taken and no additional food should 
be consumed for at least one hour after the dose is taken. 
6.6.2 
Permitted study drug adjustments 
For patients who are unable to tolerate the protocol-specified dosing schedule due to 
drug-related toxicity, certain dose adjustments are permitted in order to keep the 
patient on study drug. If a treatment interruption is needed and the patient is unable to 
resume treatment within a period of ≤ 21 days, the patient should be withdrawn from 
the study. Any changes in dose level must be recorded on the Dosage Administration 
Record CRF. 
Dosing modifications 
Please refer to Table 6-1 and Table 6-2 for dose reduction steps and criteria for 
interruption and re-initiation of nilotinib for drug-related toxicity. 
Dose reduction will only be permitted for drug-related toxicity, and this will be permitted 
at any time throughout study. 
Dose reduction guidelines for study drug-related non-hematologic toxicity 
A summary of dose reduction guidelines for study drug-related non-hematologic 
toxicity is presented in Table 6-1. No dose reductions below 400 mg/day of nilotinib will 
be allowed. If a patient cannot tolerate a minimum dose of 400 mg/day of nilotinib, the 
patient must be discontinued from the study. Any non-hematologic toxicity must be 
resolved within 28 days in order to resume study drug at the reduced dose. If a non-
hematologic toxicity does not resolve after 28 days of study drug interruption, the 
patient must be discontinued from the study. 
Table 6-1 
Summary of dose reduction guidelines for study drug-related non-
hematologic toxicity – nilotinib 
Worst toxicity 
NCI CTCAE grade  
During therapy 
No toxicity 
Maintain dose level 
 
Nilotinib 400 mg BID 
General non-hematologic 
toxicity 
 

Novartis 
Confidential 
Page 32 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Worst toxicity 
NCI CTCAE grade  
During therapy 
Grade 2 
(persisting > 7 days with 
optimal supportive care) 
Hold therapy and resume nilotinib at 400 mg BID after recovery to ≤ 
Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen 
and then resume at next lower dose level 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
≥ Grade 3 
Hold therapy and resume nilotinib at next lower dose level after 
recovery to ≤ Grade 1 is seen 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Serum creatinine 
 
Grade 2 
> 1.5 -3.0 x ULN 
Hold therapy and resume nilotinib at 400 mg BID after recovery to ≤ 
Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen 
and then resume at next lower dose level 
l→ 400 mg QD; 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
≥ Grade 3 
≥ 3.0 x ULN 
Hold therapy and resume nilotinib at next lower dose level after 
recovery to ≤ Grade 1 is seen 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Hepato-biliary [bilirubin, 
SGPT(AST), SGOT (ALT)] 
Note: If hyperbilirubinemia is due to the indirect component only, and 
hemolysis as the etiology has been ruled out as per institutional 
guidelines (e.g. review of peripheral blood smear and haptoglobin 
determination), and no amylase and/or lipase elevations are seen, 
nilotinib may be continued at the same dose at the discretion of the 
investigator. 
Grade 2 
Hold therapy and resume nilotinib at 400 mg BID after recovery to ≤ 
Grade 1 is seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen 
and then resume at next lower dose level 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 

Novartis 
Confidential 
Page 33 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Worst toxicity 
NCI CTCAE grade  
During therapy 
≥ Grade 3 
Hold therapy and resume nilotinib at next lower dose level after 
recovery to ≤ Grade 1 is seen 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Pancreatitis  
(with abdominal symptoms plus amylase and/or lipase elevation) 
Grade 2 
Hold therapy and perform abdominal CT with contrast to exclude 
pancreatic pathology. 
If CT is positive, continue to hold therapy and repeat CT, at 
investigator’s discretion. 
If CT is negative, re-start at the next lower dose level after recovery to 
≤ Grade 1 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Elevated amylase and/or 
lipase without symptoms 
 
≥ Grade 3 
Hold therapy and perform abdominal CT with contrast to exclude 
pancreatic pathology. 
If CT is positive, continue to hold therapy and repeat CT, at 
investigator’s discretion. 
If CT is negative, re-start nilotinib at the next lower dose level after 
recovery to ≤ Grade 1 
l→ 400 mg QD. 
If toxicity recurs without symptoms 
l→ continue dosing if CT negative, at investigator’s discretion. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Diarrhea 
Note: Anti-diarrheal medication is recommended at the first sign of loose 
stools or overt diarrhea. If diarrhea cannot be controlled with optimal anti-
diarrheal treatments, take the following actions: 
≥ Grade 3 
Hold therapy and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 1 is seen 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 

Novartis 
Confidential 
Page 34 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Worst toxicity 
NCI CTCAE grade  
During therapy 
Vomiting 
Note: The use of prophylactic medication for vomiting is not recommended.  
Antiemetic medication can be used as medically indicated or in the patient ‘s 
best interest. If nausea and vomiting cannot be controlled with optimal 
antiemetic treatment take the following actions: 
≥ Grade 3 
Hold therapy and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 1 is seen 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Skin rash 
 
Grade 2 
Institute symptomatic therapy 
as appropriate. If skin rash 
does not resolve with optimal 
treatments, take the following 
actions: 
Hold therapy and resume nilotinib at 400 mg BID after recovery to ≤ Grade 1 is 
seen. 
If toxicity recurs, hold therapy again until recovery to ≤ Grade 1 is seen and 
then resume at next lower dose level 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
≥ Grade 3 
Institute symptomatic therapy 
as appropriate. If skin rash 
does not resolve with optimal 
treatments, take the following 
actions 
Hold therapy and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 1 is seen 
l→ 400 mg QD. 
If another recurrence is seen 
l→ discontinue 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Cardiac QTc prolongation 
 
QTcF > 480 msec 
Hold dosing when an ECG with a QTc > 480 msec. 
● notify the sponsor. 
● 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. 
● Compliance with correct dose and administration of Nilotinib must be 
checked. 
● Perform a repeat ECG within one hour of the first QTc of > 480 msec. 
● If QTcF remains > 480 msec, repeat ECG as clinically indicated, but at 
least once a day until the QTcF returns to < 480 msec. 
Study drug may be restarted, at same dose, if reason for elevation of QTcF is 
identified and corrected so that QTcF returns to < 450 msec and to within 20 
msec of baseline within 2 weeks. 
If the QTcF is repeated and is more than 20 msec greater than baseline or 
between 450 msec and 480 msec, the dose of study drug is to be reduced as 
follows: 
● Nilotinib 400 mg BID: dose reduce to 400 mg QD. 
ECGs must be repeated 8 days (± 48 hours) after dose re-start for all patients 
who had therapy held due to QTcF > 480 msec. 
If QTcF of > 480 msec recurs, the patient is to be discontinued. 
The investigator should contact the sponsor regarding any questions that arise 
if a patient with QTc prolongation should be maintained on study. 
Cardiac “other”  
(such as unstable angina) 

Novartis 
Confidential 
Page 35 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Worst toxicity 
NCI CTCAE grade  
During therapy 
≤ Grade 3 
Hold therapy and resume nilotinib at next lower dose level after recovery to ≤ 
Grade 1 is seen. 
L→ 400 mg QD 
If another recurrence is seen 
l→ discontinue 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Grade 4 
Hold therapy and discontinue patient from study. 
Dose reduction guidelines for study drug-related hematologic toxicity 
A summary of dose reduction guidelines for ≥ Grade 3 study drug-related hematologic 
toxicity as determined by the investigator is presented in Table 6-2. No dose 
adjustments should be made for Grade 1 or 2 hematologic toxicity for nilotinib. Any 
hematologic toxicity must be resolved within 28 days in order to resume study drug at 
the reduced dose. If a hematologic toxicity does not resolve after 28 days of study drug 
interruption, the patient must be discontinued from the study.  
Table 6-2 
Summary of dose reduction guidelines for study drug-related related-
hematologic toxicity – nilotinib 
Worst toxicity 
NCI CTCAE grade  
During therapy 
No toxicity 
Maintain dose level 
 
Nilotinib 400 mg BID 
≥ Grade 3 
Hold therapy and resume at 400 mg BID after recovery to ≤ Grade 1, if 
recovery occurs within 14 days 
If toxicity persists for 15-28 days or recurs, hold therapy and resume at next 
lower dose level after recovery to ≤ Grade 1: 
 
l→ 400 mg QD 
If another recurrence is seen 
 
 
l→ discontinue. 
If recovery to ≤ Grade 1 is greater than 28 days, the patient must be 
discontinued from the study. 
Guideline for dose re-escalation of nilotinib 
Every attempt to re-escalate the dose of nilotinib to the previously administered dose 
level (i.e., dose level from which dose was reduced) should be made. This applies to 
either dose reductions due to hematologic or non-hematologic toxicities. The dose of 
nilotinib should be re-escalated if the following criteria are met at least one month after 
dose reduction: 
• All ≥ Grade 2 non-hematologic toxicities have resolved to ≤ Grade 1 
• All ≥ Grade 3 hematologic toxicities have resolved to ≤ Grade 1 
• Or alternatively, all ≥ Grade 3 hematologic and non-hematologic toxicities have 
resolved to ≤ Grade 2 and are manageable with supportive therapy 

Novartis 
Confidential 
Page 36 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
For patients whose nilotinib dose was 800 mg (as 400 mg BID) prior to dose reduction 
to 400 mg QD, the dose would be increased to 800 mg (as 400 mg BID) if the above 
described criteria are met at least one month after dose reduction. 
6.6.3 
Other concomitant medications 
All medications administered within 4 weeks prior to the administration of study drugs 
and all concomitant therapy administered during the study along with the reasons for 
therapy will be recorded in the CRF. All prior chemotherapy and biologic, immunologic, 
targeted therapy or radiation therapy, and surgery will be recorded on a separate page 
of the CRF. 
• Routine prophylactic use of recombinant growth factors is prohibited while the 
patient is on study American Society of Clinical Oncology guidelines (Ozer 2000). 
However the use of growth factors is permitted at the discretion of the investigator 
for patients with neutropenia (ANC <500x 109/L). Patients who were receiving 
recombinant erythropoietin prior to starting study drug may continue to receive 
their pre-treatment doses throughout the study. If recombinant erythropoietin is 
required for the first time while the patient is on study, (Rizzo et al 2002) its use is 
permitted. 
• Prophylactic anti-emetics should not be given. However when a patient has 
signs/symptoms of nausea and vomiting please follow directions as per Tables 6-
1 and Table 6-2. 
• QT prolonging agents. Every effort should be made NOT to administer a QT 
prolonging agent. If during the course of the study, concomitant administration of 
an agent known to prolong the QT interval is required and cannot be switched to 
an alternative therapy, nilotinib must be STOPPED. Please see www.qtdrugs.org 
for a comprehensive list of agents that prolong the QT interval as well as Post-text 
Supplement 2. During the course of the study if administration of a QT prolonging 
agent or a CYP3A4 inhibitor cannot be avoided , the Sponsor needs to be 
informed and it is strongly recommended that an ECG be obtained 24 to 48 hours 
and one week after initiating the concomitant therapy. 
• In addition to medications that can affect the QT interval (Exclusion Criteria), 
patients must be counseled not to consume grapefruit, grapefruit juice, Seville 
oranges, star fruit or star fruit juice. 
• CYP3A4 inhibitors. Every effort should be made NOT to administer strong 
CYP3A4 inhibitors (e.g, erythromycin, ketoconazole, itraconazole, voriconazole, 
clarithromycin, telithromycin, ritonavir, mibefradil). If administration of a CYP3A4 
inhibitor cannot be avoided during the study and cannot be switched to an 
alternative therapy, nilotinib must be STOPPED 
A comprehensive list of cytochrome P450 isoenzymes and CYP3A4 inhibitors and 
inducers may also be found at https://drug-interactions.medicine.iu.edu and Post-
text Supplement 4. FDA classification of CYP3A4 inhibitors can be found at 
https://www.fda.gov/cder/drug/drugInteractions/tableSubstrates.htm#classInhibit. 
Patients must be carefully monitored for potentiation of toxicity due to individual 
concomitant medication. 

Novartis 
Confidential 
Page 37 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
• CYP3A4 inducers. Inducers of CYP3A4 could increase the metabolism of nilotinib 
and thereby decrease serum concentrations. The concomitant administration of 
medications that induce CYP3A4 (e.g., phenytoin, rifampin, carbamazepine, 
phenobarbital, and St. John’s Wort) may reduce exposure to nilotinib. In patients 
for whom CYP3A4 inducers are indicated, alternative agents with less enzyme 
induction potential should be considered. Every effort should be made NOT to 
administer strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St John’s Wort) 
however, if administration of a CYP3A4 inducer cannot be avoided during the 
study, temporary discontinuation of study drug is NOT required.  
Please see https://drug-interactions.medicine.iu.edu and Post-text Supplement 4 
for a list of CYP3A4 inducers. 
• Patients taking medications chronically should be maintained on the same dose 
and dose schedule throughout the study period, as medically feasible. The days 
of full pharmacokinetic blood sampling should be representative of the other study 
days with regard to the use of chronically administered concomitant medications. 
However, if a concomitant medication is used intermittently during the study, this 
medication should be avoided on the days of full pharmacokinetic sampling, if 
medically feasible. 
• In in vitro assays, nilotinib has been shown to interact with CYP 2C9, CYP 2C8, 
CYP 2D6 and CYP 3A4. Because of the inherent risk of either reduced activity or 
enhanced toxicity of the concomitant medication and/or nilotinib, medications 
known to interact with these cytochrome P450 isoenzymes should be used with 
caution (Post-text Supplement 4). Patients using concomitant medications known 
to be metabolized by these isoenzymes will not be excluded from the study 
(except for coumarin derivatives and CYP3A4 inhibitors and inducers that are 
contraindicated); but, the patients must be carefully monitored for potential of 
toxicity due to individual concomitant medications. 
The investigator should instruct the patient to notify the study site about any new 
medications he/she takes after the start of the study drug. 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 Concomitant medications/Significant non-drug therapies after start of 
study drug CRF. 
6.6.4 
End of treatment and study drug discontinuation  
End of treatment 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion 
of the investigator at any time. Patients should be withdrawn from the study if 
pregnancy occurs. 
In addition to these requirements for study drug discontinuation, the investigator should 
discontinue study drug for a given patient if, on balance, he thinks that continuation 
would be detrimental to the patient’s well-being.  

Novartis 
Confidential 
Page 38 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
If such withdrawal occurs, or if the patient fails to return for visits, the investigator must 
determine the primary reason for a patient’s premature withdrawal from the study and 
record this information on the End of Treatment CRF. Patients may be withdrawn from 
the study prematurely for one of the following reasons: 
• Adverse event(s) 
• Abnormal laboratory value(s) 
• Abnormal test procedure result(s) 
• Protocol violation 
• Subject withdrew consent 
• Lost to follow-up 
• Administrative problems 
• Death 
• New cancer therapy 
• Disease progression 
Study drug discontinuation  
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. 
Patients who discontinue study drug before completing the study should be scheduled 
for a visit as soon as possible, at which time all of the assessments listed for the final 
visit should be performed. At a minimum, all patients who discontinue study treatment, 
including those who refuse to return for a final visit, will be contacted for safety 
evaluations during the 28 days following the last dose of study drug. 
Patients who discontinue study drug should be considered withdrawn from the study 
after the final visit assessments are performed or when it is clear that the patient will 
not return for these assessments. The last date of study drug intake should be entered 
into the Study Completion CRF and the reason for discontinuing study drug should be 
given on the comments page. If a patient who discontinued study drug performed all 
scheduled study procedures and measurements, he will be counted as a study 
completer. 
Patients lost to follow up should be recorded as such on the CRF. 
Treatment after study drug discontinuation is at the discretion of the investigator. 
Study evaluation completion 
Survival information will be collected on all study patients until 28 day safety follow up. 
7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates with an “X” the visits at which these 
assessments are performed. All data obtained from these assessments must be 
supported in the patient’s source documentation. The table indicates which data are 

Novartis 
Confidential 
Page 39 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
entered into the database (D) or remain in source documents only (S). Assessments 
that generate data for database entry and which are recorded on CRFs are listed using 
the CRF name. The screening period can be less than 14 days provided all 
assessments are completed. All other study visits may be scheduled allowing for ± 4 
days. If any visit falls outside the ± 4 day window during the active treatment period, 
the patient must be seen as soon as possible and subsequent visits should be 
scheduled in keeping with Visit 2. Please pay special attention to drug supply needs if 
the visit is not scheduled as outlined in the visit schedule table (Table 7-1). 
Patients 
moving 
from 
[CAMN107G2301] 
or 
[CAMN107DDE05] 
studies 
to 
[CAMN107DDE06] study will directly enter the follow up phase of the study after the 
screening visit. The first FU visit will be 3 months after the screening visit. 
The start of treatment date for patients included in [CAMN107DDE06] study will be 
based on the date of the last patient last visits in studies [CAMN107G2301] and 
[CAM107DDE05]. 

Novartis 
Confidential 
Page 40 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Table 7-1 
Visit evaluation schedule 
Visit No. 
Baseline 
Screening 
Core study 
Follow up5 / EoT9 
1 
2 
3 
4 
5 
6 
7 
8 
EOS 
1 - X 
Day 
 
1 
 
 
 
 
 
 
 
 
Week 
 
 
4 
8 
12 
16 
20 
24 
 
36 - X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
X 6 
 
 
 
 
 
 
 
 
 
Ad hoc criteria for patients moving from studies 
[CAMN107G2301] or [CAMN107DDE05] 
X 7 
 
 
 
 
 
 
 
 
 
pregnancy test 
X 
 
 
 
 
 
 
 
 
 
relevant medical history/ current medical 
conditions including GIST specific history1 
X 
 
 
 
 
 
 
 
 
 
Prior/ Significant non-drug therapies 
X 
 
 
 
 
 
 
 
 
 
prior adjuvant antineoplastic treatment 
X 
 
 
 
 
 
 
 
 
 
vital signs 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 X 4 
X 4 
X 4 
X 4 
X 4 
X 4 
X 4 
X 
X 4 
physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hematology2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
biochemistry2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine analysis2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT / MRI 
X 8 
 
 
X 
 
X 
 
X 
X 
X 
tumor evaluation (RECIST) 
X 8 
 
 
 
X 
 
 
X 
X 
X 
study drug administration 
X 7  
X 
X 
X 
X 
X 
X 
X 
X 
X3 
Adverse events 
X 
Ongoing data capture 
Ongoing data 
capture  
Paraffin bloc available 
X 6 
 
 
 
 
 
 
 
 
 

Novartis 
Confidential 
Page 41 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Visit No. 
Baseline 
Screening 
Core study 
Follow up5 / EoT9 
1 
2 
3 
4 
5 
6 
7 
8 
EOS 
1 - X 
Day 
 
1 
 
 
 
 
 
 
 
 
Week 
 
 
4 
8 
12 
16 
20 
24 
 
36 - X 
concomitant medication 
X 
Ongoing data capture 
Ongoing data 
capture 
Comments 
 
Ongoing data capture 
Ongoing data 
capture 
1 History to include site of primary tumor, metastatic sites, GIST histology, time of relapses
tumor Kit expression2  Please 
refer to Section 7.5.5 for individual hematology and biochemistry tests; a -4 day visit window is permitted 
3  No study drug administration at the end of treatment visit (EoT) 
4 Only in patients with prolongation of QTc-interval or suspect for prolongation of QTc-interval  
5 During the follow up period patients will continue to be followed every 6 months until progression . For patients moving from studies CAMN107G2301 or 
CAMN107DDE05 the first FU visit will be 3 months after the screening visit. 
6 Not applicable for patients moving from studies CAMN107G2301 or CAMN107DDE05 
7 Only for patients moving from studies CAMN107G2301 or CAMN107DDE05 
8 Only if CT/MRI scan was not performed within 3 months from screening visit for patients moving from studies CAMN107G2301 or CAMN107DDE05 
9 All patients will be followed for safety for 28 days following the last dose of study medication. 

Novartis 
Confidential 
Page 42 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
7.1 
Information to be collected on screening failures 
All patients who sign Informed Consent but who do not meet the Inclusion and 
Exclusion criteria at Visit 1 will only have the Screening Log pages and Demography 
section of the CRF completed. 
7.2 
Patient demographics/other baseline characteristics 
Standard demographic information and medical history will be collected. 
7.3 
Treatments 
All concomitant medication, including over-the-counter medications, taken during the 
course of the study must be recorded on the Concomitant Medications/Significant Non-
Drug Therapies CRF. 
Study drug compliance will be assessed by the investigator and/or study personnel at 
each visit using pill counts and information on the Drug Dose CRF page. Pill count 
should be captured in the Drug Compliance CRF page at each visit. 
7.4 
Efficacy 
The following efficacy assessments will be carried out: 
Tumor Evaluation with CT or MRI 
 
Tumor evaluation, (chest, abdomen and pelvis), will be assessed at baseline by means 
of CT or MRI. CT scan is the preferred modality and should be used wherever possible. 
If the baseline chest CT shows the presence of disease it should be repeated in all 
subsequent exams. Measurable lesions i.e. target lesions and the non-target lesions 
by which subsequent response assessments will be judged must be identified during 
tumor assessment at baseline; the disease must be staged and progression confirmed 
at this time. 
The CT/MRI (abdomen and pelvis) is to be repeated at week 8, week 16, week 24 and 
EOS. During the Follow up, the patients will have images according to the visit 
schedule (see Table 7-1).  
All images will be read locally at the site and this interpretation will be used for all 
clinical decisions. 
The evaluation of the primary endpoints will be done with local radiologist 
interpretations collected by the investigator in the CRF. 
Methods used for tumor measurement 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
CT and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment. CT and MRI should be performed 

Novartis 
Confidential 
Page 43 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
with contiguous cuts of 7 mm or less in slice thickness. CT should be performed using 
a 5 mm or less contiguous reconstruction algorithm; this specification applies to the 
tumors of the chest, abdomen and pelvis. 
RECIST criteria will be used for clinical decision. 
7.5 
Safety 
7.5.1 
Adverse events 
An adverse event for the purposes of this protocol is the appearance of (or worsening 
of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) occurring 
after signing the informed consent even if the event is not considered to be related to 
the study drug(s). Please refer to Section 6.1 for the protocol-specific definitions of 
study drug and study treatment. 
Adverse events will be assessed according to the Common Toxicity Criteria for 
Adverse Events (CTCAE) version 3.0. If CTCAE grading does not exist for an adverse 
event, the severity of mild, moderate, severe, and life-threatening, or grades 1 - 4, will 
be used. CTCAE grade 5 (death) will not be used in this study; rather, this information 
will be collected in the End of Treatment or Survival Information CRF page. Adverse 
event monitoring should be continued for at least 4 weeks following the last dose of 
study treatment. 
Adverse events (but not serious adverse events) occurring before starting study 
treatment but after signing the informed consent form are recorded on the Medical 
History/Current Medical Conditions Electronic Case Report Form. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant or require therapy (e.g., any 
hematologic abnormality that requires transfusion or cytokine treatment); and should 
be recorded on the Adverse Events CRF under the signs, symptoms or diagnosis 
associated with them. In addition, isolated abnormal laboratory values that are 
considered clinically significant (e.g., cause study discontinuation or constitutes in and 
of itself a Serious Adverse Event) should be recorded on the Adverse Events CRF. 
SAEs occurring after signing the Informed Consent are recorded on the Adverse Event 
CRF. 
The occurrence of adverse events should be sought by non-directive questioning of 
the patient at each visit during the study. Adverse events also may be detected when 
they are volunteered by the patient during or between visits or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse 
event should be evaluated to determine: 
1. The CTCAE grade 1-4 
2. Its relationship to each study drug (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 

Novartis 
Confidential 
Page 44 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
medication taken; non-drug therapy given; hospitalization/prolonged 
hospitalization) 
5. Whether it is serious, where a serious adverse event (SAE) is defined as one 
which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
• Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since 
signing the informed consent 
• Treatment on an emergency outpatient basis for an event not fulfilling any 
of the definitions of a SAE given above and not resulting in hospital 
admission 
• Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes 
listed above 
Unlike routine safety assessments, SAEs are monitored continuously and have 
special reporting requirements; see Section 8.1. 
All adverse events should be treated appropriately. Such treatment may include 
changes in study drug treatment including possible interruption or discontinuation, 
starting or stopping concomitant treatments, changes in the frequency or nature of 
assessments, hospitalization, or any other medically required intervention. Once an 
adverse event is detected, it should be followed until its resolution, an assessment 
should be made at each visit (or more frequently, if necessary) of any changes in its 
severity, its suspected relationship to the study drug(s), any of the interventions 
required to treat it, and its outcome. 
Information about common side effects already known about the investigational drug 
can be found in the [Investigator’s Brochure] or will be communicated between IB 
updates in the form of Investigator Notifications. This information will be included in the 
patient informed consent and should be discussed with the patient during the study as 
needed. 
7.5.1.1 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or abnormal laboratory value must be followed until resolution or stabilization of 
the event. As previously stated, dose delay of ≥ 21 days require the patient to be 

Novartis 
Confidential 
Page 45 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
discontinued from the study. However, the patient will continue to be followed for 
toxicity as previously described. All patients will be followed for safety for 28 days 
following the last dose of study medication. 
7.5.2 
Physical examination, weight, height 
A complete physical examination will be performed by the investigator at all visits. 
Information about the physical examination findings will be present in the source 
documentation at the study site. Significant findings that are present prior to the start 
of study drug must be included on the Relevant Medical History/Current Medical 
Conditions pages of the CRF. Significant findings made after the start of study drug 
which meet the definition of an Adverse Event must be recorded on the Adverse Event 
part in the CRF. 
7.5.3 
Vital signs 
At each visit (Visit 1 thru FUs) the sitting pulse rate will be measured just prior to blood 
pressure measurements. Blood pressure should be measured after at least 3 minutes 
in the sitting position. In addition, temperature and weight will be recorded; height will 
be measured at baseline only, Visit 1. 
Patients should be monitored for signs and symptoms of fluid retention. An unexpected 
rapid weight gain should be carefully investigated and appropriate treatment provided. 
7.5.4 
Performance status 
WHO Performance Status Scale will be used (see Post-text Supplement 1) to assess 
performance at screening Visit 1 (Day -14) and will be measured at each visit, from 
Day 1 thru FUs. 
7.5.5 
Laboratory evaluations 
The research site/institution will perform laboratory analyses according to the Visit 
Schedules (see Table 7-1). The Sponsor must be provided with a copy of the 
laboratory’s certification, and a tabulation of the normal ranges for each parameter 
required. Additionally, if at any time a patient has laboratory parameters obtained from 
a different outside laboratory, the Sponsor must be provided with a copy of the 
certification and a tabulation of the normal ranges for that laboratory. 
The investigator is responsible for reviewing all laboratory reports for patients in this 
study and evaluating any abnormalities for clinical significance.  
At any time during the study, abnormal laboratory parameters which are clinically 
relevant (e.g. require dose modification and/or interruption of study drug, lead to clinical 
symptoms or signs or require therapeutic intervention), whether specifically requested 
in the protocol or not, must be recorded on the appropriate comment CRF page. When 
abnormal laboratory values or test results constitute an adverse event (i.e., induces 
clinical signs/symptoms or requires therapy) they must be recorded on the Adverse 
Events CRF. 
The following assessments are to be performed: 

Novartis 
Confidential 
Page 48 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Report Form in English, and send the completed, signed form by fax within 24 hours 
to the local Novartis Integrated Medical Safety Department. 
The telephone and telefax number of the contact persons in the local department of 
Integrated Medical Safety, specific to the site, are listed in the investigator folder 
provided to each site. The original copy of the SAE Report Form and the fax 
confirmation sheet must be kept with the case report form documentation at the study 
site. 
Follow-up information is sent to the same person to whom the original SAE Report 
Form was sent, using a new SAE Report Form stating that this is a follow-up to the 
previously reported SAE and giving the date of the original report. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to 
that event regardless of when it occurs. The 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 if applicable, and whether the patient continued or withdrew 
from study participation. 
If the SAE is not previously documented in the [Investigator’s Brochure] or Package 
Insert (new occurrence) and is thought to be related to the Novartis study drug, a 
Integrated Medical Safety Department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study 
with the same drug that this SAE has been reported. 
8.2 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported 
to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Clinical Safety & Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the Novartis study drug of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
8.3 
Data Monitoring Board 
Not applicable 

Novartis 
Confidential 
Page 49 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
9 
Data review and data management 
9.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study, the field monitor will visit the site regularly to check the completeness 
of patient records, the accuracy of entries on the CRFs, the adherence to the protocol 
and to Good Clinical Practice, the progress of enrollment, and to ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, 
consisting of case and visit notes (hospital or clinic medical records) containing 
demographic and medical information, laboratory data, electrocardiograms, and the 
results of any other tests or assessments. All information on CRFs must be traceable 
to these source documents in the patient's file. Data not requiring a separate written 
record will be defined before study start and will be recorded directly on the CRFs, 
which will be documented as being the source data. The investigator must also keep 
the original informed consent form signed by the patient (a signed copy is given to the 
patient). 
The investigator must give the monitor access to all relevant source documents to 
confirm their consistency with the CRF entries. Novartis monitoring standards require 
full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and the recording of data that will 
be used for all primary and safety variables. Additional checks of the consistency of 
the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients 
will be disclosed. 
9.2 
Data collection 
Designated investigator staff must enter the information required by the protocol onto 
the Novartis CRFs that are printed on 3-part, non-carbon-required paper. Field 
monitors will review the CRFs for completeness and accuracy and instruct site 
personnel to make any required corrections or additions. The CRFs are forwarded to 
Data Management by field monitors, one copy being retained at the investigational site. 
Once the CRFs are received by Data Management, their receipt is recorded and they 
are reviewed prior to data entry. 
9.3 
Database management and quality control 
Data from the CRFs are entered into the study database by Contract Research 
Organization staff following their own internal standard operating procedures that have 
been reviewed and approved by Novartis. Subsequently, the entered data are 
systematically checked by Data Management staff, using error messages printed from 
validation programs and database listings. Obvious errors are corrected by Data 

Novartis 
Confidential 
Page 50 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Management personnel. Other errors or omissions are entered on Data Query Forms, 
which are returned to the investigational site for resolution. The signed original and 
resolved Data Query Forms are kept with the CRFs at the investigator site, and a copy 
is sent to Novartis so the resolutions can be entered into the database. Quality control 
audits of all key safety and efficacy data in the database are made prior to locking the 
database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded 
using the Medical dictionary for regulatory activities (MedDRA) terminology. 
At the conclusion of the study, the occurrence of any protocol violations will be 
determined. After these actions have been completed and the database has been 
declared to be complete and accurate, it will be locked and made available for data 
analysis. Any changes to the database after that time can only be made by joint 
agreement between the Trial Statistician and Statistical Reporting and the Clinical Trial 
Leader. 
10 
Statistical methods and data analysis 
Primary efficacy and safety analyses will be conducted on all patient data at the time 
all patients who are still receiving study drug will have completed at least 6 months of 
treatment (or discontinued prematurely). The additional data for any patients continuing 
to receive study drug past this time, as allowed by the protocol, will be further 
summarized in a report once these patients completed the study. 
The data from each center are intended to be pooled with data from other centers 
conducted under this protocol so that an adequate number of patients will be available 
for analysis. All statistical analyses will be performed by or under supervision of 
Novartis Pharma, Nuremberg, Germany. The protocol does not envisage data 
analyses carried out independently by the investigator; if performed, they should be 
submitted to Novartis before publication or presentation. 
Data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, and safety observations and measurements. 
The populations, variables, and methods for analysis will be selected for their 
relevance for testing the hypotheses of the study and are described in more detail 
below. 
10.1 
Populations for analysis 
The intent-to-treat (ITT) population will consist of all patients who received at least 
one dose of study drug and have at least one post-baseline assessment of the primary 
efficacy variable (assessment according to RECIST). Patients without any post-
baseline assessment of tumor will be included if they are defined as progressive 
disease based on clinical evaluation. 

Novartis 
Confidential 
Page 51 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
The per-protocol (PP) population consists of all patients of the intent-to-treat 
population who show no major protocol violations. The per-protocol population will be 
identified before database lock. 
Safety population: consists of all patients who received at least one dose of study 
drug and had at least one post-baseline safety assessment. 
Patients from the studies [CAMN107G2301] or [CAMN107DDE05], who skip the core 
study phase and enter directly into the follow up, will be included in the safety 
population only as they will not contribute to efficacy. 
Please note: the statement that a patient had no adverse events (on the Adverse Event 
eCRF) constitutes a safety assessment. Patients who have received at least one dose 
of study drug but who have no post-treatment safety data of any kind would be 
excluded from the safety population. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be 
summarized for the ITT population. Categorical data will be presented as frequencies 
and percentages. For continuous data, mean, standard deviation, minimum, median, 
and maximum will be presented. 
Medical history will be coded using MedDRA and will be presented by system organ 
class, MedDRA preferred term and treatment group. Separate tables will be provided 
for past medical condition and current medical condition. 
10.3 
Treatments (study drug, concomitant therapies, compliance) 
Duration (days) of application of study medication will be summarized descriptively. 
Dosage averages will be calculated including and excluding zero doses for periods of 
temporary interruption of treatment regardless of whether this was due to safety 
reasons or patients’ non-compliance. Daily dose levels will be summarized 
descriptively. Frequency of dose reduction (including temporary dose interruption) for 
safety reasons as per protocol guidelines as well as average daily dose will be 
presented by visit. Reasons for dose adjustments (including temporary dose 
interruption) will be presented by frequency distribution. Permanent treatment 
discontinuations will be analyzed by frequencies. These analyses will be performed for 
the ITT population. 
Concomitant medications and significant non-drug therapies prior to and after the start 
of the study drug will be summarized by WHO drug class. 
10.4 
Primary objective 
10.4.1 
Variable 
The primary variable is defined as the best response at month 6 determined according 
to the RECIST criteria (see Post-text supplement 3: Response Evaluation Criteria in 
Solid Tumors (RECIST)) based on local radiological assessments. 

Novartis 
Confidential 
Page 52 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The proportion of patients in whom a CR, PR or SD was observed will be presented 
with the two-sided exact 80% confidence interval (Clopper-Pearson method) for the 
ITT population. The absolute number of patients showing SD, PR or CR as well as the 
lower limit of the confidence interval for the proportion will be used to conclude 
preliminary activity or non-activity of the study drugs in this patient population according 
to the rule outlined in Section 10.6. 
10.4.3 
Handling of missing values/censoring/discontinuations 
If progression has not been documented and one or more (non-)target lesions have 
not been assessed or have been assessed using a less sensitive method than baseline, 
the response status will be determined as UNK according to RECIST. Subjects with a 
best overall response of UNK will be included in the denominator but not counted as 
non-responders. 
10.4.4 
Supportive analyses 
The proportion of patients in whom a CR, PR or SD was observed will be additionally 
presented with the appropriate 95% confidence interval for the per-protocol population. 
10.5 
Secondary objectives 
10.5.1 
Population and grouping for the analyses 
The secondary efficacy variables will be analyzed using the ITT population. For 
convenience, any tests will be performed at a two-sided significance level of 5%, and 
appropriate two-sided 95% confidence intervals will be displayed. For all safety 
analyses, the safety analyzable population will be used. 
10.5.2 
Secondary efficacy variables and analyses 
Objective response rate (ORR) is defined as the proportion of patients in whom a 
complete (CR) or partial (PR) response was observed according to RECIST at month 
6. ORR will be presented with the two-sided exact 95% confidence interval (Clopper-
Pearson method) for the ITT population. 
Additionally, absolute and relative frequencies of patients in whom a clinical benefit 
(CR/PR/SD) was observed will be presented together with the 95% confidence interval. 
Absolute and relative frequencies together with their 95% confidence interval will be 
presented furthermore for each category (CR/PR/SD/PD/UNK). 
Time to response is defined as the time from start of treatment to the first objective 
tumor response (PR or CR) observed. Patients who did not achieve a confirmed PR or 
CR will be censored at last adequate tumor assessment date when they did not 
progress (including deaths not due to underlying disease). Time to response will be 
explored graphically by presenting the Kaplan-Meier curve. 
Duration of response is defined as the time from onset of response (CR/PR) to 
objective tumor progression or death from any cause. Patients not experiencing 

Novartis 
Confidential 
Page 53 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
progression or death will be censored with the date of their last adequate tumor 
assessment. Duration of response will be explored graphically by presenting the 
Kaplan-Meier curve. 
Progression-free survival (PFS) is defined as the time from first study drug 
administration to objective tumor progression or death from any cause. If a patient has 
not had an event, PFS is censored at the date of last adequate tumor assessment. 
PFS will be explored graphically by presenting the Kaplan-Meier curve. 
Overall survival (OS) is defined as the time from first study drug administration to 
death from any cause. If a patient is not known to have died, survival will be censored 
at date of last contact. OS will be explored graphically by presenting the Kaplan-Meier 
curve. 
10.5.3 
Safety parameters and analyses 
Safety will be evaluated using assessment of adverse events and laboratory data. The 
assessment of safety will be based mainly on the frequency of adverse events and on 
the number of laboratory values that are new or worsening based on the common 
toxicity criteria (CTC) grade. Other safety data (e.g. vital signs) will be considered as 
appropriate. Any statistical tests performed to explore the data will be used only to 
highlight any interesting comparisons that may warrant further consideration. 
Safety data of the patients from the [CAMN107G2301] or [CAMN107DDE05] studies, 
who skip the core study phase and enter directly into the safety follow up, will be 
included in the safety analysis. 
10.5.3.1 Adverse events (AE) 
All adverse events recorded during the study will be summarized. Adverse events will 
be coded by primary system organ class and preferred term according to the Medical 
Dictionary for Regulatory Activities (MedDRA). The incidence of treatment-emergent 
adverse events (new or worsening from baseline) will be summarized by the number 
and percentage of patients in each primary system organ class and preferred term. For 
summaries by severity (based on CTC grades) of event, the most severe occurrence 
for a particular preferred term will be used for a given patient. In the data listings of 
adverse events, the severity of an AE, whether or not an AE is study drug related, and 
whether or not it is a serious AE will be indicated. Deaths, all adverse events, serious 
adverse events, AE leading to study drug discontinuation, AE causing dose adjustment 
or interruption, and AE requiring additional therapy will be listed. 
10.5.3.2 Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade calculated 
using appropriate CTC. Laboratory data will be summarized by presenting summary 
statistics of raw data and changes from baseline values, by presenting worsening 
tables and shift tables using CTC grades as well as normal ranges (baseline to most 
extreme post-baseline value). Listings of laboratory values will be provided by 
laboratory test, notable values will be flagged.. 

Novartis 
Confidential 
Page 54 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
10.5.3.3 Other safety data 
Data from other tests (e.g., electrocardiogram or vital signs) will be listed, notable 
values will be flagged, and any other information collected will be listed as appropriate. 
10.5.4 
Biomarkers 
 need to be looked at in correlation with clinical 
response and clinical outcome. 
Other areas of interest include frequency of overall mutations and individual genotypes, 
location of mutations within the gene and its effect on its resistance profile, and 
mutation rate versus treatment duration. 
Not 
applicable 
for 
patients 
moving 
from 
studies 
[CAMN107G2301] 
or 
[CAMN107DDE05]. 
10.6 
Sample size calculation 
The study follows an exact binomial single-stage design (A’Hern 2001). The study 
requires 39 evaluable subjects to decide whether the proportion responding, p, is less 
than or equal to p0 = 50% or greater than or equal to p1 = 70%. 
If the number of responses is 24 or more, the hypothesis that p is less than or equal to 
p0 = 50% is rejected with a target error rate of 10% and an actual error rate of 10%. If 
the number of responses is 23 or less, the hypothesis that p is greater than or equal to 
p1 = 70% is rejected with a target error rate of 10% and an actual error rate of 9.4%. 
The design was estimated using the procedure for single-stage phase II trials of NCSS 
Trial and PASS 2002. 
Table 10-1 
Design features for exact binomial single-stage design 
p0 
p1 
Targeted 
Cut-Off 
R + 1 
N 
Actual 
α 
β 
α 
β 
50% 
70% 
10% 
10% 
24 
39 
10% 
9.4% 
p0 is the maximum response proportion of a poor drug. p1 is the minimum response 
proportion of a good drug. N is the sample size. If the number of responses is greater 
or equal to R+1, p0 is rejected. If the number of responses is lower or equal to R, p1 is 
rejected. α is the probability of rejecting that p is lower or equal to p0 when this is true. 
β is the probability of rejecting that p is greater or equal to p1 when this is true. 
10.7 
Power for analysis of critical secondary variables 
Not applicable 

Novartis 
Confidential 
Page 55 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
11 
References 
A’Hern RP (2001): Sample size tables for exact single-stage phase II designs. Statist 
Med 20:859 – 866 
Benjamin RS, Rankin C, Fletcher C, et al (2003) Phase III dose-randomized study of 
Imatinib mesylate for GIST:Intergroup S0033 early results. Proc Am Soc Clin Oncol. 
Abstr 3271 
Benjamin RS, Choi H, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, 
Charnsangavej C et al (2007) We should Decist Using RECIST, at Least in GIST. J 
Clin Oncol. 25, 1760-1764 
Bertucci F, et al (2012) Effect of five years of imatinib on cure for patients with 
advanced GIST: Updated survival results from the prospective randomized phase III 
BFR14 trial. J Clin Oncol 30, 2012 (suppl; abstr 10095). 
Blanke CD, Demetri GD, von Mehren M, et al (2008a). Long-term results from a 
randomized Phase II trial of standard- versus higher-dose imatinib mesylate for 
patients with unresectable or metastatic gastrointestinal stromal tumors expressing 
KIT. J Clin Oncol 26, 620-625. 
Blanke CD, Rankin C, Demetri GD, et al (2008b) Phase III randomized, intergroup 
trial assessing imatinib mesylate at two dose levels in patients with unresectable or 
metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: 
S0033. J Clin Oncol 26, 626-632. 
Blay JY, Bonvalot S, Casali P, et al (2005)Consensus meeting for the management 
of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-
21 March 2004, under the auspices of ESMO. Ann Oncol. 16(4):566-78 
Choi H, et al (2007) Correlation of computed tomography and positron emissions 
tomography in patients with metastatic gastrointestinal stromal tumor treated at a 
single institution with imatinib mesylate: Proposal of new computed tomography 
response criteria. J Clin Oncol. 25, 1753-1759. 
Corless CL, Fletcher JA, Heinrich M, et al (2004) Biology of gastrointestinal stromal 
tumors. J Clin Oncol. 22, 3813-3825 
Dai D, Zeldin DC, Blaisdell JA, et al (2001) and arachidonic acid. Pharmacogenetics. 
11:597-607 
Demetri GD, von Mehren M, Blanke CD, et al (2002) Efficacy and safety of Imatinib 
mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 347:472-480  
Demetri, GD, van Oosterom AT, Blackstein M et al (2005) Phase 3, multicenter, 
randomized, double-blind, placebo trial of SU11248 in patients (pts) following failure 
of imatinib for metastatic GIST ASCO GI Symposium ASCO Annual Meeting. Abstr n. 
4000 
Demetri GD, van Oosterom AT, Garrett CR, et al (2006) Efficay and safety of 
sunitinib in patients with advanced gastrointestinal stromal tumor after failure of 
imatinib: a randomized controlled trial.Lancet 368:1329-38 
Dileo P, Bauer S, Van den Abbeele A, et al (2006) Results with AMN107, a novel 
kinase inhibitor, in gastrointestinal stromal tumor (GIST):Preclinical rationale and 

Novartis 
Confidential 
Page 56 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
early results in a patient (Pt) with imatinib (IM)-resistant GIST. 2006 Gastrointestinal 
Cancer Symposium. Abstr n. 53" 
Eubank W & Mankoff D. (2004) Current and future uses of positron emission 
tomography in breast cancer imaging. Semin Nucl Med. 34(3):224-240 
Heinrich MC, Blanke CD, Druker BJ, et al (2002) Inhibition of KIT tyrosine kinase 
activity: a novel molecular approach to the treatment of KIT-positive malignancies. J 
Clin Oncol. 20:1692-1703 
Heinrich MC, Corless CL, Demetri GD, et al (2003a) Kinase mutations and Imatinib 
response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 
21:4342-4349 
Heinrich MC, Corless CL, Duensing A, et al (2003b) PDGFRA activating mutations in 
gastrointestinal stromal tumors. Science. 299:708-710 
Innocenti FA, Grimsley CB, Das SB et al (2002) Haplotype structure of the UDP-
glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetic. 
12:725-733 
Joensuu H (2006)] Sunitinib for imatinib-resistant GIST Lancet 368: 1303-1304 
Lamba JK, L in YS, Thummel K, et al (2002). Common allelic variants of cytochrome 
P4503A4 and their prevalence in different populations. Pharmacogenetics. 12:121-
132 
Le Cesne A, Perol D, Ray-Coquard I, et al (2005) Interruption of imatinib in GIST 
patients with advanced disease: updated results of the perspective French Sarcoma 
Group randomized phase III trial on survival and quality of life.J Clin Oncol, ASCO 
Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 
2005: 9031 
Maki RG, Fletcher JA, Heinrich MC, et al (2005) Results from a continuation trial of 
SU11248 in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumor 
(GIST). ASCO Annual meeting. Abstr n. 9011 
Mehren M, Reichardt P, Casali P, et al (2007) A phase I study of nilotinib alone and 
in combination with imatinib (IM) in patients (pts) with imatinib-resistant 
gastrointestinal stromal tumors (GIST) - Study update Journal of Clinical Oncology, 
2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 
Supplement), 2007: 10023 
Ozer H (ed) (2000)] Update of recommendations for the use of hematopoietic cloning 
stimulating factors. American Society of Clinical Oncology Growth Factor Expert 
Panel. 
Prenen H, Guetens G, de Boeck G et al (2006) Cellular uptake of the tyrosine kinase 
inhibitors imatinib and AMN107 in Gastrointestinal stromal tumor cell lines. 
Pharmacology. 77(1):11-16 
Rankin C, Von Mehren M, Blanke C, et al (2004) Dose effect of Imatinib in patients 
with metastatic GIST – Phase III Sarcoma Group Study S0033. Proc Am Soc Clin 
Oncol. Abstr 9005 

Novartis 
Confidential 
Page 57 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Reichardt P, Casali PG, Blay J-Y, et al (2006) A Phase I study of nilotinib alone and 
in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal 
tumors (GIST) - Study updateAnnals Oncol; 17: suppl 9; abstract 415P 
Rizzo J, Lichtin A, Steven W, et al (2002) Use of epoietin in patients with cancer: 
evidence based clinical practice guidelines of the American Society of Clinical 
Oncology and the American Society of Hematology. J Clin Oncol. 20:4083-4107 
Singer S, Rubin BP, Lux ML, et al (2002) Prognostic value of KIT mutation type, 
mitotic activity, and histologic subtype in gastrointestinal stromal tumors. J Clin 
Oncol. 20:3898-3905 
Stroobants S, Goeminne J, Seegers M, et al (2003) 18FDG-Positron emission 
tomography for the early prediction of response in advanced soft tissue sarcoma 
treated with imatinib mesylate (Glivec©). Eur J Cancer. 39:2012-2020 
Tamborini E, Bonadiman L, Greco A, et al (2004) A new mutation in the KIT ATP 
pocket causes acquired resistance to Imatinib in a gastrointestinal stromal tumor 
patient. Gastroenterology. 127:294-9  
Tosoni A, Nicolardi L, Brandes AA, et al (2004) Current clinical management of 
gastrointestinal stromal tumors. Expert Rev Anticancer Ther. 4:595-605 
Van Oosterom AT, Judson IR, Verweij J, et al (2002) Update of phase I study of 
Imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal 
tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 
38 Suppl 5:S83-S87 
Verweij J, van Oosterom A, Blay JY, et al (2003)] Imatinib mesylate (STI571 Glivec, 
Gleevec) is an active agent for gastrointestinal stromal tumors, but does not yield 
responses in other soft-tissue sarcomas that are unselected for a molecular target: 
results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J 
Cancer. 39:2006-2011 
Verweij J, Casali PG, Zalcberg J, et al (2004) Progression-free survival in 
gastrointestinal stromal tumors with high-dose Imatinib: randomized trial. Lancet. 
364:1127-1134 
Weber WA, Petersen W, Schmidt B. et al (2003) Positron emission tomography in 
non-small cell lung cancer:prediction of response to chemotherapy by quanatative 
assessment of glucose use. J Clin Oncol. 21(14):2651-2657 
Yin OQ, Gallagher N, Tanaka C, et al (2009) Effects of hepatic impairment on the 
pharmacokinetics of nilotinib: an open-label, single-dose, parallel-group study. 
Clinical Therapeutics; 31: 2459-2469. 
Young H, Baum R, Cremerius K, et al (1999) Measurement of clinical and subclinical 
tumor response using [18F]-fluorodeoxyglucose and positron emission tomography: 
review and 1999 EORTC recommendations. Eur J Cancer. 35(13):1733-1782 
Zalcberg JR, Verveij J, Casali PG, et al (2005) Outcome of patients with advanced 
gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg 
after progression on 400 mg. Eur J Cancer. 41(12):1751-7 

Novartis 
Confidential 
Page 58 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Appendix 1: Administrative procedures 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance 
with the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, 
with applicable local regulations (including European Directive 2001/20/EC and US 
Code of Federal Regulations Title 21), and with the ethical principles laid down in the 
Declaration of Helsinki. 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved 
by 
a 
properly 
constituted 
Institutional 
Review 
Board/Independent 
Ethics 
Committee/Research Ethics Board (IRB/IEC/REB) before study start. 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. Prior to study start, the 
investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs/REBs and regulatory 
authorities as required. 
Informed consent 
Eligible patients may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC/REB-approved informed consent, or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative of the patient. Informed consent must be obtained before conducting 
any study-specific procedures (i.e., all of the procedures described in the protocol). In 
cases where the subject’s legally acceptable representative gives consent, the subject 
(e.g., minors, patients with severe dementia), should be informed about the trial to the 
extent compatible with the subject’s understanding and if capable, the subject should 
assent, sign and personally date the written informed consent. The process of 
obtaining informed consent should be documented in the patient source documents. 
In emergency situations when prior consent of the subject is not possible and the 
subject’s legally acceptable representative is not available, enrollment of the subject 
should require measures described in the protocol with documented favorable opinion 
of the IRB/IEC/REB. The subject or the subject’s legally appointed representative 
should be informed about the trial as soon as possible and consent to continue and 
other consent as appropriate should be requested. 
A proposed informed consent form that complies with the ICH GCP guideline and 
regulatory requirements and is considered appropriate for this study is provided as an 
attachment. Any changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of 

Novartis 
Confidential 
Page 59 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
the approved version must be provided to the Novartis monitor after IRB/IEC/REB 
approval. 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol 
amendment that must be approved by Novartis, Health Authorities where required, and 
the IRB/IEC/REB. Only amendments that are required for patient safety may be 
implemented prior to IRB/IEC/REB approval. Notwithstanding the need for approval of 
formal protocol amendments, the investigator is expected to take any immediate action 
required for the safety of any patient included in this study, even if this action represents 
a deviation from the protocol. In such cases, Novartis should be notified of this action 
and the IRB/IEC/REB at the study site should be informed within 10 working days. 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in 
the clinical trial agreement. 
Study drug supply and resupply, storage, and tracking/drug accountability 
Study drugs must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator 
and designated assistants have access. Upon receipt, the study drugs should be 
stored according to the instructions specified on the drug labels. Clinical supplies are 
to be dispensed only in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements 
of each country. They will include storage conditions for the drug, the drug name and 
dose but no information about the patient. 
The investigator must maintain an accurate record of the shipment and dispensing of 
study drug in a drug accountability ledger. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the trial. Patients will be asked to 
return all unused study drug and packaging 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 the Novartis monitor or to the 
Novartis address provided in the investigator folder at each site. 
 
 
 

Novartis 
Confidential 
Page 60 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Post-text supplement 1: ECOG Performance Status Scale 
Criteria for Estimation of Performance Status 
Grade 
Scale 
0 
Fully active, able to carry out all pre-disease performance without restriction. (Karnofsky 
100%) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g. light housework, office work. (Karnofsky 80-90%) 
2 
Ambulatory and capable of all self-care, but unable to carry out work activities. Up and 
about more than 50% of waking hours (Karnofsky 60-70%) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
(Karnofsky 40-50%) 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
(Karnofsky 10-30%) 
5 
Dead (Karnofsky 0%) 
Sources: 
Oken, MM et al, Am J Clin Oncol 5:649-655, 1982 
Karnofsky, DA et al, Cancer 1:634-656, 1948 
 
 
Post-text supplement 2: Medication that may prolong the QT interval  
A list of drugs associated with QT prolongation and/or Torsades de Pointe is 
available online at www.qtdrugs.org. 
 
 

Novartis 
Confidential 
Page 61 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Post-text supplement 3: Response Evaluation Criteria in Solid Tumors 
(RECIST) 
RECIST criteria for evaluation of tumor response 
Eligibility 
Only patients with measurable disease at baseline should be included in the study: 
• Measurable disease - the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
• Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter ≥ 20mm using conventional techniques or ≥ 10mm 
with spiral CT scan (with minimum lesion size no less than double the slice 
thickness). 
• Non-measurable lesions - all other lesions, including small lesions (longest 
diameter  
< 20mm with conventional techniques or < 10mm with spiral CT scan), i.e. bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitis cutis/pulmonis, abdominal masses that are not 
confirmed and followed by imaging techniques, and cystic lesions. 
Methods of tumor measurement 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 14 days before the beginning of the 
treatment. 
• The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
• CT and MRI: CT and MRI are the best currently available and reproducible methods 
to measure target lesions selected for response assessment. Conventional CT and 
MRI should be performed with cuts of 10mm or less in slice thickness contiguously. 
Spiral CT should be performed using a 5-8mm contiguous reconstruction algorithm. 
This applies to tumors of the chest, abdomen and pelvis. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Ultrasound: When the primary endpoint of the study is objective response 
evaluation, ultrasound (US) should not be used to measure tumor lesions. It is, 
however, a possible alternative to clinical measurements of superficial palpable 
lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful 

Novartis 
Confidential 
Page 62 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
to confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses 
in this specific context require sophisticated equipment and a high level of expertise 
that may only be available in some centers. Therefore, the utilization of such 
techniques for objective tumor response should be restricted to validation purposes 
in specialized centers. However, such techniques can be useful in confirming 
complete pathological response when biopsies are obtained. 
• Cytology and histology: Cytology and histology can be used to differentiate 
between PR and CR in rare cases (i.e. after treatment to differentiate between 
residual benign lesions and residual malignant lesions in tumor types such as germ 
cell tumors). Cytologic confirmation of neoplastic nature of any effusion that 
appears or worsens during treatment is required when the measurable tumor has 
met the criteria for response or stable disease. Under such circumstances, the 
cytologic examination of the fluid collected will permit differentiation between 
response or stable disease (an effusion may be a side effect of the treatment) or 
progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when 
they are superficial (i.e. skin nodules and palpable lymph nodes). For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are 
classified at baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions up to a maximum of five lesions per organ 
and 10 lesions in total, representative of all involved organs should be identified as 
target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest diameter for all target lesions will be calculated and 
reported as the baseline sum of the longest diameter. The baseline sum of the 
longest diameter will be used as reference by which to characterize the objective 
tumor response. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions 
not fulfilling the criteria for target lesions at baseline. Measurements of these lesions 
are not required, but the presence or absence or worsening of each should be noted 
throughout the study. 
Evaluation of target and non-target lesions 
To assess tumor response, the sum of the longest diameter for all target lesions will 
be calculated (at baseline and throughout the study). At each assessment response is 
evaluated first separately for target (Table 11-1) and non-target lesions (Table 11-2). 

Novartis 
Confidential 
Page 63 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
These evaluations are then used to calculate the overall lesion response considering 
both, the target and non-target lesions together (Table 11-3). 
Table 11-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response 
(CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum longest diameter. 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of the longest diameter of target 
lesions, taking as reference the smallest sum of longest diameter 
recorded since the treatment started or the appearance of one or more 
new lesions. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of the longest 
diameter since the treatment started. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a less sensitive 
method than baseline. 
 
 
 

Novartis 
Confidential 
Page 64 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
 
Table 11-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response 
(CR): 
Disappearance of all non-target lesions 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) 
Progressive Disease 
(PD): 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.1 
Unknown (UNK) 
Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a less 
sensitive method than baseline. 
Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician does prevail and the progression status should be confirmed later 
on by the review panel (or study chair). 
The response for non-target lesions is CR only if all non-target lesions which were 
evaluated at baseline are now all absent. If any of the non-target lesions is still present, 
the response can only be ‘Incomplete response/Stable disease’ unless any of the 
lesions was not assessed (in which case response is UNK) or worsened (in which case 
response is PD). 
Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the 
target lesion response, non-target lesion response and presence of new lesions as 
shown below in Table 11-3. 
Table 11-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion 
response 
CR 
CR 
No 
CR1 
CR 
Incomplete response/SD 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1 This overall lesion response also applies when there are no non-target lesions at baseline 
2 Once confirmed PR was achieved, all these assessments are considered PR. 
 

Novartis 
Confidential 
Page 65 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
If the evaluation of any of the target or non-target lesions identified at baseline could 
not be made during follow-up, the overall status must be ‘unknown’ unless progression 
was seen. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the CR. 
Best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). In general, the patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
The best overall response for each patient is determined from the sequence of overall 
(lesion) responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression. 
• PR = at least two determinations of PR or better at least 4 weeks apart before 
progression (and not qualifying for a CR). 
• SD = at least one SD assessment > 6 weeks after start of treatment (and not 
qualifying for CR or PR). 
• PD = progression or death due to underlying cancer ≤ 12 weeks after start of 
treatment (and not qualifying for CR, PR or SD). Patients with symptoms of rapidly 
progressing disease without radiologic evidence will be classified as progression 
only when clear evidence of clinical deterioration is available and patient 
discontinued due to ‘Disease progression’. 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD 
after more than 6 weeks or early progression within the first 12 weeks) 
Overall lesion responses of CR must stay the same until progression sets in, with the 
exception of a UNK status. A patient who had a CR cannot subsequently have a lower 
status, e.g. PR or SD, as this would imply that one or more lesions reappeared, in 
which case the status would become a PD. 
Overall lesion responses of PR must stay the same or improve over time until 
progression sets in, with the exception of a UNK status. However, if a patient has a PR 
(≥ 30% reduction of tumor burden compared to baseline) at one assessment, followed 
by a < 30% reduction from baseline at the next assessment (but not > 20% increase 
from previous smallest sum), the objective status at that assessment should be SD. 
Once a confirmed PR was seen, the overall lesion response should be considered PR 
(or UNK) until progression is documented. 

Novartis 
Confidential 
Page 66 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
If the patient progressed but continues study medication, further assessments are not 
considered for the determination of best overall response. 
The best overall response for each patient will be determined based on investigator 
assessments (‘Investigator best overall lesion response’). 
 
 

Novartis 
Confidential 
Page 67 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
Post-text supplement 4: Substrates of cytochrom P450 isoenzym  
Patients should be instructed not to take grapefruit, St John’s Wort or Seville (sour) 
orange juice while receiving study treatment throughout the study due to potential 
CYP3A4 induction or inhibition. 
A list of drugs that are inducers and inhibitors of CYP3A4 is provided at https://drug-
interactions.medicine.iu.edu. 
 
Table 11-4 
Medications that can induce CYP3A4 
Category  
Drug Names 
Strong inducers 
of CYP3A41 
 
avasimibe, 
carbamazepine, 
enzalutamide, 
lumacaftor, phenobarbital, phenytoin, rifabutin, 
rifampicin, mitotane, St. John’s wort (Hypericum 
perforatum)4 
 
Moderate 
inducers of 
CYP3A42 
bosentan, 
dabrafenib, 
efavirenz, 
etravirine, 
genistein5, 
lersivirine 
, 
lopinavir, 
modafinil, 
nafcillin,semagacestat, 
talviraline, 
telotristat, 
thioridazine, tipranavir/ritonavir 
 
Weak inducers 
of CYP3A43 
 
amprenavir, aprepitant, armodafinil, artesunate/ 
mefloquine, bexarotene, boceprevir, brivacetam, 
clobazam, 
danshen 
(Salvia 
miltiorrhiza)4, 
dexamethasone, 
echinacea 
(Echinacea 
purpurea)1, 
elvitegravir-cobicistat-emtricitabine-
tenofovir 
(Stribild), 
eslicarbazepine, 
ginkgo 
(Ginkgo 
biloba)4, 
ginseng4, 
glycyrrhizin5, 
isavuconazole, lesinurad, methylprednisolone, 
nevirapine, 
ombitasvir/ 
paritaprevir/ 
dasabuvir/ritonavir (Viekira Pak), oritavancin, 
oxcarbazepine, 
pioglitazone, 
pleconaril, 
prednisone, pretomanib, primidone, quercetin5, 
raltegravir, 
ritonavir, 
rufinamide, 
sarilumab, 
sirukumab, sorafenib, sulfinpyrazone, telaprevir, 
terbinafine, ticagrelor, ticlopidine, topiramate, 
troglitazone, 
vemurafenib, 
vicriviroc/ritonavir, 
vinblastine, yin zhi huang4 
 
1 A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive 
substrate for that CYP by equal or more than 80%. 
2 A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a 
substrate for that CYP by 50-80%. 
3 A weak inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate 
for that CYP by 20-50%. 
4 Herbal product 
5 Food product 
 

Novartis 
Confidential 
Page 68 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
This list was based on information from the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, from the Indiana University School of Medicine’s “Clinically 
Relevant” Table, from the University of Washington’s Drug Interaction Database. This 
list may not be comprehensive and may be updated periodically. Refer to Novartis 
Oncology Clinical Pharmacology Internal Memorandum, Drug-drug interactions (DDI) 
Database (last updated January 2018) for update or more details. 
 
Table 11-5 
Medications that can inhibit CYP3A4 
Category  
Drug Names 
Strong inhibitors 
of CYP3A41 
 
atazanavir/ritonavir7, 
boceprevir, 
cobicistat, 
conivaptan, clarithromycin, danoprevir/ritonavir7, 
darunavir/ 
ritonavir7, 
elvitegravir/ritonavir7, 
grapefruit juice6, idelalisib, indinavir, indinavir/ 
ritonavir7, itraconazole, ketoconazole, lopinavir 
/ritonavir7, 
mibefradil, 
nefazodone, 
nelfinavir, 
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira 
Pak)7, 
posaconazole, 
ritonavir, 
saquinavir/ 
ritonavir7, saquinavir, telaprevir, telithromycin, 
tipranavir/ritonavir7, troleandomycin, voriconazol 
Moderate 
inhibitors of 
CYP3A42 
aprepitant, amprenavir, asafoetida resin (Ferula 
asafoetida)4, atazanavir, cimetidine, casopitant, 
ciprofloxacin, crizotinib, cyclosporine, darunavir, 
diltiazem, dronedarone, erythromycin, faldaprevir, 
fluconazole, 
grapefruit 
juice6, 
imatinib, 
isavuconazole, netupitant, nilotinib, Schisandra 
sphenanthera (nan wu wei zi)4, tofisopam, 
verapamil 
Weak inhibitors 
of CYP3A43 
 
almorexant, alprazolam, amiodarone, amlodipine, 
atorvastatin, 
azithromycin, 
berberine4, bicalu-
tamide, blueberry juice8, brodalumab, chlorzo-
xazone, cilostazol, clotrimazole, cranberry juice8, 
daclatasvir, delavirdine, evacetrapib, everolimus, 
flibanserin, 
fluvoxamine, 
fosaprepitant 
(IV), 
fostamatinib, garden cress seeds (Lepidium 
sativum)5, ginkgo (Ginkgo biloba)4, goldenseal 
(Hydrastis canadensis)4, grazoprevir, guan mai 
ning4, isoniazid, ivacaftor, lacidipine, linagliptin, 
lomitapide, obeticholic acid, oral contraceptives, 
palbociclib, pazopanib, peppermint oil5, piperine5, 
pomelo (Citrus grandis)5, propiverine, ranitidine, 
ranolazine, resveratrol4, roxithromycin, Seville 
orange juice5, simeprevir, sitaxentan, suvorexant, 
tabimorelin, tacrolimus, teriflunomide, ticagrelor, 
tolvaptan, tong xin luo4 
1 A strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by equal or more than 5-fold. 
2 A moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold. 
3 A weak inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 2-foldbut equal to or more than 1.25-fold. 

Novartis 
Confidential 
Page 69 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
4 Herbal product 
5 Food product 
6 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation 
was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
7 Combination ritonavir-boosted regimens are listed here in the DDI memo as strong CYP3A inhibitors 
(to avoid potential confusion), even though some are considered moderate CYP3A inhibitors in the 
UW DDI Database. 
8 The effect of certain fruit juices varies widely among brands and is concentration-, dose-, and 
preparation dependent. 
This list is based on information from the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, from the Indiana University School of Medicine’s “Clinically 
Relevant” Table and from the University of Washington’s Drug Interaction Database. 
Please note that this is not an exhaustive list. Please refer to footnotes. Refer to 
Novartis Oncology Clinical Pharmacology Internal Memorandum, Drug-drug 
interactions (DDI) Database (last updated January 2018) for update or more details. 
 
Table 11-6 
CYP3A4 substrates: Narrow therapeutic index, sensitive, and others 
Category  
Drug Names 
Narrow 
Therapeutic 
index substrates 
of CYP3A41 
alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, 
ergotamine, 
fentanyl, 
pimozide, 
quinidine, 
sirolimus, 
tacrolimus, 
terfanadine, thioridazine 
Sensitive 
substrates of 
CYP3A42 
alfentanil, alpha-dihydroergocryptine, almorexant, 
alisoporivir, aplaviroc, aprepitant, atazanavir, 
atorvastatin, 
avanafil, 
bosutinib, 
brecanavir, 
brotizolam, budesonide, buspirone, capravirine, 
casopitant, cobimetinib, conivaptan, danoprevir, 
darifenacin, darunavir, dasatinib, dronedarone, 
ebastine, eletriptan, elvitegravir, eplerenone, 
everolimus, felodipine, fluticasone, grazoprevir, 
ibrutinib, indinavir, isavuconazole, ivabradine, 
ivacaftor, 
levomethadyl 
(LAAM), 
lomitapide, 
lopinavir, lovastatin, lumefantrine, lurasidone, 
maraviroc, midazolam, midostaurin, naloxegol, 
neratinib, nisoldipine, paritaprevir, perospirone, 
quetiapine, ridaforolimus, saquinavir, sildenafil, 
simeprevir, simvastatin, tacrolimus, terfenadine, 
ticagrelor, tilidine, tipranavir, tolvaptan, triazolam, 
ulipristal, 
vardenafil, 
venetoclax, 
vicriviroc, 
voclosporin 
Other 
Substrates of 
CYP3A43 
alprazolam, ambrisentan, amlodipine, antipyrine, 
aripiprazole, artemether, avosentan, boceprevir, 
bosentan, buprenorphine, Cannabis sativa4, 
carbamazepine, dexloxiglumide, dextromethor-
phan, 
diazepam, 
docetaxel, 
enzalutamide, 

Novartis 
Confidential 
Page 70 
Amended Protocol Version 06 (clean version) 
 
Study No. CAMN107DDE06 
 
gemigliptin, 
halofantrine, 
imipramine, 
lansoprazole, lidocaine, linagliptin, loperamide, 
loratadine, losartan, lurasidone, macitentan, 
methadone, mirodenafil, montelukast, morphine, 
nelfinavir, 
netupitant, 
nevirapine, 
nifedipine, 
nilotinib, nitrendipine, omeprazole, ospemifene, 
oxycodone, paclitaxel, pazopanib, pioglitazone, 
quinine, 
ranolazine, 
repaglinide, 
rifabutin, 
ritonavir, 
roflumilast, 
saxagliptin, 
selegiline, 
sertraline, sibutramine, sotrastaurin, telaprevir, 
theophylline, 
tirilazad, 
tolterodine, 
udenafil, 
vincristine, voriconazole 
1 Narrow therapeutic index substrates are drugs whose exposure-response relationship indicates that 
increases in their exposure levels by the concomitant use of an inhibitor may lead to serious safety 
concerns or drugs which have <2-fold difference in the minimum toxic concentrations and minimum 
effective concentrations in the blood (thus safe and effective use requires careful dosage titration and 
patient monitoring). 
2 Sensitive substrates are drugs that demonstrate an increase in AUC of ≥5-fold with strong index 
inhibitors of a given metabolic pathway in clinical DDI studies. 
3 Other substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold with strong index 
inhibitors of a given metabolic pathway in clinical DDI studies. 
4 Tetrahydrocannabinol (∆9THC) and cannabidiol (CBD) are major constituents. ∆9THC is primarily 
metabolized by CYP2C9 to an active metabolite 11-hydroxy-∆9-THC (11-OH-THC). CBD is 
extensively metabolized by CYP2C19 and CYP3A4 to eight monohydroxylated metabolites. The 
effects of multiple daily doses of rifampicin 600 mg for 10 days, ketoconazole 400 mg for 6 days and 
omeprazole 40 mg for 6 days on the PK of ∆9THC, 11-OH-THC and CBD after a single dose (4 
sprays) of an oromucosal spray were determined in a randomized, crossover, parallel study in three 
groups of 12 male subjects. Ketoconazole increased the Cmax and AUC0-24 of ∆9THC by 1.2- and 
1.8-fold, respectively, increased the Cmax and AUC0-24 of 11-OH-THC by 3.0- and 2.6-fold, 
respectively, and increased the Cmax and AUC0-24 of CBD by 2- and 2-fold, respectively. Rifampicin 
decreased the Cmax and AUC24 of ∆9THC by 40 and 20%, respectively, decreased the Cmax and 
AUC0-24 of 11-OH-THC by 85 and 87%, respectively, and decreased the Cmax and AUC24 of CBD 
by 50 and 60%, respectively. There were no effects of omeprazole on the plasma concentrations of 
all three cannabis constituents. 
 
This list of CYP substrates was compiled from the Indiana University School of 
Medicine’s “Clinically Relevant” Table; from the FDA’s “Guidance for Industry, Drug 
Interaction Studies” and from the University of Washington’s Drug Interaction Database. 
This list may not be comprehensive and may be updated periodically. Refer to Novartis 
Oncology Clinical Pharmacology Internal Memorandum, Drug-drug interactions (DDI) 
Database (last updated January 2018) for update or more details.