Conditions: Thyroid Cancer
Keywords: Thyroid Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the effectiveness of two anticancer drugs, everolimus and pasireotide, in patients with thyroid cancer when the cancer is no longer responding to treatment with radioiodine or where it is deemed unsafe for the patient to receive additional radioiodine treatment. The investigators also want to establish the best manner of taking the two medications when used together to treat thyroid cancer. In particular, the investigators want to know if it is better to give both at the same time or add a second medication after the first one has stopped working.

This study will also look at specific substances called biomarkers in your blood, and in the tumor tissue which are involved in the growth of tumor cells, and determine if the levels of these biomarkers are related to your response to treatment or development of side effects.

Everolimus, also known by the brand name, Afinitor, is a biologic drug approved by the Food and Drug Administration (FDA) for the treatment of kidney cancer. It works by preventing cancer cells from multiplying and it also makes them more likely to die from the treatment.

Pasireotide also known by the name, SOM230 is a new medication that is not yet approved by the FDA for the treatment of cancer. It is a newer form of a drug called octreotide, which is approved for the treatment of cancer arising from endocrine organs. Pasireotide works by binding to a protein called somatostatin receptor, which is expressed in many tissues throughout the body including thyroid cancer cells. Pasireotide prevents the action of somatostatin by binding to these receptors.

Detailed description:

Arms:
arm 1: CURRENTLY CLOSED TO ACCRUAL--Everolimus alone followed by Everolimus + Pasireotide at the time of progression arm 2: CURRENTLY CLOSED TO ACCRUAL--Pasireotide alone followed by Everolimus + Pasireotide at the time of progression arm 3: CURRENTLY CLOSED TO ACCRUAL

Interventions: intervention 1: Everolimus intervention 2: Pasireotide intervention 3: Everolimus and Pasireotide
Intervention descriptions: intervention 1: Everolimus 10 mg daily continuously (switch to 2-drug combination at progression if no intolerable toxicity) intervention 2: Pasireotide 1200 mcg bid for 4 weeks followed by Pasireotide long acting release (LAR) 60 mg i.m. once every 4 weeks intervention 3: Everolimus 10 mg daily continuously together with Pasireotide 1200 mcg bid for 4 weeks followed by Pasireotide long acting release (LAR) 60 mg i.m. once every 4 weeks

Protocol document:
Prot_SAP_000.pdf: 
 
(WCI-1777; Version No. 06/ Date 03-08-2014) 
 
Protocol No. CSOM230CUS18T 
 
 
 
 
 
Pasireotide (SOM230C) and Everolimus (RAD001) 
Clinical Trial Protocol CSOM230CUS18T 
A 3-Arm Randomized Phase II Trial Evaluating Single Agent and 
Combined Efficacy of Pasireotide and Everolimus in Adult 
Patients with Radioiodine-Refractory Differentiated and 
Medullary Thyroid Cancer 
  


 
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List of changes to protocol version 6, dated 03-09-2014 
Pages 6-8: Update list of investigators and participating sites 
Page 21: Delete “Table and Figures Error”  
Page 36: Clarify and update the follow-up schedule for study subjects 
Page 37: Update criteria for iodine refractory thyroid cancer 
Page 43: Clarify acceptable interval between screening and initiation of treatment 
Page 45: Delete “Table and Figures error”  
Page 47: Correct wrong references in Table 6-3 as follows:  
- 
Grade 3 pneumonitis  reference to Table 3-2 changed to Table 6-5;  
- 
Grade 2 and 3 Mucositis reference to section  4.4.4 changed to section on 
“Management of stomatitis/oral Mucositis/mouth ulcers ” 
- 
Grade 3  Hyperlipidemia  reference to section 4.4.5 for management changed to 
section on “Management Guidelines for Hyperlipidemia and Hyperglycemia” 
- 
Grade 3 Hyperglycemia section 4.4.6 changed to section; “Management 
Guidelines for Hyperlipidemia and Hyperglycemia” 
Page 54: Changed reference to Table 3-7 to Table 6-8 for management guidelines for Hep C.  
Page 54: Change CTCAE v 3.0 v 4.0 in the footnote to Table 6-8 
Page 55: Clarify recommendations for Blood Glucose monitoring  
Page 65: Specify the +/- 2 day window allowed for scheduled assessments 
Page 66: Added title header to table of Schedule of Events 
Page 68: Correct footnote reference to Hepatitis Screening section” on page 62 and change 
reference to table 3-3 and 3-4 to 6-7 and 6-8. 
Page 79: Update contact information for study regulatory specialists 
Page 81: Section 7.5.7 – Electrocardiogram; clarify the schedule of EKG testing to match 
Table 7-1 and footnote.  
Page 83: Section 8.1: clarified that adverse event reporting schedule should follow IRB 
guidance 
Page 99: APPENDIX B  - clarify that samples are to be collected through end of cycle 6 only 
Page 99: Added detailed sampled preparation for PBMC and serum  


 
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Protocol No. CSOM230CUS18T 
 
List of changes to protocol version 5 dated 10-29-2012 (page 
number according to the tracked version): 
Pages 3 -6: Update to study staff and participating sites 
Page 35: Update patient assignment schema to include Arms A1 and B1 designation for 
patients who progressed and started 2-drug combination 
Page 38: Update the QTcF requirement from 450ms to 470ms for exclusion #11 according to 
the guidance letter from Novartis study team dated September 13, 2012. 
Patient 42: Add arms A1 and B1 as designation for patients switching from single agent 
therapy to 2-drug combination at the time of progression. 
Page 43, section 6-4: corrected time frame within which to initiate treatment following 
registration and screening 
 
Page 43, section 6-5: include further clarification for Arms A1 and B1 designation for patients 
who switch to 2-drug therapy following progression on single agent therapy. 
 
Page 53, last paragraph: Additional information on hyperglycemia management guidelines 
included. 
 
Page 60; section 6-9: update the criteria for subject withdrawal due to treatment delay 
resulting from treatment-emergent toxicity 
 
Page 62-64: update the treatment schedule table 
 
Page 74, section 7.5.1.4: Update the contact information for AE reporting to the coordinating 
center at the Winship Cancer Institute 
 
Page 75; section 7.5.4: Update details and frequency of SOC and research related blood tests 
 
Page 7.7, section 7.7.1: clarify that PBMC collection is optional


 
(WCI-1777; Version No. 6/ Date 03-08-2014) 
 
Protocol No. CSOM230CUS18T 
 
 
List of changes to protocol version 4 dated 01-05-2012: 
Pages 3 -5: Update to study staff and participating sites 
Page 35: Update inclusion criteria #10 regarding modified LFT criteria 
Pages 36 & 37: update exclusion criteria 9 and 13 
Pages 53-54: Include details of the SOM230 Management Guidelines for Suspected Hepatic 
Toxicity 
Pages 60-62: Update study schema to incorporate additional required LFT tests on C1D22 and 
C2D22 
Pages 71 & 72: Update Novartis contact Fax number for SAE reporting 


 
(WCI-1777; Version No. 6/ Date 03-08-2014) 
 
Protocol No. CSOM230CUS18T 
 
 
 
Authors: 
Taofeek K. Owonikoko, MD, PhD 
Version number: 
6.0 (modified protocol) 
Original Version Release date: 
March 15, 2010 
Current Version Release Date 
March 08, 2014 
 
Principal Investigator 
Taofeek K. Owonikoko, MD, PhD 
Associate Professor 
Department of Hematology & Medical 
Oncology 
Emory University 
Atlanta, GA 30322 
Tel: 404-778-5575; 
Fax: 404-778-5230 
e-mail: towonik@emory.edu 
Co-investigators 
Amy Chen, MD 
Head and Neck Surgery 
Emory University 
Rathi Pillai, MD 
Hematology & Medical Oncology 
Emory University 
Fadlo Khuri, MD 
Hematology & Medical Oncology 
Emory University  
Dong M. Shin, MD 
Hematology & Medical Oncology 
Emory University  
Nabil Saba, MD 
Hematology & Medical Oncology 
Emory University 
Suresh Ramalingam, MD 
Hematology & Medical Oncology 
Emory University 
Emory University 
Shi-Yong Sun, PhD 


 
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Protocol No. CSOM230CUS18T 
 
Hematology & Medical Oncology 
Emory University  
Deborah Baumgarten, MD 
Department of Radiology 
Emory University 
Zhengjia Nelson Chen, PhD 
Study Statistician, Biostatistics Core 
Winship Cancer Institute 
 
 Gerard M. McGorisk 
Cardiology Division 
Emory University  
Research Coordinator 
Jacene Myrie 
Jacene R. Myrie, CCRC 
1365 Clifton Road NE, Suite C3012 
Atlanta, GA 30322 
Phone: 404-778-4383 
Fax:       404-778-4389 
PIC#: 64576 
Email:   jacene.myrie@emory.edu 
Regulatory Contact 
Emory: 
Vanessa H. Phelan, BS 
1256 Briarcliff Road,Bldg. A, 421W-A 
Atlanta, GA 30306 
Ph. 404.778.2918 | Fax. 404.778.4004 
Email: vanessa.h.phelan@emory.edu  
Collaborating Sites: 
NIKKI (Michelle) Brumbelow, MS, 
CCRC 
Multi- Site Coordinator 
1365 Clifton Road NE, Suite C3012 
Atlanta, GA 30322 


 
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Protocol No. CSOM230CUS18T 
 
Tel: 404.778.5747 | Fax: 404.778.0417 
Michelle.N.Brumbelow@emory.edu 
 
 
Participating Institutions 
 
Local Principal Investigator 
Emory University  
(Lead Institution and Coordinating Center) 
Winship Cancer Institute 
Atlanta, GA  
Taofeek K. Owonikoko, MD, PhD 
University of Pittsburgh Cancer Institute 
Pittsburgh, PA 
Julie Bauman, MD 
baumanje@upmc.edu 


 
(WCI-1777; Version No. 6/ Date 03-08-2014) 
 
Protocol No. CSOM230CUS18T 
 
 
Table of Contents 
 
1 
Introduction ..................................................................................................................... 12 
1.1 
Overview of thyroid cancer ................................................................................. 12 
1.2 
Somatostatin analogs in the treatment of patients with thyroid cancer ......... 14 
1.3 
Pasireotide (SOM230) ......................................................................................... 15 
1.4 
RAD001 (everolimus) .......................................................................................... 23 
2 
Study rationale/purpose .................................................................................................. 29 
2.1 
Selection of doses .................................................................................................. 32 
3 
Objectives ......................................................................................................................... 33 
3.1 
Primary objectives ............................................................................................... 33 
3.2 
Secondary objectives ........................................................................................... 33 
3.3 
Exploratory objectives ......................................................................................... 33 
4 
Study design ..................................................................................................................... 33 
4.1 
Treatment ............................................................................................................. 35 
4.2 
Follow-up .............................................................................................................. 35 
5 
Population ........................................................................................................................ 36 
5.1 
Inclusion criteria .................................................................................................. 37 
5.2 
Exclusion criteria ................................................................................................. 38 
6 
Treatment ......................................................................................................................... 40 
6.1 
Investigational and control drugs....................................................................... 40 
6.2 
Study drugs........................................................................................................... 40 
6.3 
Treatment arms ................................................................................................... 42 
6.4 
Patient Registration and Numbering ................................................................. 42 
6.5 
Treatment assignment ......................................................................................... 43 
6.6 
Treatment blinding .............................................................................................. 44 
6.7 
Treating the patient ............................................................................................. 44 
6.8 
Other concomitant medications.......................................................................... 59 
6.9 
Study drug discontinuation ................................................................................. 62 
7 
Visit schedule and assessments ....................................................................................... 63 
7.1 
Information to be collected on screening failures ............................................. 67 
7.2 
Patient demographics/other baseline characteristics ....................................... 67 
7.3 
Treatments ............................................................................................................ 67 


 
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Protocol No. CSOM230CUS18T 
 
7.4 
Efficacy ................................................................................................................. 67 
7.5 
Safety ..................................................................................................................... 73 
7.6 
Pharmacokinetics ................................................................................................. 79 
7.7 
Exploratory biomarker assessments .................................................................. 79 
8 
Data Review and Data Management ............................................................................. 80 
8.1 Data Monitoring Committee .......................................................................................... 80 
9 
Statistical methods and data analysis ............................................................................ 83 
9.1 
Objective RR and PFS as endpoints .................................................................. 83 
9.2 
CBR as endpoints ................................................................................................. 84 
9.3 
Other Endpoints: ................................................................................................. 84 
9.4 
Correlative Study Analyses: ............................................................................... 85 
10 Protocol amendments, or changes in study conduct .................................................... 85 
10.1 
Declaration of Helsinki .......................................................................................... 85 
10.2 
Ethics and Good Clinical Practice ......................................................................... 85 
10.3 
Protocol Modification ............................................................................................ 85 
11 Regulatory Considerations ............................................................................................. 86 
11.1 
Institutional Review Board/Ethics Committee approval ....................................... 86 
11.2 
Informed consent ................................................................................................... 87 
11.3 
Subject confidentiality ........................................................................................... 87 
11.4 
Disclosure and confidentiality ............................................................................... 88 
11.5 
Study records requirements ................................................................................... 88 
11.6 
Publication of results ............................................................................................. 88 
11.7 
Premature discontinuation of study ....................................................................... 88 
12 References ........................................................................................................................ 90 
13 APPENDICES .................................................................................................................. 95 
13.1 
APPENDIX A- Performance Status Criteria .................................................... 95 
13.2 
APPENDIX B – Blood sample collection and processing ................................ 96 
13.3 
APPENDIX C - Medication Diary ..................................................................... 97 
13.4 Attached Supplement – Emory Winship DSMP Policy ............................................ 99 
 
List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 


 
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b.i.d. 
bis in diem/twice a day 
CRF 
Case Report/Record Form 
CS&E 
Clinical Safety and Epidemiology 
CRD 
Clinical Research and Development 
CRO 
Contract Research Organization 
CT 
Computer Tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DM 
Diabetes Mellitus 
ECG 
Electrocardiogram 
HBcAb 
hepatitis B core antibodies 
HBs Ab 
hepatitis B surface antibodies 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hsst 
Human somatostatin receptor 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
ITT 
Intent to Treat 
i.v. 
intravenous(ly) 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
LAR 
Long Acting Release 
LFTs 
liver function tests 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum tolerated dose 
o.d. 
omnia die/once a day 
PCR 
Polymerase Chain Reaction  
PK/PD 
Pharmacokinetic/Pharmacodynamic 
p.o. 
per os/by mouth/orally 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
q.d. 
Once a day 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous 
SOP 
Standard Operating Procedure 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit Normal 
US 
Ultrasound 


 
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Protocol No. CSOM230CUS18T 
 
 
List of tables 
Table 1-1 
Binding profile for octreotide and pasireotide at hsst1-5 (IC50, M) ...... 16 
Table 1-2 
Pasireotide s.c.: Number (%) of patients with most frequent AEs 
(greater than or equal to 8% for any dose group) regardless of 
relationship to study drug [CSOM230B2202] ...................................... 19 
Table 1-3 
Mean (SD) pharmacokinetic parameters of pasireotide in carcinoid 
patients (N=26) following s.c. b.i.d. doses of pasireotide 
[CSOM230B2202] ................................................................................ 20 
Table 1-4 
Pasireotide LAR: Number (%) of patients with most frequent AEs 
(> 5% for any dose group) regardless of relationship to study drug 
(preliminary data from study SOM230C2110) ..................................... 22 
Table 1-5 
Median (Mean plus or minus SD) trough plasma concentrations of 
pasireotide on days 28, 56 and 84 in carcinoid patients following 
three monthly i.m. injections of 20 mg (N=5), 40 mg (N=7) or 60 
mg (N=8) pasireotide LAR [CSOM230C2110] .................................... 23 
Table 6-3  
Criteria for dose-modification in case of suspected SOM230 and 
RAD001 toxicity for non-hematologic toxicity .................................... 46 
Table 6-4 
Criteria for dose-modification in case of suspected SOM230 and 
RAD001 for hematologic toxicity ......................................................... 47 
Table 6-7  
Guidelines for management of hepatitis B ............................................ 51 
Table 6-8  
Guidelines for management of hepatitis C ............................................ 52 
 
 


 
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Protocol No. CSOM230CUS18T 
 
 
1 
Introduction 
1.1 
Overview of thyroid cancer  
 
Thyroid cancer is the most common endocrine cancer worldwide representing approximately 
1% of all cancers and responsible for 0.5% of all cancer related deaths. The worldwide 
incidence of thyroid cancers has however, increased significantly in the last 2 decades with a 
near doubling of the incidence rate.1-5 A review of the US population cancer surveillance 
database showed that the incidence of thyroid cancer increased from 3.6 per 100,000 in 1973 
to 8.7 per 100,000 in 2002.5 This increase cuts across racial groups with a 150% in the US 
Caucasian population and a 73% increase in African Americans.6 Approximately 40,000 new 
cases of thyroid cancers were diagnosed in the US in 2008. Whereas a large majority of 
patients with thyroid cancers present with localized disease and therefore achieve disease 
control with surgical resection, there is a substantial rate of disease relapse in up to a third of 
patients. Half of such relapses occur at distant sites with mortality approaching 50% at 5 years 
with currently available systemic treatment options. Radioactive iodine has been the mainstay 
of systemic therapy for metastatic differentiated thyroid cancers.7 However, alternative 
treatment options are warranted due to the limitations imposed by radiation exposure limits, 
and the histologic progression with loss of differentiation and impaired uptake of radioiodine 
which can occur in up to 70% of patients with original diagnosis of papillary thyroid 
carcinoma. The use of biologic agents targeting cellular pathways in thyroid cancer has shown 
some promise. Multi-targeted tyrosine kinase inhibitors such as sorafenib, sunitinib, axitinib 
and motesanib have produced encouraging clinical benefit with objective responses (mainly 
partial responses) observed in approximately 15 - 30% of patients with iodine refractory 
disease. Majority of the patients experienced disease stabilization with a median progression 
free survival ranging between 40 and 80 weeks.8-10  
 
Medullary thyroid Cancer: Vandetanib is a multi-targeted tyrosine kinase inhibitor with 
predominant activity against EGFR and VEGFR kinase enzyme activity. This drug received 
approval from the U. S. Food and Drug Administration for the treatment of symptomatic or 
progressive locally advanced, or metastatic medullary thyroid cancer patients. The drug was 
evaluated in an international, multicenter, double-blind trial that randomized MTC patients in 
a 2:1 ratio to receive either Vandetanib or placebo. The study met its primary objective of a 
PFS improvement in patients treated with Vandetanib (HR=0.35; 95% CI: 0.24, 0.53; 
p<0.0001). At the primary PFS analysis, 15% of the patients had died and no significant OS 
difference was noted. The overall response rate was 44% versus 1% in favor of patients 
randomized to receive Vandetanib.  
The most common adverse events included diarrhea/colitis, rash, dermatitis acneiform, 
nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain, decreased 


 
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calcium, increased ALT, and decreased glucose. Frequent grade 3-4 adverse reactions were 
diarrhea/colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. 
Adverse reactions resulting in death in patients receiving vandetanib (n=5) were respiratory 
failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, and sepsis. 
In addition, two deaths in patients receiving vandetanib (one sudden death and one death from 
cardiopulmonary arrest) were noted after data cut-off. QT prolongation, torsades de pointes, 
and sudden death are included in a boxed warning. Due to the toxicity profile of this agent, a 
mandatory Risk Evaluation Mitigation Strategy Program and a restricted distribution program 
was required at the time of its approval in April 2011. While this is a great therapeutic 
advancement in this patient population, the adverse event profile of this agent makes it 
unsuitable for a significant number of patients either with slowly progressive disease, limited 
symptoms or preexisting cardiac disorder. More effective and better tolerated agents will be 
needed for this patient group. 
As characteristic of other endocrine tumors, somatostatin receptor expression has been 
demonstrated in various histologic types of thyroid cancer.11-13 While the role of somatostatin 
receptor signaling in regulating hormone secretion has been well established, it is only more 
recently that its important role as an endogenous inhibitor of cellular proliferation and 
activator of apoptosis is becoming recognized. This  antiproliferative effect of somatostatin 
receptor activation has been shown to be both a direct effect as well as off target result of its 
activation of phosphotyrosine phosphatases that subsequently inhibit the activity of non-
somatostatin receptors such as the Insulin-like Growth Factor (IGF) and Epidermal Growth 
Factor (EGF) Receptors, which play key role in cellular proliferation and survival.  Tyrosine 
phosphorylation of endogenous proteins such as ERK and Akt induced by the somatostatin 
isoform, SS-14, was clearly shown to result in inhibition of growth hormone and IGF1 mRNA 
expression.14 In addition, somatostatin receptor activation using octreotide, potently disrupts 
downstream signaling through the phosphatidyl inositol 3 (PI3) kinase and the mitogen 
activated protein kinase (MAPK) pathways.15 Particularly important is the inhibition of PI3 
kinase activity due to the dissociation and dephosphorylation of its p85 subunit following 
somatostatin receptor 2 activation. It is clear from the preceding summary that preclinical 
studies have provided substantial evidence linking somatostatin receptor inhibitory activity on 
cellular proliferation to its modulation of the PI3 kinase/Akt/mTOR pathway. 
Thyroid stimulating hormone is the key driver of proliferation in normal and neoplastic 
thyroid epithelial cells. This effect is mediated  by convergence of signaling on the 
AKT/mTOR pathway.16 Indeed, upstream stimulation of mTOR signaling induced by PTEN 
haploinsufficiency in mice harboring a dominant-negative mutant thyroid hormone receptor 
beta (TRbeta(PV/PV) mice) significantly increased the rate of progression of spontaneously 
formed thyroid tumor and occurrence of lung metastasis leading to reduced survival as 
compared with PTEN haplosufficent TRbeta(PV/PV)Pten(+/+) mice.17 Furthermore, a potent 
and specific inhibitor of the PI3 kinase signaling, LY294002, inhibited downstream mTOR 
signaling and resulted in reduced thyroid tumor growth and metastasis.18 The available 
preclinical evidence demonstrating the important roles of somatostatin receptor and mTOR 
pathway signaling in thyroid cancer development and progression provides a justification and 


 
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Protocol No. CSOM230CUS18T 
 
a strong rationale for a systematic evaluation of agents targeting these pathways in patients 
with thyroid cancer. We therefore propose to evaluate the efficacy of everolimus, pasireotide 
and their combinations in patients with radioiodine refractory thyroid cancers.  
 
1.2 
Somatostatin analogs in the treatment of patients with thyroid cancer 
There is to date no published report of a prospective trial evaluating somatostatin analogue 
therapy in thyroid cancer. There is, however, a limited number of case series and case reports 
showing a variable outcome when patients with radiorefractory or medullary thyroid cancer 
were treated with somatostatin analogue. 
Robbins et al. reported the result in two patients with progressive metastatic papillary thyroid 
cancer no longer responsive to high doses of 131I or showing lack of uptake on 131I 
scintigraphy. Pretreatment 111In-pentetreotide scans confirmed the expression of somatostatin 
receptors by the metastatic deposits. Following approximately 4 months of therapy with long 
acting octreotide (Sandostatin LAR Depot) therapy, significant reduction was observed in 
tumor volume and standard uptake values between baseline and restaging 18F-FDG-PET 
scans.19  
A case series of 8 patients with symptomatic metastatic medullary thyroid carcinoma treated 
with short acting octreotide in combination with recombinant interferon alpha-2b was 
reported by Lupoli et al. Octreotide was given at a single daily dose of 150 micrograms for 6 
months followed by a daily dose of 300 micrograms for an additional 6 months. Interfreon 
was administered at a dose of 5.000.000 IU intramuscularly 3 times a week for 12 months. 
Two patients discontinued therapy due to treatment associated toxicities. Although no 
anatomic response was observed in the tumor deposits, there was symptomatic improvement 
in five patients. Biochemical response was recorded with significant reduction in serum 
calcitonin and carcinoembryonic antigen levels within 3 months of starting treatment.20 
 
Long acting octreotide therapy was also shown to be associated with durable biochemical 
response lasting up to 17 months in three patients with metastatic medullary thyroid 
carcinoma, two of whom had MEN IIa syndrome.  Similar to the case series by Lupoli et al. 
maximal biochemical response was achieved within 3 months with maximal percent decrease 
in mean serum calcitonin of 47, 52 and 81% compared to basal values and 45, 60 and 63% in 
carcinoembryonic antigen (CEA) levels. Response was not durable in the patient with the 
sporadic form of disease and anatomic correlate of the biochemical response was not 
reported.21 
 
Lanreotide is a cyclic octapeptide somatostatin analogue with affinity for type 2 and type 5 
somatostatin receptor subtypes. Vitale et al. combined the long acting form of this agent with 
recombinant interferon alpha-2b in seven patients with medullary thyroid carcinoma. There 


 
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Protocol No. CSOM230CUS18T 
 
was symptomatic improvement in nearly all patients with associated biochemical response 
while 5 out of 7 patients achieved disease stabilization.22  
The use of somatostatin analogue therapy for poorly differentiated follicular or papillary 
thyroid showed poor disease control in part because toxicity limited prolonged treatment. In a 
series of twelve patients with somatostatin receptor expression confirmed by scintigraphy, 
only three patients were able to tolerate long term treatment lasting one year or more. All 
three showed disease progression on FDG PET scan.23  
Overall, experience with somatostatin analogue therapy in thyroid cancer is limited. Available 
published data suggest that this class of drugs have some efficacy in well differentiated 
thyroid cancer but little or no anticancer activity in poorly differentiated or anaplastic tumors. 
1.3 
Pasireotide (SOM230) 
Pasireotide is an injectable somatostatin analogue. It is a novel cyclohexapeptide with the 
following chemical name: (2-Aminoethyl)carbamic acid (2R,5S,8S,11S,14R,17S,19aS)-11-
(4-aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-
hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl 
ester, di[(S)-2-aminosuccinic acid] salt. 
Like natural somatostatin and other somatostatin analogues (SRIFa), pasireotide exerts its 
pharmacological activity via binding to somatostatin receptors (sst). There are five known 
somatostatin receptors: sst 1, 2, 3, 4 and 5. Somatostatin receptors are expressed in different 
tissues under normal physiological conditions. Somatostatin analogues activate these 
receptors with different potencies24 and this activation results in a reduced cellular activity 
and inhibition of hormone secretion. Somatostatin receptors are strongly expressed in many 
solid tumors, especially in neuroendocrine tumors where hormones are excessively secreted 
e.g. acromegaly,25 GEP/NET26 and Cushing’s disease.27 
The somatastatin analogues currently approved for clinical use (octreotide and lanreotide) 
have a high affinity to sst subtype 2 (sst2), with moderate or no affinity to the remaining 
subtypes. Pasireotide is a novel cyclohexapeptide somatostatin analogue that exhibits a unique 
binding profile, binding with high affinity to four of the five known human somatostatin 
receptors. (Table 1-1) Compared to Sandostatin® (octreotide acetate), pasireotide exhibits a 
binding affinity which is 30-40 times higher for human sst1 and sst5, 5 times higher for 
human sst3, and similar to the affinity for sst2 receptors. A detailed summary of available 
preclinical data is provided in the [Investigator’s Brochure]. 


 
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Table 1-1 
Binding profile for octreotide and pasireotide at hsst1-5 (IC50, M) 
Compound 
sst 1 
sst2 
sst3 
sst4 
sst5 
octreotide 
acetate 
(SMS) 
2.8x10-7 
3.8x10-10 
7.1x10-9 
>10-6 
6.3x10-9 
Pasireotide 
(SOM230) 
9.3x10-9 
1.0x10-9 
1.5x10-9 
>10-6 
1.6x10-10 
Ratio of IC50: 
octreotide/ 
pasireotide  
30 
0.4 
5 
-- 
40 
Chemical name 
Chemical 
name: 
(2-Aminoethyl)carbamic 
acid 
(2R,5S,8S,11S,14R,17S,19aS)-11-(4-
aminobutyl)-5-benzyl-8-(4-benzyloxybenzyl)-14-(1H-indol-3-ylmethyl)-4,7,10,13,16,19-
hexaoxo-17-phenyloctadecahydro-3a,6,9,12,15,18-hexaazacyclopentacyclooctadecen-2-yl 
ester, di[(S)-2-aminosuccinic acid] salt 
Chemical structure 
N H
N
O
O
O
N
H
N
H
O
NH
O
O
NH
O
NH
NH
O
O
NH2
N
H2
N
H2
O
O
OH
OH
N
H2
O
O
OH
OH
 
Mechanism of action 
SOM230 is a novel cyclohexapeptide somatostatin analogue that exhibits a unique binding 
profile with high affinity to four of the five known human somatostatin receptors. As 
compared to Sandostatin®, SOM230 exhibits a binding affinity, which is 30-40 times higher 
for human sst1 and sst5, 5 times higher for human sst3, and 2.5 times lower for human sst2. In 
preclinical experiments, SOM230 showed, in comparison to Sandostatin®, a more pronounced 
IGF-1 suppression in four species and a longer biological presence leading to slower 
elimination. 


 
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Protocol No. CSOM230CUS18T 
 
Human experience 
 Pasireotide s.c. 
Pasireotide when given subcutaneously (s.c.) was well-tolerated at doses up to 600 µg b.i.d., 
900 µg b.i.d. and 1200 µg b.i.d by acromegalic, Cushing’s disease and carcinoid tumor 
patients, respectively. For all indications the most frequently reported adverse events were 
gastrointestinal, predominantly diarrhea, nausea and abdominal pain. Generally these events 
were mild, transient and only occasionally caused patients to discontinue treatment. 
Hyperglycemia was also observed for some patients in the different indications. When 
hyperglycemia occurred, it was most common in patients with impaired fasting glucose or 
diabetes mellitus at baseline. However hyperglycemia in these patients was responsive to 
appropriate diabetic management such as adjustments in oral antidiabetic  treatment, or in 
some cases the addition of insulin. Occasionally laboratory abnormalities in liver function 
tests and pancreatic enzymes have been observed at higher doses of pasireotide. These events 
however have been transient. 
Overall the safety profile of pasireotide is comparable to that of currently available 
somatostatin analogues. However as pasireotide has a broader binding profile (binds to 4 of 
the 5 sst),  and thus more closely resembles natural somatostatin, it may impact secretion of 
hormones by the pancreas, pituitary, thyroid, adrenals and the gastrointestinal tract.  Hence 
parameters of glucose metabolism (fasting blood glucose, HbA1C), pituitary function (GH, 
IGF-1, prolactin, ACTH), thyroid function (free T4, TSH) and the adrenals (serum cortisol) 
will be monitored in this study. 
Preliminary safety data are available from a Phase II study [CSOM230B2202] in 45 patients 
with symptomatic metastatic carcinoid disease inadequately controlled by octreotide LAR 
who received pasireotide s.c. doses from 300 µg s.c. b.i.d. up to 1200 µg b.i.d. for a mean of 
20 weeks. Pasireotide s.c. has been found to be generally well-tolerated by these patients, with 
the most common adverse events being mild diarrhea, nausea and abdominal pain. Blood 
glucose increases occurred in some patients, particularly in those with preexisting DM or 
impaired fasting glucose, but were moderate and manageable by adjustment in oral 
hypoglycemic medications in most cases. Weight loss was also observed in 18 patients. 
Maximum weight loss occurred within 4 to 6 months on the study drug, with a stabilization of 
effect after approximately 6 months. There was no apparent relationship between the weight 
loss and pasireotide dose. 
Preliminary efficacy data from this study also supports that pasireotide is active in patients 
refractory/resistant to Sandostatin LAR, as partial or complete symptom control was observed 
in 12 of 44 patients (27%). Complete response was achieved in two patients at the pasireotide 
600 µg s.c. b.i.d. dose and one patient at the 900 µg s.c. b.i.d. dose. Nine patients achieved 
partial response to treatment, three at each of the following doses: 600, 750, and 900 µg s.c. 
b.i.d. 


 
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Protocol No. CSOM230CUS18T 
 
The mean pasireotide plasma concentration versus time profiles are shown in Figure 1-1.  The 
mean PK parameters of Cmin, Cmax and AUC0-6hr for pasireotide are listed in Table 1-2. Since 
there is no biomarker available for clinical response in carcinoid patients and since clinical response was observed with similar frequency at doses of 600 to 900 g s.c. b.i.d., the target 
pasireotide concentration for symptom control was estimated as approximately 10 ng/mL 
from the mean Cmin value at these doses (Table 1-2), assuming that a constant drug level is 
required for pharmacological activity. 
Further details on pasireotide s.c. can be found in the [Pasireotide s.c. Investigator’s 
Brochure]. 


Novartis 
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Protocol No.CSOM230C2303 
 
Table 1-2 
Pasireotide s.c.: Number (%) of patients with most frequent AEs (greater than or equal to 8% for any dose group) regardless 
of relationship to study drug [CSOM230B2202] 
 
Pasireotide sc 
 
 
Adverse event  
(preferred term) 
 
300- 
≤600µg 
(N=45) 
n (CTC≥ grade3) 
 
>600- 
≤900µg 
(N=39) 
n (CTC≥ grade3) 
 
>900- 
≤1200µg 
(N=42) 
 n (CTC≥ grade3) 
 
>1200- 
≤1500µg 
(N=35) 
 n (CTC≥ grade3) 
 
>1500- 
≤1800µg 
(N=31) 
 n (CTC≥ grade3) 
 
>1800- 
≤2400µg 
(N=10) 
 n (CTC≥ grade3) 
 
Any dose  
(N=45) 
n (%) 
 n (CTC≥ grade3) 
Weight decreased 
6  
1  
  5  
1  
5  
1  
19 (42.2) 
Abdominal pain 
6 (2) 
3  
4  
4  
2  
0 
     15 (33.3) (2) 
Nausea 
          6 (1) 
2  
5  
2  
3 (1) 
0 
      13 (28.9) (1) 
Fatigue 
4  
1  
1  
1  
6  
0 
12 (26.7) 
Diarrhea 
1  
1  
 3 (1) 
1  
6 (2) 
0 
      11 (24.4) (3) 
Hyperglycemia 
1  
1  
0 
 2 (2) 
          2 (1) 
1  
     7 (15.6) (3) 
Peripheral edema 
1  
0 
1  
2  
3  
0 
7 (15.6) 
Flatulence 
2  
1  
1  
2  
1  
0 
5 (11.1) 
Diabetes mellitus 
1  
0 
0 
 2 (1) 
0 
1  
      4 (8.9) (1) 
Vertigo 
1  
2  
0 
0 
1  
0 
4 (8.9) 
Dizziness 
2  
1  
0 
1  
0 
0 
4 (8.9) 
Vomiting 
2 (1) 
1  
2  
0 
2 (1) 
0 
      4 (8.9) (1) 
Dysgeusia 
0 
1  
0 
1  
2  
0 
4 (8.9) 
Nasopharyngitis 
0 
1  
1  
1  
1  
0 
4 (8.9) 
Dyspnea 
1  
1  
2 (1) 
0 
1  
0 
      4 (8.9) (1) 
Hypokalemia 
1  
1  
1  
0 
0 
1  
4 (8.9) 
Arthralgia 
0 
0 
2  
0 
2  
0 
 4 (8.9) 
Source:  [CSOM230B2202] 


 
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Figure 1Error! No text of specified style in document.-1 
Mean (SD) plasma concentration 
versus time profiles of pasireotide in carcinoid patients (N=26) at week 4 
following b.i.d. doses of pasireotide s.c. [CSOM230B2202] 
Time (hr)
0
1
2
3
4
5
6
7
SOM230 Plasma Conc. (ng/mL)
0
20
40
60
80
100
150 g s.c. b.i.d. (N=1)
450 g s.c. b.i.d. (N=4) 
600 g s.c. b.i.d. (N=6)
750 g s.c. b.i.d. (N=7) 
900 g s.c. b.i.d. (N=7)
1200 g s.c. b.i.d. (N=1)
 
Source:  [CSOM230B2202] 
Table 1-3 
Mean (SD) pharmacokinetic parameters of pasireotide in carcinoid patients 
(N=26) following s.c. b.i.d. doses of pasireotide [CSOM230B2202] 
Dose (s.c.) 
Cmin 
(ng/mL) 
Cmax 
(ng/mL) 
AUC(0-6hr) 
(ng∙hr/mL) 150 g bid (N=1)
 
1.4 
4.7 
14.8 450 g bid (N=4)
 
5.1 (1.6) 
15.2 (3.9) 
58.5 (9.5) 600 g bid (N=6)
 
10.7 (7.2) 
27.9 (12.6) 
108 (56.8) 750 g 
bid (N=7) 
10.5 (4.1) 
32.5 (10.2) 
130 (37.1) 900 g bid (N=7)
 
13.9 (9.2) 
32.4 (12.5) 
124 (49.7) 1200 g bid (N=1)
 
23.3 
73.8 
271 
Source:  [CSOM230B2202] 
Pasireotide long acting release formulation 
Pasireotide LAR in healthy volunteers 
Preliminary data from a healthy volunteer [study CSOMC2101] which assessed single i.m. doses 
of pasireotide LAR up to 60 mg (N=5 per cohort) show that pasireotide LAR was well-tolerated, 
and that the adverse events observed are comparable with those observed with octreotide LAR. 
Diarrhea was the most common adverse event which was sometimes associated with abdominal 


 
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pain and/or flatulence. The gastrointestinal events were mild or moderate in severity. About half 
of the subjects reported transient mild injection site pain. Two volunteers on the 60 mg dose had 
mild increases in fasting blood glucose (< 123 mg/dL) with all values returning to normal within 
28 days after the LAR injection. 
The exposure of pasireotide was dose-proportional with Cmax of the extended release phase as 9.6 
± 5.1 ng/mL and 15.8 ± 3.3 ng/mL for 40 mg and 60 mg doses, respectively.  Multiple dose 
simulation suggested that this LAR formulation is suitable for monthly (q 28 d) dosing.  The 
simulated trough concentrations (Ctrough.ss) at steady state were 5.5 and 11.5 ng/mL for the 40 and 
60 mg doses, respectively.   
Further details on the safety and PK of pasireotide LAR in healthy volunteers can be found in the 
[Pasireotide LAR Investigators’ Brochure]. 
Pasireotide LAR in carcinoid patients 
Safety 
Preliminary safety data are available from 20 carcinoid patients inadequately controlled by 
somatostatin analogues treated with pasireotide LAR in an ongoing study [CSOM230C2110] 
(Table 1-4). These patients were under treatment with pasireotide LAR i.m. depot injections at 
doses of 20 mg, 40 mg or 60 mg for up to six weeks at the time of the safety summary. 
Pasireotide LAR was generally well-tolerated. The most commonly reported AEs were 
gastrointestinal, however, most of these events were considered unrelated to study drug.   


 
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Table 1-4 
Pasireotide LAR: Number (%) of patients with most frequent AEs (> 5% for any 
dose group) regardless of relationship to study drug (preliminary data from 
study SOM230C2110) 
 
 
Adverse Event  
(Preferred term) 
Pasireotide LAR 
20mg  
(N=5) 
n (CTC= grade3) 
Pasireotide LAR 
40mg  
(N=7) 
n (CTC= grade3) 
Pasireotide LAR 
60mg  
(N=8) 
n (CTC= grade3) 
Pasireotide LAR 
Any dose  
(N=20)n (%) 
(n=CTC grade3) 
Diarrhea                       
1 
2 
2 
5 (25.0%) 
Fatigue                         
1 
2 (1) 
1 
4(20.0%) (1)  
Dyspnea 
1 
2 (1) 
1 
4 (20.0%) (1) 
Flushing 
1 
1 (1) 
1 (1) 
3 (15.0%) (2) 
Back Pain 
1 
1 
1 
3 (15.0%) 
Nausea 
1 
1 
0 
2 (10.0%) 
Palpitations 
0 
2 
0 
2 (10.0%) 
Abdominal Pain           
1 
1 
0 
2 (10.0%) 
Steatorrhea 
1 
1 
0 
2 (10.0%) 
Asthenia                       
1 
1 
0 
2 (10.0%) 
Headache 
0 
1 
1 
2 (10.0%) 
Anorexia                      
0 
1 
1 
2 (10.0%) 
Hyperglycemia 
0 
1 (1) 
1 
2 (10.0%) (1)  
Odema Peripheral        
0 
1 
0 
1 (5.0%) 
Erythema 
1 
0 
0 
1 (5.0%) 
Source: [SOM230C2110] 
Pharmacokinetics 
Interim PK analysis has shown that a steady state appeared to be achieved following three 
monthly i.m. injections of 20 mg (N=5), 40 mg (N=7) or 60 mg (N=8) pasireotide LAR in 
carcinoid patients. The mean (SD) concentration versus time profiles of pasireotide are shown in 
Figure 1-2. The median (mean ± SD) trough plasma concentrations of pasireotide on days 28, 56 
and 84 are shown in Table 1-3. The release pattern of pasireotide from the first injection of 40 
and 60 mg LAR in carcinoid patients (Figure 1-2) was very similar to that of a single-dose of 40 
and 60 mg LAR in healthy volunteers. PK exposures to pasireotide on day 84 at steady state in 
carcinoid patients (Table 1-3) were roughly 2-fold higher than the simulated concentrations at 
steady state following multiple doses in healthy volunteers (Section 1.3.2.1). 


 
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Figure 1Error! No text of specified style in document.-2 
Mean (SD) plasma concentration 
versus time profiles of pasireotide in carcinoid patients following three monthly 
i.m. injections of 20 mg (N=5), 40 mg (N=7), or 60 mg (N=8) pasireotide LAR 
[CSOM230C2110] 
Time (day)
0
20
40
60
80
100
SOM230 Plasma Conc. (ng/mL)
-10
0
10
20
30
40
50
Car LAR 20 mg 
Car LAR 40 mg 
Car LAR 60 mg 
 
Source: [SOM230C2110] 
Table 1-5 
Median (Mean plus or minus SD) trough plasma concentrations of pasireotide on 
days 28, 56 and 84 in carcinoid patients following three monthly i.m. injections of 
20 mg (N=5), 40 mg (N=7) or 60 mg (N=8) pasireotide LAR [CSOM230C2110] 
Dose (mg) 
Day 28 (ng/mL) 
Day 56 (ng/mL) 
Day 84 (ng/mL) 
20 (N=5) 
2.7 (N=2) 
5.7 (N=1) 
6.9 (N=1) 
40 (N=7) 
7.2 (10.6 ± 8.2) (N=6) 
5.9 (13.8 ± 16.8) (N=3) 
12.0 (17.7 ± 10.5) (N=3) 
60 (N=8) 
14.2 (15.6 ± 9.2) (N=8) 
28.2 (28.5 ± 7.8) (N=4) 
16.9 (16.2 ± 4.8) (N=4) 
Source: [SOM230C2110] 
 
1.4 
RAD001 (everolimus) 
RAD001 (everolimus) is a novel oral derivative of rapamycin.  
RAD001 has been in clinical development since 1996 as an immunosuppressant in solid organ 
transplantation and has obtained marketing authorization (Certican®) for prophylaxis of rejection 
in renal and cardiac transplantation in a number of countries, including the majority of the 
European Union. RAD001 has been in development for patients with various malignancies since 
2002.  
RAD001 is being investigated as an anticancer agent based on its potential to act: 


 
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 Directly on the tumor cells by inhibiting tumor cell growth and proliferation  
 Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced proliferation of 
endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is well 
established, and the mTOR pathway has been implicated in the regulation of tumor 
production of proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
At weekly and daily schedules and at various doses explored, RAD0001 is generally well 
tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) associated 
with RAD001 therapy are manageable. Non-infectious pneumonitis has been reported with 
mTOR inhibitors but is commonly low-grade and reversible. 
mTOR pathway and mechanism of action 
At cellular and molecular level RAD001 acts as a signal transduction inhibitor. RAD001 
selectively inhibits mTOR (mammalian target of rapamycin), a key and a highly conservative 
serine-threonine kinase, which is present in all cells and is a central regulator of protein synthesis 
and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR is the only 
currently known target of RAD001.28 
mTOR is downstream of PI3K/AKT pathway, a pathway known to be dysregulated in a wide 
spectrum of human cancers (e.g. through loss/mutation of the PTEN negative regulator; through 
PI3K mutation/amplification; through AKT/PKB overexpression/overactivation; through 
modulation of TSC1/TSC2 tumor suppressors). In addition, activation of the PI3K/AKT/mTOR 
pathway is frequently a characteristic of worsening prognosis through increased aggressiveness, 
resistance to treatment and progression.  
The main known functions of mTOR include the following:28, 29 
 mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels, 
facilitating cell-cycle progression from G1 to S phase in appropriate growth conditions. 
 The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors.  
 Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and activating 
the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates translation of important 
massages, including those encoding the HIF-1 proteins, c-myc, ornithine decarboxylase, and 
cyclin D1, as well as ribosomal proteins themselves.  
 The activation of mTOR pathway leads to the increased production of pro-angiogenic factors 
(i.e., VEGF) in tumors and to tumor, endothelial and smooth muscle cell growth and 
proliferation. 
 The regulation of mTOR signaling is complex and involves positive regulators, such as AKT 
that phosphorylate and inactivate negative regulators such as the Tuberous Sclerosis 
Complex (TSC1/TSC2). 


 
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mTOR is represented by two structurally and functionally distinct multiprotein signaling 
complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR complex 
2, rapamycin insensitive).30  
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also known as PKB, 
protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2).29 Activated AKT 
phosphorylates TSC2, which lead to the dissociation of TSC1/TSC2 complex, thus inhibiting the 
ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small G-protein, to 
remain in a GTP bound state and to activate mTORC1. AKT can also activate mTORC1 by 
PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of mTORC1.31, 32  
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly by 
receptor tyrosine kinase (RTK) signalling.31 It has been suggested that mTORC2 phosphorylates 
and activates a different pool of AKT that is not upstream of mTORC1. PHLPP phosphatase 
plays a role of a negative regulator. mTORC2 is rapamycin insensitive and is required for the 
organization of the actin cytoskeleton.30 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone rapamycin and 
its derivatives, such as RAD001. Once these agents bind to the 12 kDa cytosolic FK506-binding 
protein immunophilin FKBP12, the resulting rapamycin-FKBP12 complexes bind to a specific 
site near the catalytic domain of mTORC1 and inhibit phosphorylation of mTOR substrates. As a 
consequence, downstream signaling events involved in regulation of the G1 to S-phase transition 
are inhibited. This mechanism is thought to be responsible for the immunosuppressive effects of 
rapamycin as well as its putative antineoplastic activity.33 As many cancers are characterized by 
dysregulation of G1 transit (for example, overexpression of cyclin or cyclin-dependent kinases), 
inhibition of mTOR becomes an intriguing target for inducing cytostasis.29  
Preclinical studies 
Pre-clinical investigations have demonstrated that RAD001 is a potent inhibitor of the 
proliferation of a range of human tumor cell lines in-vitro with IC50s ranging from sub/low nM 
to µM concentrations, concentrations capable of being reached in patients at the doses used in 
clinical trials.  
RAD001 was shown to have activity in human tumor cell lines originating from lung, breast, 
prostate, colon, kidney, melanoma and glioblastoma. RAD001 was also shown to have activity in 
human pancreatic neuroendocrine cells, where induction of apoptosis was reported,34 as well as 
in acute myeloid leukemia cells,35 adult T-cell leukemia cells,36 diffuse large B cell lymphoma 
cells (DLBCL;37 pancreatic tumor cells,38 ovarian cancer cells39-41 and hepatocellular carcinoma 
cells.42  
As a single agent, RAD001 inhibited proliferation in three mantle cell lymphoma cell lines 
(Jeko1, SP49 and NCEB1) approximately 40–65% compared to control cells. This was 
associated with G1 cell-cycle arrest and reduced phosphorylation of the mTOR downstream 
target, 4E-BP1.43  
In a clonogenic assay using cells derived from 81 patient-derived tumor xenografts never 
cultured in vitro (11 human tumor types with 3 to 24 tumors each: bladder, colon, gastric, 
NSCLC [adeno, squamous epithelium and large cell], SCLC, breast, ovary, pancreatic, renal, 


 
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melanoma, and pleural mesothelioma), RAD001 inhibited colony formation in a concentration-
dependent manner. In addition, normal hematopoetic stem cells were insensitive to RAD001, 
with an IC50 about 15 fold higher than the tumor lines.  
RAD001 also inhibits the proliferation of human umbilical vein endothelial cells (HUVECS), 
with particular potency against VEGF-induced proliferation. The inhibition of endothelial 
proliferation and antiangiogenic activity of RAD001 was confirmed in vivo, as RAD001 
selectively inhibited VEGF-dependent angiogenic response. Mice with primary and metastatic 
tumors treated with RAD001 showed a significant reduction in blood vessel density when 
compared to controls at well tolerated doses. Additionally, activity in a VEGF-impregnated s.c. 
implant model of angiogenesis and reduced vascularity (vessel density) of RAD001-treated 
tumors (murine melanoma) provided evidence of in vivo effects of angiogenesis. 
RAD001 also inhibits tumor growth in-vivo in xenografted, syngeneic and orthotopic animal 
models, residing longer in tumor tissue than in plasma and demonstrating high tumor penetration 
in a rat pancreatic tumor model. These effects occurred within the dose range of 2.5 to 10 mg/kg 
p.o. daily. Typically, the antitumor activity of RAD001 monotherapy was that of reduction of 
tumor growth rates rather than producing regressions or stable disease. 
RAD001, administered p.o., was a potent inhibitor of tumor growth and well tolerated in: 
 s.c. mouse xenograft model, established from a variety of tumor cell lines of diverse 
histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), including a Pgp170 
overexpressing multi-drug resistant tumor line  
 in a series of low-passage tumor xenografts established directly from human tumor material, 
maintained only in vivo and considered highly predictive of therapeutic outcome in patients. 
These included breast (5 lines), colorectal (9 lines), gastric (3 lines), lung (22 lines including 
adenocarcinomas, epidermoid cell, large cell and small cell histotypes), melanoma (6 lines), 
ovarian (4 lines), pancreatic (3 lines) and renal (6 lines) 
 in two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic melanoma) 
Taken together, these data indicate the broad antiproliferative potential of RAD001. 
It is not clear which molecular determinants predict responsiveness of tumor cells to RAD001. 
Molecular analysis has revealed that relative sensitivity to RAD001 in vitro correlates with the 
degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal 
protein. PTEN status alone may not be predictive of RAD001 relative in vitro sensitivity, 
however in some cases (i.e., GBM) there is also a correlation with PTEN status. 
In preclinical models, the administration of RAD001 is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (pS6) and 
p4E-BP1, and occasionally with an increase in phosphorylation AKT (pAKT).  
Pre-clinical safety 
In safety pharmacology studies, RAD001 was devoid of relevant effects on vital functions 
including the cardiovascular, respiratory and nervous systems. RAD001 had no influence on QT 
interval prolongation. Furthermore, RAD001 showed no antigenic potential. Although RAD001 
passes the blood-brain barrier, there was no indication of relevant changes in the behavior of 


 
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rodents, even after single oral doses up to 2000mg/kg or after repeated administration at up to 40 
mg/kg/day. Based on these findings, the potential of RAD001 to affect vital functions in patients 
is considered to be low. 
RAD001 is considered to have no genotoxicity or carcinogenicity potential. All significant 
adverse events observed in preclinical toxicology studies with RAD001 in mice, rats, monkeys 
and minipigs were consistent with its anticipated pharmacologic action as an antiproliferative 
and immunosuppressant and at least in part reversible after a 2- or 4-week recovery period with 
the exception of the changes in male reproductive organs, most notably testes. Ocular effects 
(lenticular disorders) observed in rats were not observed in any other species and are considered 
to be a species-specific disorder. 
More pre-clinical information is provided in the [Investigator’s Brochure]. 
Clinical experience 
RAD001 Pharmacokinetics 
RAD001 is rapidly absorbed with a median tmax of 1-2 hours. The bioavailability of the drug is 
believed to be 11% or greater. The AUC0-τ is dose-proportional over the dose range between 5 to 
70 mg in the weekly regimen and 5 and 10 mg in the daily regimen. Cmax is dose-proportional 
between 5 and 10 mg for both the weekly and daily regimens. At doses of 20 mg/week and 
higher, the increase in Cmax is less than dose-proportional. The coefficient of variation between 
patients is approximately 50%.  
Trough levels (24 hour post-dose) correlate well with AUC0-τ at steady-state during daily 
administration. 
In whole blood, at a daily dose of 10 mg,  about 20% of RAD001 is confined in plasma with 
26% being unbound. The remaining 80% is sequestered in blood cells.  
RAD001 is extensively metabolized in the liver and eliminated in the bile. Major metabolites are 
inactive. Elimination half-life is approximately 30 hours. The clearance of RAD001 is 
approximately halved in patients with mild-moderate hepatic impairment (Child-Pugh Class A or 
B), while renal impairment has little or no impact on the pharmacokinetics of RAD001. 
Age, weight and gender in the adult population do not affect the pharmacokinetics of RAD001 to 
a clinically relevant extent. The clearance of RAD001 is reduced in children. 
Pharmacokinetic characteristics are not notably different between Caucasian and Japanese 
subjects, whereas in Black patients population pharmacokinetic studies have shown an average 
20% higher clearance. 
A high-fat meal altered the absorption of RAD001 with 1.3 hour delay in tmax, a 60% reduction in 
Cmax and a 16% reduction in AUC. 
RAD001 is a substrate of CYP3A4 and a substrate and a moderate inhibitor of the multi-drug 
efflux pump P-glycoprotein (P-gP, MDR1, ABCB1). Hence, its metabolism is sensitive to drugs 
which modify these enzymes (substrates, inducers, or inhibitors of these enzymes). Competitive 
inhibition could occur when RAD001 is combined with drugs which are also CYP3A4 or P-
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Table 6-9 (Section 6-8) lists examples of clinically relevant CYP3A inhibitors and inducers. 
Please refer to Section 6-8 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications. 
More information on RAD001 pharmacokinetics is provided in the [Investigator’s Brochure]. 
RAD001 Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the biomarker p70S6 kinase 
1 [S6K1] in peripheral blood mononuclear cells [PBMC]) suggests that 5-10 mg daily should be 
an adequate dose to produce a high-degree of sustained target inhibition ([Study C2101] / [Study 
2102].44 Furthermore, molecular pharmacodynamic (MPD) studies, using immunocytochemistry 
(IHC) in biopsied tumor tissue, assessed the degree of inhibition and its duration for pS6, p4E-
BP1 and pAKT expression with the daily and weekly dosing. There was high inhibition of the 
downstream markers S6K1 and 4E-BP1 at 5mg/day, which was complete at 10 mg/day, while 
preliminary results suggest increase in pAKT expression with maximal effect at 10 mg daily 
([Study C2107].45 
More information is provided in the [Investigator’s Brochure]. 
Clinical experience with RAD001 
RAD001 has been investigated as a component of multi-drug immunosuppression in solid organ 
transplantation since 1996 and was approved for the indication of prophylaxis of organ rejection 
in adult patients receiving an allogeneic renal or cardiac transplant on 8 Jul 2003 by the 
European Union under the trade name of Certican®. The most frequent adverse drug reactions in 
this context are highly specific to the transplant context. However, certain events are 
generalizable, most notably myelosuppression, skin disorders and increases in blood lipid levels. 
RAD001 (everolimus) was approved by the United States Food and Drug Administration in 
March 2009 for the treatment of advanced renal cell carcinoma for patients with advanced renal 
cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. 
 
RAD001 has been in development for patients with cancer since 2002. Approximately 4000 
patients with various malignancies have been treated in either Novartis sponsored or non-
Novartis sponsored, and 3 healthy volunteer clinical studies as of 31 Aug 2008. Overall, Novartis 
sponsored a total of 28 studies of RAD001 administered either as single-agent (n=13), or in 
combination with other anti-tumor agents (n=15). Ongoing or completed Investigator sponsored 
studies also enrolled over 1000 patients globally. 
Eight single-agent Novartis sponsored trials have or are being conducted in various advanced 
malignancies. Five Phase I studies evaluated several escalating doses with either weekly or daily 
administration (Studies C2101/02, C2106, C2107, C1101) of RAD001 with the  objective to 
identify an optimal regimen and dosage, based on safety, pharmacokinetics and knowledge of the 
drug’s molecular effects on various tumors. The 10 mg/day and 50-70 mg/week dosages were 
proposed for further studies, when using RAD001 as a single agent, and as a target maximum 
dose in combination studies. In addition the Phase I studies, conducted in prostate cancer (Study 


 
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C2106) and in Japanese patients with advanced cancers (Study C1101), evaluated the safety and 
the molecular changes in tumor, associated with the administration of RAD001.  
Two Phase II monotherapy studies were designed to evaluate the safety and efficacy of a single 
dose of 10 mg administered daily including Study C2235 in advanced NSCLC (n=81) and Study 
C2239 in advanced pancreatic neuroendocrine tumors (n=160). 
A Phase III, randomized, double blind, placebo controlled study in patients with mRCC who 
progressed on a VEGFr TKI demonstrated that everolimus, administered daily at an oral dose of 
10 mg administered provides positive clinical benefit (Motzer, 2008). Median progression free 
survival (PFS) was prolonged from 1.87 months for patients receiving placebo to 4.01 months 
for everolimus treated patients, assessed by central independent review blinded to clinical data 
(hazard ratio 0.30, 95% CI 0.22-0.40, p<0·0001). 
Updated results presented at the American Society of Clinical Oncology 2009 Genitourinary 
Cancers Symposium (Kay et al, 2009) demonstrated everolimus as having even greater 
superiority to placebo in the primary endpoint of PFS. Median PFS was prolonged from 1.9 
months for patients receiving placebo to 4.9 months for everolimus-treated patients, assessed by 
central independent review blinded to clinical data (hazard ratio 0.33, 95% CI 0.25-0.43, 
p<0.001). 
Overall, the most frequent adverse effects suspected to be related to RAD001 have been 
stomatitis, rash,  anemia, fatigue, asthenia, diarrhea, anorexia, nausea, hypercholesterolemia, 
mucosal inflammation, vomiting, hypertriglyceridemia, cough, peripheral edema, dry skin, 
epistaxis, pruritus and dyspnea. The most common Grade 3 or 4 adverse reactions suspected to 
be related to treatment were anemia, infections, hyperglycemia, stomatitis, fatigue, lymphopenia, 
hypercholesterolemia, pneumonitis, and elevated gammaglutamyltransferase concentrations. 
Non-infectious low-Grade (Grade 1/2) pneumonitis has led to development of treatment 
guidelines for the disorder (Table 6-5). The primary DLT has been severe (Grade 3) stomatitis, 
and occasionally fatigue, hyperglycemia, and neutropenia. For more information on known 
undesirable effects of RAD001 refer to Section 6-7.  
Further detailed information regarding RAD001 clinical development, safety and efficacy is 
provided in the [Investigator’s Brochure]. 
2 
Study rationale/purpose 
 
Preclinical data in non small cell lung cancer cell lines and cell lines from other tumor types have 
clearly established that isolated inhibition of the mTOR pathway through downstream blockade 
with rapamycin analogues engenders a compensatory activation of survival pathway response 
with increased signaling through AKT, MEK/ERK and EGFR (Figure 1).46-48 Dual blockade of 
the mTOR and the alternative survival pathways however results in increased efficacy (Figure 2 
and 3).46-49 It remains unclear, however, whether initial mTOR inhibitor therapy to induce 
cellular addiction to the survival pathway is superior to the reverse schedule of blocking the 
survival pathway prior to mTOR inhibition. Also, superiority of any these schedules over 
simultaneous inhibition with combined mTOR and for instance a PI3/Akt inhibitor is yet to be 


 
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established. Further, despite the implicated role for somatostatin receptor activity in thyroid 
proliferation, anecdotal reports of treatment with somatostatin analogues, octreotide and 
lanreotide, in differentiated thyroid cancer showed mixed result of efficacy. Although majority of 
patients derived symptomatic benefit, objective tumor responses as assessed by functional and 
anatomic imaging were very limited. The promise with this class of drugs in thyroid cancer is 
probably best achieved either by the use of more potent somatostatin analogues or in 
combination with other targeted agents. Pasireotide is a new generation somatostatin analogue 
that targets four of the five known isoforms of the somatostatin receptor. It is anticipated that this 
broad activity will result in greater antitumor effect compared to the highly selective 
somatostatin analogues. By combining Pasireotide and Everolimus, we anticipate greater 
antitumor efficacy without compromising the expected symptomatic improvement. We therefore 
seek to establish the activity of each agent alone as well as determine whether maximal pathway 
inhibition using both drugs together will result in improved clinical outcome in this 3-arm phase 
II trial. To provide some insight into the question of the optimal sequence of administration of 
the two agents, patients on the single agent arm of the trial will be allowed to receive the second 
agent in combination at the time of disease progression.  
 
 
Figure 2-1: Effects of prolonged treatment with mTOR inhibitors on Akt phosphorylation. A, 
the indicated cell lines were treated with DMSO and 10 nmol/L rapamycin (Rap) or RAD001 for 
24 h. B, the indicated cell lines were treated with DMSO (D), 1 nmol/L rapamycin (R), or 
RAD001 (R1) for the given times. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. C, PC-


 
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3 cells were treated with the given concentrations of rapamycin or RAD001 for the indicated 
times. D, U937 or Jurkat cells were treated with the given concentrations of rapamycin or 
RAD001 for 24 h. The cells were then harvested from the aforementioned treatments for 
preparation of whole-cell protein lysates and subsequent Western blot analysis.48  
 
 
Figure 2-2: Combination of RAD001 and LY294002 augments growth inhibition of lung cancer 
cells in cell culture (A and B) and in nude mice (C and D). A, the individual cell lines, as 
indicated, were seeded in 96-well plates. On the second day, they were treated with the indicated 
concentrations of RAD001 (RAD) alone, 2 µmol/L LY294002 alone, and their respective 
combinations. After 3 d, plates were subjected to determination of cell number using a SRB 
assay. Columns, mean of four replicate determinations; bars, SD. B, H460 cells at a density of 
250 per well were seeded in 12-well plates. On the second day, cells were treated with the 
indicated concentrations of RAD001 alone, 2.5 µmol/L LY294002 alone, and their respective 
combinations. The same treatments were repeated every 3 d. After 10 d, the plates were stained 
for the formation of cell colonies with crystal violet dye. The picture of the colonies was then 
taken using a digital camera. C and D, four groups of mice with either A549 (C) or H460 (D) 
xenografts were treated with vehicle control, RAD001 alone, LY294002 (LY) alone, and 
RAD001 plus LY294002 on the same day after grouping. After 14 d, the mice were sacrificed 


 
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and the tumors were removed. Tumor sizes were measured once every 2 d. Points, mean (n = 6); 
bars, SD. *, P < 0.05; **, P < 0.01; and ***, P < 0.001, compared with vehicle control; #, P < 
0.05, compared with RAD001 treatment.47 
Figure 2-3: Involvement of PI3K in 
rapamycin-mediated increase of Akt and 
eIF4E phosphorylation (A and B) and 
enhancement of rapamycin-mediated growth 
inhibitor effects by LY294002 in NSCLC 
cells (C and D). A, H157 cells were 
pretreated with 5 µmol/L LY294002 for 30 
minutes and then cotreated with the 
indicated concentrations of rapamycin (Rap) 
for 3 hours. The cells were subjected to 
preparation of whole cell protein lysates for 
detection of the indicated proteins using 
Western blotting. B, H157 cells were 
pretreated with 20 µmol/L U0126, PD98059 
(PD), and SB203580 (SB), respectively, and 
10 µmol/L LY294002 (LY) for 30 minutes, 
and then cotreated with 10 nmol/L 
rapamycin. After 3 hours, the cells were 
subjected to preparation of whole cell 
protein lysates for detection of the indicated 
proteins using Western blot analysis. C, the 
individual cell lines, as indicated, were 
seeded in 96-well plates. On the second day, 
they were treated with the indicated 
concentrations of LY294002 alone, 1 nmol/L rapamycin alone, and their respective 
combinations. After 3 days, plates were subjected to determination of cell number using a SRB 
assay. Columns, means of four replicate determinations; bars, ±SD. D, H460 cells at a density of 
250 cells per well were seeded in 12-well plates. On the second day, cells were treated with the 
indicated concentrations of LY294002 alone, 1 nmol/L rapamycin alone, and their respective 
combinations. The same treatments were repeated every 3 days. After 10 days, the plates were 
stained for the formation of cell colonies with SRB dye. The picture of the colonies was then 
taken using a digital camera.47 
2.1 
Selection of doses 
Everolimus will be dosed at the once daily dose of 10 mg orally continuously. This is the 
maximum tolerated dose of the drug when dosed on daily continuous schedule. This dose is also 
the efficacious anticancer dose approved for the treatment of patients with renal cell cancer. The 
planned dose of Pasireotide LAR is 60 mg intramuscular injection to be given approximately 
once every 4 weeks. A company-sponsored phase I study of this combination has already 
determined the proposed doses of 60mg Pasireotide LAR in combination with everolimus 10 mg 
once daily, to be safe and tolerable.50 The study is currently enrolling more patients into an 


 
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expansion cohort to obtain additional safety and toxicity data. The final result of this phase I trial 
is awaited within the next 6 months in time for any dose adjustment for Pasireotide in the current 
study.  
3 
Objectives 
3.1 
Primary objectives 
To determine the Response Rate [(complete response (RR) + partial response (PR)] of 
everolimus, pasireotide and the combination of both agents in the therapy of radioiodine 
refractory differentiated and medullary thyroid cancer. 
To establish the progression free survival associated with everolimus, pasireotide and the 
combination of both agents in radioiodine refractory differentiated and medullary thyroid cancer. 
3.2 
Secondary objectives 
To determine the clinical benefit rate (CBR: CR + PR + SD)of everolimus, pasireotide and the 
combination of both agents when used as the frontline treatment for radioiodine refractory 
differentiated and medullary thyroid cancer. 
Determine the Time to Treatment Failure (TTF) for each arm of the study 
Assess the rate of and time to biochemical response using changes in serum concentrations of 
thyroglobulin, carcinoembryonic antigen (CEA), chromogranin A and calcitonin 
To obtain additional safety data regarding concurrent and sequential administration of 
Everolimus and pasireotide 
 
3.3 
Exploratory objectives 
Correlate the level of expression of mTOR pathway signaling proteins in archival tumor tissue 
with the clinical activity of everolimus 
Correlate the level of expression of somatostatin receptor expression and IGF1-R in archival 
tumor tissue with clinical efficacy of Pasireotide 
Exploratory analysis of disease response based on histology and FDG PET uptake  
 
4 
Study design 
This is an open-label, 3-arm, non comparative phase II clinical trial to study the single agent and 
combined efficacy of pasireotide and everolimus in patients with iodine refractory, differentiated 
(papillary, follicular and their variants) and medullary thyroid cancer. Patients will be randomly 
assigned to one of three arms to receive single agent pasireotide, everolimus or the combination 
of both drugs (Figure 4). Patient randomization will be stratified by histology, (medullary versus 
non medullary thyroid cancer). In order to explore the optimal schedule of administration, 


 
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patients who were initially randomized to the single agent arm will be allowed to receive the 
second agent at the time of disease progression. Such patients, however, may only proceed with 
the trial if they achieve disease stabilization or objective response at the end of the first 2 cycles 
of 2-drug combination and without experiencing any grade ≥ 4 hematologic or grade ≥ 3 non-
hematologic toxicities. Everolimus will be administered once daily continuously on days 1 to 28; 
pasireotide will be administered as a long acting intramuscular depot injection given once every 
4 weeks. One cycle will be defined as 4 weeks with response assessment with cross sectional 
imaging planned for the end of every even numbered cycle. Biochemical response will be 
assessed using serum-based tumor markers (Thyroglobulin, CEA, calcitonin) specific or 
informative for the histologic subtype of thyroid cancer. Patients will be evaluated at the end of 
cycle 1 and cycle 2, and subsequently after every 2 cycles along with restaging scans. 
 
The study design for this Phase II trial is a randomized screening design with multiple arms. A 
simple winner arm is selected only from the arms shown to be superior to the historical control. 
Between arms: Eligible patients will be randomly assigned to one of three arms to receive single 
agent pasireotide, everolimus or the combination of both drugs. Randomization is conducted 
with a block of 3 patients in order to balance the enrollment in each arm (The first of the 3 
patients entered consecutively is randomly assigned to any of the 3 arms; the second patient is 
randomly assigned to one of the remaining 2 arms and the third patient to the last arm).  
 
Within arms: Within each of the 3 arms, a Simon’s 2-stage MinMax design is used. Eighteen 
evaluable patients will be enrolled into stage I. At least one objective response is required to 
proceed to stage II accrual of 10 additional patients for a total of 28 patients per arm. At least 3 
patients must achieve objective response for the particular treatment arm to be considered worthy 
of further clinical evaluation in this disease.  
 
Between Arms: Any treatment arm closed to accrual after the first stage interim analysis will be 
considered an inferior arm and will be excluded from comparison for the winner of trials. 
The arm with the best overall RR at the end of full enrolment will be adjudged the winner to be 
considered for further development. In the event of identical RR between the arms or if none of 
the arms met the RR criterion (less than 3 objective responses after full patient enrolment), the 1-
yr PFS rate will be employed to determine a winner. Based on recent clinical trials of targeted 
agents in similar patient population, 90% of patients were alive at 1 year and median progression 
free survival ranged between 9 and 18 months.8-10 We assume a conservative estimate that only 
20% of the patients will be progression free at 1 year if the treatment is ineffective while 50% or 
more of the patients will be progression free at the same time point with an effective regimen. 
For this purpose, a 1-year PFS rate of 50% or greater will be considered sufficient activity to 
justify further evaluation of the treatment in this disease. Assuming a 20% or lower 1-year PFS 
rate with an inactive regimen and a 50% or greater rate with an active regimen, 28 patients 
enrolled onto each arm will classify the treatment as having sufficient activity for further 
evaluation with a probability of 0.95 (power against the alternative hypothesis p = 0.05). In this 
respect, the arm with the highest 1-yr PFS rate will be judged the winner. In the event of a tie 
between the arms for both the RR and 1-yr PFS rate, the arm with the best profile in terms of 
safety and tolerability will be considered the overall winner to be selected for further evaluation 
in this disease. The power calculation for PFS assessment assumes full enrolment of 28 patients 


 
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to the treatment arm, therefore any arm closed to further accrual following the initial interim 
analysis will not be considered for PFS endpoint assessment. 
 
 
Figure 4-1: Statistical Consideration for Power and Sample Size 
 
Primary Efficacy Decision Using Simon’s MinMax Design Based on RR:  
P0 = 5% vs. P1 = 15% 
Power = 80%; α = 0.20 
First Stage Sample Size 
Upper Limit for First Stage Rejection of Drug 
18 
0 
Maximum Sample Size 
Upper Limit for Second Stage Rejection of Drug 
28 
2 
 
Secondary Efficacy Decision Based on 1-Year PFS Rate Endpoint at the End of Complete 
Enrolment;  
Total enrolment of 28 patients per arm 
Duration of enrolment: 30 months 
Additional follow-up time: None 
1-year PFS Rate 
P0 
P1 
20% 
50% 
Power 
95% 
2-sided α  
0.05 
 
4.1 
Treatment 
Everolimus (10mg) orally continuously day 1-28 
Pasireotide LAR 60 mg i.m. day 1 of each cycle 
Safety and efficacy will be assessed throughout the treatment period. 
4.2 
Follow-up 
Patients will remain on treatment and be followed at regularly scheduled office visit until 
treatment discontinuation due to progression, withdrawal of consent, or intolerable toxicity. 
Patients who discontinued therapy for reason of toxicity will be monitored at least monthly via 
phone or office visit until resolution of the adverse event. “All patients will be contacted for 
survival follow-up at least monthly via phone or office visit until death or the completion of the 
trial (LPLV + 30 days). 
 


 
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Figure 4-2: Flow diagram of the study schema, screening, stratification and randomization to 
one of 3 arms. 
5 
Population 
Ninety adult patients with pathologically confirmed medullary or differentiated thyroid cancer 
who no longer benefit from or are intolerant of radioiodine therapy will be enrolled in the study. 
Patients will be enrolled across all participating sites in order of registration into the study. 
Patients who meet the eligibility and screening requirement will be stratified by histology,for the 
purposes of randomization to one of the 3 treatment arms. Patients will be randomly assigned to 
one of three treatment arm as described in the statistics section for a total of thirty patients in 
each arm. 
 
Inclusion/exclusion criteria 
The investigator or his/her designee must ensure that all patients who are offered enrollment in 
the study meet all of the following inclusion and exclusion criteria: 


 
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5.1 
Inclusion criteria 
 
1. Histologic or cytologic confirmation of thyroid cancer (papillary, follicular, medullary); 
histologic variants such as Hurthle and tall cell variants are allowed. 
2. Biochemical or radiologic documentation of disease progression within the last 12 months 
prior to enrollment. 
3. Presence of at least one site of measurable disease according to RECIST criteria version 1.1 
4. Patient must have radioiodine refractory disease as defined by one or more of the following 
conditions: 
 All cases of medullary thyroid carcinoma 
 No iodine-uptake on a post- radioactive iodine treatment scan (in presence of low iodine 
diet and thyroid stimulating hormone (TSH) suppression) in an anatomically defined 
lesion that qualifies as target lesion by RECIST criteria 
OR 
 If there is demonstrable iodine-uptake: the last radioiodine therapy of (≥ 100 mCi)  was 
given within the last 16 months OR if given more than 16 months before enrollment, 
there is evidence of disease progression after each of the last two radioiodine treatment 
performed within 16 months of each other (each dose should be ≥ 100mCi)  
OR 
 If the patient has received the maximum cumulative life time dose of radioactive iodine 
treatments of at least 600 mCi 
 If the patient declines or is intolerant of radioiodine therapy or if with progressive disease 
that is, in the opinion of the treating physician, likely to benefit from biologic therapy 
rather than further iodine therapy e.g. patient with heavy burden of disease 
5. Age ≥ 18 years. 
6. Minimum of four weeks since any major surgery or since completion of radiation (patients 
should have adequately recovered from the acute toxicities of any prior therapy). 
7. ECOG performance status  2. 
8. Life expectancy of at least 6 months. 
9. Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, 
Hgb > 9 g/dL. 
10. Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal (ULN), 
and serum transaminases activity ≤ 3 x ULN,. 
11. Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN or GFR of 60cc/ml using 
the formula of Cockroft and Gault. 
12. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x 
ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be 
included after initiation of appropriate lipid lowering medication. 
13. Women of childbearing potential must have a negative serum pregnancy test within 7 days of 
the administration of the first study treatment.  Women must not be lactating. Both men and 


 
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women of childbearing potential must be advised of the importance of using effective birth 
control measures during the course of the study. 
14. Signed informed consent to participate in the study must be obtained from patients after they 
have been fully informed of the nature and potential risks by the investigator (or his/her 
designee) with the aid of written information. 
15. INR and PTT ≤1.5 x ULN.  (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose 
of warfarin or on a stable dose of LMW heparin for >2 weeks at time of randomization.) 
 
5.2 
Exclusion criteria 
1. Prior treatment with not more than 1 systemic agent (including chemotherapy or biologic 
agent e.g. vandetanib for patients with medullary thyroid cancer)    
2. Patients who have undergone major surgery within 4 weeks prior to study enrollment 
(tracheotomy, feeding tube or vascular access catheter placement and interventional 
procedures such as bronchoscopy, upper GI endoscopy or colonoscopy are not considered 
major surgery). 
3. Chronic treatment with systemic steroids or another immunosuppressive agent. 
4. Patients should not receive immunization with attenuated live vaccines during study period 
or within 1 week of study entry. Close contact with those who have received attenuated live 
vaccines should be avoided during treatment with everolimus. Examples of live vaccines 
include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, 
varicella and TY21a typhoid vaccines. 
5. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require 
glucocorticoids for brain or leptomeningeal metastases. 
6. Patients with  prior or concurrent malignancy except for the following: adequately treated 
basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any 
other cancer from which the patient has been disease free for five years. 
7. Patients with uncontrolled diabetes mellitus or a fasting plasma glucose > 1.5 ULN. Note: 
Optimal glycemic control should be achieved before starting trial therapy. At the principal 
investigator’s discretion, non-eligible patients can be re-screened after adequate medical 
therapy has been instituted. 
8. Patients with symptomatic cholelithiasis (asymptomatic gall stone discovered on screening 
US should be reviewed by the PI but will not lead to automatic exclusion) 
9. Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).  
• History of liver disease, such as cirrhosis or chronic active hepatitis B and C.  
• Presence of Hepatitis B surface antigen (HbsAg) 
• Presence of Hepatitis C antibody test (anti-HCV)  
Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done 
at screening for all patients.  HBV DNA and HCV RNA PCR testing are required at 
screening for all patients with a positive medical history based on risk factors and/or 
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10. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, 
sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, 
advanced heart block or a history of acute myocardial infarction within the six months 
preceding enrollment 
11. QT related exclusion criteria 
• 
QTcF at screening > 470 msec.  
• 
History of syncope or family history of idiopathic sudden death.  
• 
Sustained or clinically significant cardiac arrhythmias. 
• 
Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, 
cardiac failure, clinically significant/symptomatic bradycardia, or high-grade AV block. 
• 
Concomitant disease(s) that could prolong QT such as autonomic neuropathy 
(caused by diabetes, or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism 
or cardiac failure  
• 
Concomitant medication(s) known to increase the QT interval. 
12. Patients with the presence of active or suspected acute or chronic uncontrolled infection or 
with a history of immunocompromise, including a positive HIV test result (ELISA and 
Western blot).  
13. Patients who have any severe and/or uncontrolled medical conditions or other conditions that 
could affect their participation in the study such as: 
 
Severely impaired lung function (as defined as spirometry and DLCO that is 50% of the 
normal predicted value and/or 02 saturation that is 88% or less at rest on room air) 
 
Any active (acute or chronic) or uncontrolled infection/ disorders.   
 
Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the treatment with the study therapy 
 
Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of RAD001  
 
Patients who have a history of drug abuse in the 6 month period prior to receiving 
treatment with pasireotide or RAD001 
 
History of, or current alcohol misuse/abuse within the past 12 months 
 
Acute or chronic pancreatitis 
14. Women who are pregnant or breast feeding, or women/men of reproductive potential who are 
not using and unwilling to practice an effective method of birth control. (Women of 
childbearing potential must have a negative serum pregnancy test within 7 days prior to 
administration of pasireotide and RAD001).  
15. Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate 
contraception, during the study and for 8 weeks after the end of treatment 
16. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins 
(sirolimus, temsirolimus) or to its excipients 
17. Known hypersensitivity to somatostatin analogues or any component of the pasireotide or 
octreotide LAR formulations  
18. History of noncompliance to medical regimens 


 
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19. Patients unwilling to or unable to comply with the protocol 
20. Patients taking medications known to be strong CYP3A inhibitors (Table 6-5).  
6 
Treatment 
6.1 
Investigational and control drugs 
Known undesirable effects of study drug/treatment 
For information on Pasireotide and Everolimus, please refer to Section 1, Human experience, and 
the Investigator Brochure. 
6.2 
Study drugs 
 
SOM230C 
Study drug: pasireotide LAR (long-acting release) i.m. depot injection 
Inactive 
ingredients 
of 
pasireotide 
LAR 
include: 
mannitol, 
carmellose 
sodium 
(carboxymethylcellulose sodium), poloxamer 188 and water for injection. Inactive ingredients 
of pasireotide s.c. include: mannitol, tartaric acid, sodium hydroxide and water for injection.  
For detailed information on pasireotide, please refer to Sections 1.3 and 1.4 or the pasireotide 
Investigator Brochures.  
How supplied 
Study drug, Pasireotide LAR i.m. depot injections will be supplied in open-label packaging 
by Novartis as a powder in vials containing 20 mg and 40 mg  labeled as SOM230 LAR, with 
ampoules containing 2 mL of vehicle (for reconstitution). No syringes or needles will be 
provided with the pasireotide study drug supplies.  
Preparation and storage 
Prior to reconstitution, vials should be brought to room temperature.  Pasireotide LAR should 
then be prepared as follows: 
Table 6-1 
Handling and preparation of pasireotide LAR dose 
Dose  
Volume to be injected 
20 mg 
1 x 20 mg vial + 2 mL vehicle; whole volume to be injected 
40 mg 
1 x 40 mg vial + 2 mL vehicle: whole volume to be injected 
60 mg 
1 x 20 mg vial + 1 x 40 mg vial + 2 mL vehicle; whole volume to be 
injected 
Doses should be prepared and administered immediately after preparation.   
Novartis will supply pasireotide LAR as long as the patient remains on study, shows 
continuous benefit from treatment, and there are no safety concerns. Medication labels will 


 
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comply with the legal requirements of the U.S. and will be printed in English. The storage 
conditions for pasireotide LAR will be described on the medication label. Bottles must be 
stored in a safe, secure location.  
All study medication will be supplied to each site directly by Novartis. Under the 
responsibility of each site’s lead investigator, drug supplies must be kept in an appropriate, 
secure area (e.g. locked cabinet) and stored in accordance with the conditions specified on the 
drug labels. The investigator must maintain an accurate record of the shipment and dispensing 
of the study drug in a drug accountability ledger. An accurate record of the date and amount of 
study drug dispensed to each subject must be available for inspection at any time. 
All drug supplies are to be used only for this protocol and not for any other purpose. Unless 
specifically instructed by Novartis, the investigator must not destroy any drug labels, or any 
unused drug supply. 
 
The storage condition for the study drug will be described on the medication label. 
Administration 
Pasireotide LAR will be administered i.m., intragluteally, every 4 weeks. The starting dose 
will be 60 mg.  The reconstitution has to be performed just prior to administration of the 
suspension. A minimal standing time can be tolerated for the reconstituted suspension in the 
vial. Prior to administration, the reconstituted suspension in the vial should be shaken again 
before withdrawal in the syringe. The i.m. injection must be given immediately after 
withdrawal of the reconstituted suspension from the vial to the syringe. 
 
RAD001 Administration 
The study drug RAD001 will be self-administered (by the patients themselves). The investigator 
will instruct the patient to take the study drug exactly as specified in the protocol. RAD001 will 
be administered orally as once daily dose of 10 mg continuously from study day 1 until 
progression of disease or unacceptable toxicity. Patients will be instructed to take RAD001 in the 
morning, at the same time each day.  
RAD001 may be taken by the patient with or without food. However, dietary habits around the 
time of RAD001 intake should be as consistent as possible throughout the study. 
If vomiting occurs, no attempt should be made to replace the vomited dose.  
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded. 
Medication labels will comply with US legal requirements and be printed in English. They will 
supply no information about the patient. The storage conditions for study drug will be described 
on the medication label. 
RAD001 will be provided by Novartis. RAD001 is formulated as tablets for oral administration 
of 2.5mg, 5mg and 10mg strengths. Tablets are blister-packed under aluminum foil in units of 10 
tablets, which should be opened only at the time of administration as drug is both hygroscopic 
and light-sensitive. 


 
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6.3 
Treatment arms 
Arm A: Everolimus 10 mg daily continuously (switch to 2-drug combination at progression if no 
intolerable toxicity) 
 
Arm A1: Patient switching from single agent everolimus to 2-drug combination will be re-
registered as Arm A1 
 
Arm B: Pasireotide LAR 60mg i.m. once every 4 weeks (switch to 2-drug combination at 
progression if no intolerable toxicity) 
 
Arm B1: Patient switching from pasireotide LAR single agent to 2-drug combination will be re-
registered as Arm B1 
 
Arm C: Everolimus 10 mg daily continuously together with Pasireotide LAR 60mg i.m. once 
every 4 weeks 
6.4 
Patient Registration and Numbering 
Each enrolled patient will be assigned a composite number consisting of the three letter 
abbreviation for the study, a single digit for the center, a 3 digit number representing the next 
higher number serially from 1 – 90 followed by a single letter representing the arm to which the 
patient was randomized e.g. “PEC/1/001/C” meaning Pasireotide, Everolimus or combination 
study, Emory center, patient number 1, randomized to the combination arm. 
Eligible patients will be entered on study centrally at the Emory University Winship Cancer 
Institute by the Study Coordinator. To verify slot availability, all sites should call the Study 
Coordinator: 
Jacene R. Myrie, CCRC 
Phone: 404-778-4383 
Fax:       404-778-4389 
PIC#: 64576 
Email:jacene.myrie@emory.edu 
Before an investigator may enroll patients, a signed IRB approval letter and approved consent 
form must be on file with the coordinating center at Emory WINSHIP CANCER INSTITUTE. 
Prior to discussing protocol entry with a patient, call or e-mail to verify slot availability. 
Once it is confirmed that a slot is available, call and fax a completed eligibility checklist, 
required laboratory tests and signed consent form to the coordinator at (404-778-4389) between 
9 a.m. and 4 p.m. ET, Monday through Friday. 


 
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At the time of registration, WINSHIP CANCER INSTITUTE coordinating center will verify the 
following: 
 
 IRB approval at the registering institution 
 Patient eligibility 
 Existence of a signed consent form 
 Existence of a signed authorization for use and disclosure of protected health 
information. 
 Patient consent for tumor biopsy or special studies (if applicable) 
 
After verifying eligibility, the Emory WINSHIP CANCER INSTITUTE Clinical Research 
Coordinator will contact the study statistician, Zhengjia (Nelson) Chen, PhD; (Research 
Assistant Professor, Department of Biostatistics and Bioinformatics, Rollins School of Public 
Health & Biostatistics Shared Core Resource; 1365 Clifton Road NE, Building B, Room B4110; 
Tel: 404-778-2017; Fax: 404-778-5016. Email: zchen38@emory.edu) to randomize patient, 
assign a study number and a dose. The coordinator is expected to fax a confirmation back to the 
registering site within 24 hours. 
Treatment on this protocol cannot begin prior to registration and must be administered at each 
site under the supervision of a medical oncologist. 
All screening procedures should be completed within 14 days prior to treatment unless otherwise 
specified in the Study Calendar or specific sections of this protocol. Issues that would cause 
treatment delays should be discussed with the Principal Investigator.  If a patient does not receive 
protocol therapy following registration, the patient’s registration on the study may be canceled.  
The Study Coordinator and or the study PI should be notified of cancellations as soon as 
possible.  
Investigational agents may be ordered by a participating site only after the initial IRB approval 
for the site has been forwarded to the study regulatory specialist at the Emory University 
WINSHIP CANCER INSTITUTE. 
6.5 
Treatment assignment 
Eligible patients will be randomly assigned to one of three arms to receive single agent 
Everolimus (Arm A), Pasireotide (Arm B) or the combination of both drugs (Arm C). 
Randomization is conducted with a block of 3 patients in order to balance the enrollment in each 
arm (The first of the 3 patients entered consecutively is randomly assigned to any of the 3 arms; 
the second patient is randomly assigned to one of the remaining 2 arms and the third patient to 
the last arm). 
Patients who progress while on single agent therapy (Arms A or B) and proceed with the 2-drug 
combination will be re-registered into Arm A1 and Arm B1 respectively for everolimus and 
pasireotide arms.  


 
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6.6 
Treatment blinding 
This is an unblinded randomized trial. Both the investigator and the patient will be aware of 
treatment assignment at the time of enrolment. 
6.7 
Treating the patient 
Study drug administration 
Everolimus is an oral drug to be self-administered by the patient with or without food and 
preferably around the same time every day. 
Pasireotide is parenterally administered. The long acting formulation of Pasireotide will be 
administered intramuscularly by trained Oncology nurse at the beginning of each cycle. All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded. 
The investigational study drugs used in the course of this trial are pasireotide (SOM230) and 
everolimus (RAD001).  Novartis will supply pasireotide and everolimus free of charge for study 
participants. 
Permitted study drug adjustments 
 
Toxicity will be assessed using the NCI-CTC for Adverse Events, version 4.0 (CTCAEv4.0, 
(http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev4.pdf)). For 
patients who are unable to tolerate the protocol-specified SOM230C and RAD001 dosing 
schedule, dose-adjustment guidelines are given below. 
The following dose modification schedules will be used where dose adjustment is necessitated 
by treatment related adverse events. The listed starting dose of Pasireotide may change if the 
ongoing phase I study established that higher doses of Pasireotide can be safely combined with 
the established dose of Everolimus. 
 
 
Table Error! No text of specified style in document.6-2 
SOM230C + RAD001 Dose Levels 
 
Pasireotide LAR 
 
Dose level 
Dose and schedule 
0 (starting dose) 
60 mg i.m. Q 4 weeks 
Decrease 1 dose level 
40 mg i.m. Q 4weeks 
Decrease 2 dose levels 
 
20 mg i.m. Q 4 weeks 
Everolimus 
 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg daily day 1 - 28 


 
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Decrease 1 dose levels 
5 mg daily day 1 - 28 
Decrease 2 dose levels 
5 mg daily days 1 - 21 of a 28-day cycle 
Decrease 3 dose levels 
5 mg every other day for a 28-day cycle 
 


 
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Table 6-3 Criteria for dose-modification in case of suspected SOM230 and RAD001 toxicity for 
non-hematologic toxicity 
Toxicity 
Actions 
Grade 2  
(except pneumonitis  [refer to Table 6-5] and mucositis) 
If the toxicity is tolerable to the patient, maintain the 
same dose.  
If the toxicity is intolerable to patient, interrupt 
RAD001 and pasireotide until recovery to grade 1. 
Then reintroduce RAD001 and pasireotide at one lower 
dose level. 
 
 
Grade 2 mucositis 
If the toxicity is tolerable to the patient, maintain the 
same dose.  
If the toxicity is intolerable to patient, interrupt 
RAD001 and pasireotide until recovery to grade 1. 
Then reintroduce RAD001 and pasireotide at one lower 
dose level.  See Management of stomatitis/oral 
Mucositis/mouth ulcers  for further details. 
 
Grade 3 
(except hyperlipidemia and hyperglycemia and mucositis and 
pneumonitis) 
Interrupt RAD001 and pasireotide until recovery to 
grade 1. Then reintroduce RAD001 and pasireotide at 
one lower dose level.   
If the same toxicity recurs at CTC grade ≥3 SOM230 
and RAD001 will be discontinued. 
 
 
Grade 3 hyperlipidemia 
Grade 3 hyperlipidemia (hypercholesterolemia and/or 
hypertriglyceridemia) should be managed using 
medical therapies, see Management Guidelines for 
Hyperlipidemia and Hyperglycemia.  Dose reduction 
of RAD001 and pasireotide can be considered but is 
not required. 
 
Grade 3 hyperglycemia 
Grade 3 hyperglycemia should be managed using 
medical therapies, see Management Guidelines for 
Hyperlipidemia and Hyperglycemia.  Dose reduction 
of RAD001 or pasireotide can be considered but is not 
required. 
 
Grade 3 mucositis 
For Grade 3 mucositis, interrupt RAD001 until 
recovery to grade 1. Then reintroduce RAD001 and 
pasireotide at one lower dose level See Management of 
stomatitis/oral Mucositis/mouth ulcers for further 
details. 
 
Grade 3 pneumonitis 
Please refer to Table 6-5 
Grade 4 
Discontinue pasireotide and RAD001. 


 
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Any non-hematological toxicity requiring interruption for > 3 
weeks 
Discontinue pasireotide and RAD001. 
Table 6-4Criteria for dose-modification in case of suspected SOM230 and RAD001 for hematologic 
toxicity  
Toxicity 
Actions 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥ 50x109/L)  
Interrupt RAD001 until recovery to grade 1 (>75 x109/L). 
Then reintroduce RAD001 at initial dose. 
If thrombocytopenia again returns to grade 2,  interrupt 
RAD001 until recovery to grade 1. Then reintroduce 
RAD001 at the lower dose level.  
Grade 3 Thromboc yt openia (platelets <50, ≥ 25 x10 9/L)  
Interrupt RAD001 until recovery to grade ≤1 (platelets ≥ 75 
x109/L).  Then resume  RAD001 at one dose level lower.  If 
grade 3 thrombocytopenia recurs, discontinue RAD001. 
Grade 4 Thrombocytopenia (platelets < 25 x109/L)  
Discontinue RAD001. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt RAD001 until recovery to grade 1 ( neutrophils ≥ 
1.5 x 109/L). Then resume RAD001 at the initial dose.  If 
ANC again returns to Grade 3, hold RAD001 until the ANC ≥ 
1.5 x 109/L.  Then resume RAD001 dosing at the lower dose 
level.  Discontinue patient from study therapy for a third 
episode of grade 3 neutropenia. If clinically indicated, patient 
with prolonged neutropenia may be treated with growth 
factors. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt RAD001 until recovery to grade 
( 1  (neutrophils ≥ 1.5 x 109/L). Then 
resume RAD001 at the lower dose level. 
If grade 3 or grade 4 neutropenia occurs 
despite this dose reduction, discontinue 
RAD001. . If clinically indicated, patient 
with prolonged neutropenia may be 
treated with growth factors. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt RAD001 until resolution of 
fever and neutropenia to grade ≤ 1. Hold 
further RAD001 until the ANC ≥ 
1,500/mm3 and fever has resolved. Then 
resume RAD001 at the lower dose level. 
If febrile neutropenia recurs, discontinue 
RAD001. If clinically indicated, patient 
with prolonged neutropenia may be 
treated with growth factors. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue RAD001. 
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 3 weeks 
Discontinue RAD001 
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed 
using medical therapies (see Sec. 3.2.5.2). 


 
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Management of non-infectious pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious pneumonitis 
(grade 2 = not interfering with activities of daily living or grade 3 = interfering with activities of 
daily living and oxygen indicated) have been noted in patients receiving RAD001 therapy. Non-
infectious pneumonitis has been associated with RAD001 and other mTOR inhibitors (Atkins 
2004). In order to monitor for asymptomatic (grade 1) pulmonary infiltrates, a chest X-ray is 
required if a CT scan of chest is not used for bi-monthly disease evaluations. Additional chest 
CT scans may be performed, when clinically necessary. If non-infectious pneumonitis develops, 
a consultation with a pulmonologist should be considered. If the patient develops grade 3 
pneumonitis, treatment with RAD001 should be interrupted and the patient should be treated as 
medically indicated (short course corticosteroids, oxygen, etc). 
Management of non-infectious pneumonitis suspected to be associated with RAD001 and dose 
modifications instructions are provided in Table 6-2 and Table 6-3, respectively. 
Table 6-5 
Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
RAD001 Dose Adjustment 
Grade 1 
CT scans with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, and 
room air O2 saturation at rest. 
Repeat chest x-ray/CT scan every 2 
Cycles until return to baseline. 
No specific therapy is 
required 
Administer 100% of RAD001 dose. 
Grade 2 
CT scan with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, and 
room air O2 saturation at rest. 
Repeat each subsequent Cycle until 
return to baseline. Consider 
bronchoscopy *  
Symptomatic only. 
Prescribe 
corticosteroids if 
cough is troublesome. 
Reduce RAD001 dose until recovery to ≤ 
Grade 1. RAD001 may also be interrupted 
if symptoms are troublesome. Patients will 
be withdrawn from the study if they fail to 
recover to ≤ Grade 1 within 3 weeks. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing 
including: spirometry, DLCO, and 
room air O2 saturation at rest.; 
Repeat each subsequent Cycle until 
return to baseline. Bronchoscopy is 
recommended * 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Hold treatment until recovery to ≤ Grade 1. 
May restart protocol 
treatment within 2 weeks at a reduced dose 
(by one level) if evidence of clinical 
benefit. 
Patients will be withdrawn from the study 
if they fail to recover to ≤ Grade 1 within 2 
weeks.  
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 saturation 
at rest. Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is recommended *. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 
 
 


 
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Other Known Undesirable Side Effects of everolimus 
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a 
randomized phase III study for the treatment of metastatic renal cell carcinoma. In total, 165 
patients were exposed to everolimus 10 mg/day for ≥4 months. The median age of patients was 
61 years (range 27 to 85). The most common adverse reactions (incidence ≥10%) were 
stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, vomiting, 
cough, peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnea. The most 
common grade 3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, fatigue, and 
pneumonitis. 
The median duration of blinded study treatment was 141 days (range 19 to 451) for patients 
receiving everolimus and 60 days (range 21 to 295) for those receiving placebo. The rates of 
treatment-emergent adverse reactions resulting in permanent discontinuation were 7% and 0% 
for the everolimus and placebo treatment groups, respectively. Most treatment-emergent adverse 
reactions were grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were 
reported in 39% versus 7% of patients receiving everolimus and placebo, respectively. Deaths 
due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were 
observed on the everolimus arm. 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, 
viral or protozoan infections, including infections with opportunistic pathogens. Localized and 
systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, 
such as aspergillosis or candidiasis and viral infections including reactivation of hepatitis B 
virus, have been described in patients taking everolimus. Some of these infections have been 
severe (e.g. leading to respiratory or hepatic failure) and occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with everolimus. Treat 
pre-existing infections prior to starting treatment with everolimus. While taking everolimus, be 
vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute 
appropriate treatment promptly and consider interruption or discontinuation of everolimus. If a 
diagnosis of invasive systemic fungal infection is made, discontinue everolimus and treat with 
appropriate antifungal therapy. 
 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have also been seen in this 
setting with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce 
the risk of Hepatitis B virus reactivation and associated morbidity and mortality (Loomba 2008). 
A detailed assessment of Hepatitis B/C medical history and risk factors must be done for all 
patients at screening, with testing performed prior to the first dose of everolimus.  
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, 
dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or 
without respiratory impairment) have been observed with everolimus. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting a patient on everolimus. Mouth ulcers, 


 
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stomatitis and oral mucositis have been seen in patients treated with everolimus. In such cases 
topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should 
be avoided as they may exacerbate the condition. Antifungal agents should not be used unless 
fungal infection has been diagnosed. 
Elevations of serum creatinine, usually mild, have been reported in clinical trials. Monitoring of 
renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is 
recommended prior to the start of everolimus therapy and periodically thereafter. 
Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported in clinical 
trials. Monitoring of complete blood count is recommended prior to the start of everolimus 
therapy and periodically thereafter. 
Everolimus is not recommended in patients with severe hepatic impairment, (Child-Pugh class 
C). 
The use of live vaccines and close contact with those who have received live vaccines should be 
avoided during treatment with everolimus. 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been reported as 
serious adverse reactions. Electrolytes should be monitored in patients treated with everolimus. 
More detailed information regarding everolimus reported suspected toxicities and individual 
cases is provided in the [Investigator’s Brochure]. 
 
Management of Hepatitis reactivation 
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during 
anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation and 
associated HBV morbidity and mortality.51 
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 6-6 provides details of monitoring and prophylactic therapy according to the baseline 
results of viral load and serologic markers testing. 
 
Table 6-6 
Action to be taken for positive baseline hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should 
be started 1-2 weeks prior to 
first dose of  study drug 
No prophylaxis 
Monitor HBV-DNA approximately 
No specific 
action 


 
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Test 
Result 
Result 
Result 
Result 
Result 
Monitor HBV-DNA 
approximately every 4 weeks 
 
every 4 weeks 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug.     
For patients who have already received study drug prior to the approval of the amendment, the same process should 
be followed at the patient's next visit. The first HBV-DNA result would be regarded as baseline. 
For hepatitis B reactivation, definition and management guidelines, see Table 6-7 Guidelines for management of 
hepatitis B.   
 
Table 6-7 Guidelines for management of hepatitis B 
HBV reactivation  (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation 
is 
defined 
as:   
[Increase of 1 log in HBV-
DNA 
relative 
to 
baseline 
HBV-DNA value OR new 
appearance 
of 
measurable 
HBV-DNA] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral  
AND 
Interrupt study drug administration until resolution:  
 ≤ grade 1 ALT (or baseline ALT, if > grade 1) and 
 ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-started at one 
dose lower, if available. If the patient is already receiving the lowest dose of 
study drug according to the protocol, the patient should restart at the same 
dose after resolution. Both antiviral therapies should continue at least 4 
weeks after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue study drug but 
continue both antiviral therapies at least 4 weeks after last dose of study 
drug. 
For patients with baseline 
results:  
Negative 
HBV-DNA 
and 
HBsAg  
AND  
[Positive HBs Ab (with no 
prior history of vaccination 
against HBV), OR positive 
HBc Ab]  
------------------------------------- 
reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat : Start first antiviral medication  
AND 
Interrupt study drug administration until resolution:  
  ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-started at one 
dose lower, if available. If the patient is already receiving the lowest dose of 
study drug according to the protocol, the patient should restart at the same 
dose after resolution. Antiviral therapy should continue at least 4 weeks 
after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue study drug but 
continue antiviral therapy at least 4 weeks after last dose of study drug. 


 
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* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-
activation), unless considered life threatening by the investigator; in which case they should be recorded as grade 4 
(CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation is the date on which 
both DNA and ALT criteria were met (e.g. for a patient who was HBV-DNA positive on 01-JAN-10 and whose 
ALT reached ≥ 5 × ULN on 01-APR-10, the date of viral reactivation is 01-APR-10). 
 
Monitoring for hepatitis C 
The following two categories of patients should be monitored every 4 weeks for HCV 
reactivation: 
 Patients with detectable  HCV RNA-PCR test at baseline. 
 Patients known to have a history of HCV infection, despite a negative viral load test at 
baseline (including those that were treated and are considered ‘cured’) 
For definition of hepatitis C reactivation and the management guidelines, see Table 6-8 
Guidelines for management of hepatitis C. 
Table 6-8 Guidelines for management of hepatitis C 
HCV reactivation* 
For patients with baseline results:  
Detectable HCV-RNA,  
 
reactivation is defined as: 
ALT elevation x 5 ULN  
Discontinue study drug  
 
 
For patients with baseline results: 
Knowledge of past hepatitis C 
infection with no detectable HCV-
RNA,   
 
reactivation is defined as: 
New appearance of detectable HCV-
RNA  
Discontinue study drug 
 
* All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v4.0 Metabolic Laboratory/Other: Viral Re-
activation), unless considered life threatening by the investigator; in which case they should be recorded as grade 4 
(CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation).  
 
Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with everolimus as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, please 


 
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classify the adverse event as such. Please follow the paradigm below for treatment of 
stomatitis/oral mucositis/mouth ulcers: 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth wash 
or salt water (0.9%) mouth wash several times a day until resolution. 
2. For more severe toxicity (Grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or Grade 3 in which case patients cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 
anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®). 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should 
be avoided in all patients due to their strong inhibition of everolimus metabolism, thereby 
leading to higher everolimus exposures. Therefore, topical antifungal agents are preferred if 
an infection is diagnosed. Similarly, antiviral agents such as acyclovir should be avoided 
unless a viral infection is diagnosed. 
Note:  Stomatitis/oral mucositis should be appropriately graded using the functional grading 
given on the NCI-CTC for adverse events, version 4.0. 
Management Guidelines for Hyperlipidemia and Hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits. 
Blood tests to monitor hyperlipidemia must be taken in the fasting state.. Hyperlipidemia and 
hypertriglyceridemia should be treated according to local best clinical practice. Patients should 
be monitored clinically and through serum chemistry for the development of rhabdomyolysis and 
other adverse events as required in the product label/data sheets for HMG-CoA reductase 
inhibitors. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting trial therapy. 
Hyperglycemia is known to be associated with the treatment with somatostatin analogues (SSA). 
Clinical studies of pasireotide in healthy volunteers and in patients with Cushing’s disease, 
acromegaly or carcinoid syndrome have reported transient, asymptomatic increases in fasting 
and postprandial glucose levels. Novartis has conducted 2 clinical studies ([sSOM230B2216] 
and [SOM230B2124) to further understand the mechanism of pasireotide-induced 
hyperglycemia and to evaluate the clinical utilotiy of anti-diabetes agents in the management of 
pasreiotide-induced hyperglycemia. Preliminary results suggest that pasireotide induces insulin 
suppression particularly in the postprandial period, as being the key mechanistic driver of 
hyperglycemia. Based on the mechanisms of pasireotide-induced hyperglycemia and findings 
from the [SOM230B2124] study, appropriate management for the pasireotide-induced 
hyperglycemia includes the use of oral anti-diabetic agents for mild to moderate hyperglycemia, 


 
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such as incretin enhancers (e.g. GLP-1 analogues or DPP4 inhibitors or insulin secretagogues). 
Metformin is not recommended. Insulin should be used for moderate to sever hyperglycemia.  
Clinical monitoring and self-monitoring of blood glucose level 
In addition to the laboratory evaluation of blood glucose level at the regularly scheduled visits, 
patients are recommended to self-monitor their blood glucose (fasting and postprandial 
assessment) using a home glucometer. This self-monitoring guidance is to provide adequate and 
proactive monitoring so that pasireotide-induced hyperglycemia can be adequately managed and 
treated.  
Patients with the history of increased blood glucose level in the past are recommended to self-
monitor blood glucose twice a day (fasting and two hours after a meal). Patients with normal 
blood glucose level without history of elevated blood glucose levels in the past should be 
recommended to measure blood glucose level every other day. Patients should be instructed to 
record the blood glucose value in a glucose diary and contact the study site immediately, if the 
glucose level rises beyond 130mg/dL in a fasting state or 180 mg/dL after a meal. 
During the study, all patients with HbA1c = 7 % and or fasting plasma glucose (FPG) > 130 
mg/dL (7.2 mmol/L), or 2-hour post-prandial capillary glucose (PPG) = 180 mg/dL (10 mmol/L) 
on two consecutive measurements that are within 14 days, should be considered for the 
following: 
 
• 
Referral to a diabetes specialist for evaluation and appropriate management 
• 
Provided information and receive teaching on diabetes disease management 
• 
Monitoring of blood glucose by fingerstick twice daily (fasting morning blood glucose and 2-
hour post-meal) if not already done. Patients, who monitor blood glucose should keep a diary of 
their glucose values and present the collected data to their physician/ diabetes specialist for 
evaluation and appropriate management. 
 
Management Guidelines for ECG Monitoring for Prolonged QT 
ECG frequency for SOM230 LAR studies: 
ECG monitoring is recommended at the following time points: 
 Baseline (before SOM230 LAR injection) 
 21 days after 1st SOM230 LAR injection  
 21 days after 3rd SOM230 LAR injection 
 Cycle 6 (before SOM230 LAR injection) 
 Every 3 cycles after Cycle 6 
 ECG should be done at any time when clinically indicated 
 
ECG procedures in the event of prolonged QTc 
 If at any visit a QTcF>480 msec is observed, the following steps need to be taken: 
 
o A cardiology consultation must be sought as soon as practicable but within 7 days of the 
initial abnormal ECG and the cardiologist must re-evaluate the ECG (this can be done by 
the central cardiologist if the trial has one). 
o If a QTcF>480msec is NOT confirmed, no further action needs to be taken. 


 
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o If a QTcF>480msec is confirmed, a cardiologist must perform a thorough examination 
(such as reviewing baseline ECG, concurrent medications and performing a 
cardiovascular examination (including at least a cardiac auscultation)) to assess the 
patient for cardiovascular risk factors. 
 
o If based upon the assessment by the cardiologist, the investigator considers that there is 
an acute cardiovascular safety risk and that the patient should not continue with study 
medication, the patient needs to be discontinued immediately (discontinuation criteria to 
be followed). 
 
o If following the examination by the cardiologist, the investigator considers that there is 
not an acute cardiovascular safety risk and that the patient could continue to receive study 
medication, a Holter ECG (24hr) must be recorded soon as practicable but within 7 days 
after the initial abnormal ECG or at the next SOM230 LAR injection. The Holter-ECG 
must be started 30min prior to an injection of study medication. 
 
o The results of the ECGs, cardiac examination, Holter-ECGs and the recommendation by 
the cardiologist must be evaluated by the investigator to determine whether the patient 
should continue in the trial or not (discontinuation criteria to be followed). 
 
 Cmax drug concentration visit: If at a Day 21 visit (day 21 after any injection of 
Pasireotide/Octreotide LAR) a Cmax QTcF>480 msec is observed for the first time for a 
patient at a given dose level, the following steps need to be taken: 
o A cardiology consultation as described in the preceding section must be sought as soon as 
practicable but within 7 days after the initial abnormal ECG and prior to the next Pasireotide/ 
Octreotide LAR injection. 
o All steps described in the preceding section must be followed, however if a Holter ECG is 
required, a 24hour Holter ECG must be recorded when the patient receives the next scheduled 
Pasireotide/ Octreotide LAR injection. The Holter ECG should be started 30min prior to the 
injection. 
 
 Trough concentration visit e.g. day 1 of a new cycle: If at any visit a trough level 
QTcF>480 msec is observed for the first time for a patient at a given dose level, the 
following steps need to be taken: 
o A cardiology consultation as described in the preceding section must be sought as soon as 
practicable but within 7 days after the initial abnormal ECG and prior to the next 
Pasireotide/Octreotide LAR injection. 
o All steps described in the preceding section must be followed; however if a Holter-ECG is 
required, a 24hour Holter-ECG must be recorded and evaluated prior to the next injection of 
Pasireotide/Octreotide LAR. The Pasireotide/Octreotide injection must be postponed until the 
Holter-ECG results are available with a maximal permissible delay of 7 days. If the outcome 
of the cardiac evaluation is that the patient may receive a further dose of Pasireotide/ 
Octreotide LAR, then a second 24hr Holter-ECG must be done on the day of the LAR 
injection.  


 
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o This Holter ECG should be started 30min prior to the injection. 
 
Table 6-8a: Guidelines for dose modification for QT prolongation while on SOM230 
Adverse event 
Action 
*Grade ≤ 2  
No study drug adjustments  
*Grade ≥ 3 and judged as 
at least possibly drug 
related  
·     Further injections should be held for at least 7 days and until toxicity 
improves to ≤ Grade 1.  
·     If toxicity improves to grade ≤ 1 within 7 days, no dose reduction is 
required.  
·     If toxicity improves to grade ≤ 1 in 8-14 days, resume treatment with a 
single dose level reduction.  
·     If toxicity improves to grade ≤ 1 in 15-28 days, resume treatment with 
two dose level reductions.  
·     If toxicity fails to improve to grade ≤ 1 within 28 days, study treatment 
must be discontinued unless there is clear evidence of therapeutic benefit 
from the study regimen, in which case continued treatment is left to the 
discretion of the Overall Principal Investigator.  
·     If any toxicity recurs at CTCAE grade ≥ 3, treatment must be 
discontinued.  
QTc CTC grade 1 (≤ 480 
msec)  
·     No study drug adjustments  
QTc CTC grade 2 (> 480 
or ≤ 500 msec) either 
drug related or drug 
unrelated  
Patient is to be referred to a cardiologist for evaluation and appropriate 
management, and the patient can remain in the study  
·     Patient’s study drug dose will be reduced to 1 dose level down  
QTc CTC grade ≥ 3 (> 
500 msec)  
Discontinue study drug  
Follow patient for safetyA  
 
SOM230 Management Guidelines for Suspected Hepatic Toxicity 
In case of suspected SOM230-related hepatic injury manifesting as abnormal LFTs, the 
following steps should be followed within 72 hours of awareness of abnormal liver function 
tests: 
 Liver-directed medical history and physical examination (i.e. assess occupational hazards, 
concomitant medications including OTC meds, intercurrent illness, etc) 
 Liver chemistry tests: ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if 
total bilirubin is > 2.0x ULN), Alb, PT (INR), ALP, and GGT 
 Hepatitis screen:  
o anti-HAV, IgM (to confirm acute hepatitis A) 
o HbsAg, Anti-HBc 
o anti-HCV (if positive, PCR viral load should be assessed),  
o Anti-HEV 
o ANA antibodies, anti-smooth muscle anti-bodies, CMV, EBV 
 Perform abdominal ultrasound (liver and biliary tree) 
 
Liver chemistry tests should be monitored every 3-4 days until resolution or return to baseline 
status. 


 
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 For ALT or AST > 5x ULN and ≤ 8x ULN: 
 Study medication should be temporarily interrupted and liver chemistry tests 
monitored every 3-4 days until resolution or return to baseline 
 If resolution or return to baseline does not occur after 2 weeks, the patient 
should be discontinued. 
 If ALT or AST returns to less than 5x ULN, study drug can be resumed and 
patient can continue study per protocol 
 If ALT or AST rises above 5x ULN anytime after study drug is resumed, then 
study drug should be discontinued immediately. 
Follow-up LFT monitoring will take place at 3-4 day intervals (Table 2). 
SOM230 Hepatic-related discontinuation criteria 
Study medication should be discontinued immediately if any of the discontinuation criteria 
below are met: 
 ALT or AST > 3x ULN and Total Bilirubin > 2x ULN and ALP < 2x ULN 
 ALT or AST > 5x ULN and ≤ 8x ULN persistent for more than 2 weeks 
 ALT or AST > 8x ULN 
Re-challenge of study medication is prohibited once discontinuation criteria are met. 


 
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SOM230 LFT Management Algorithm 


 
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Follow-up for toxicities 
Patients who interrupt or permanently discontinue SOM230 and RAD001 due to an adverse 
event or abnormal laboratory value should be followed at least weekly for 28 days after the last 
dose of SOM230 and RAD001, and subsequently at monthly intervals until resolution or 
stabilization of the event, whichever comes first. If a patient requires a SOM230 and RAD001 
dose delay of > 21 days from the intended day of the next scheduled dose, then the patient should 
be discontinued from the study. 
All patients will be followed for adverse events and serious adverse events for 28 days following 
the last dose of SOM230 and RAD001. 
 
6.8 
Other concomitant medications 
Concomitant therapy 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the patient about any new medications he/she is or has taken after 
the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be recorded. 
The following restrictions apply during the entire duration of the study: 
 No other investigational therapy should be given to patients. 
 No anticancer agents other than the study medication should be given to patients. If such 
agents are required for a patient then the patient must first be withdrawn from the study. 
 Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided 
 Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. 
Concomitant use should be avoided 
 Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution.  If patient requires co-administration of moderate 
CYP3A4 inhibitors or PgP inhibitors, reduce the dose of RAD001 to 5 mg daily. Additional 
dose reductions to 5 mg every other day may be required to manage toxicities. If the inhibitor 
is discontinued the RAD001 dose should be returned to the dose used prior to initiation of the 
moderate CYP3A4/PgP inhibitor. 
 Avoid the use of strong CYP3A4 inducers. If patient requires co-administration of strong 
CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, Phenobarbital, St. 
John’s wort), the patient should be monitored as per protocol and discontinued from 
study treatment if progression occurs. An increase in the dose of RAD001 from 10 mg up 
to 20 mg daily should be considered, using 5 mg increments. Enzyme induction usually 
occurs within 7-10 days, therefore RAD001 dose should be increased to 15 mg daily, 7 days 


 
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after the start of the inducer therapy.  If no safety concerns are seen within the next 7 days, 
the dose can be increased again to 20 mg daily.  This dose of RAD001 is intended to achieve 
similar AUC to the range observed without inducers.  However, there are no clinical data 
with this dose adjustment in patients receiving strong CYP3A4 inducers.  If the strong 
inducer is discontinued the RAD001 dose should be returned to the dose used prior to 
initiation of the strong CYP3A4/PgP inducer. 
 No chronic treatment with systemic steroids or another immunosuppressive agents (at a dose 
equivalent of greater than 20 mg prednisone per day) or other immunosuppressive agents). 
Topical or inhaled corticosteroids are allowed. 
 RAD001 may affect the response to vaccinations making the response to the vaccination less 
effective. Live vaccines should be avoided while a patient is treated with RAD001. 
 QT prolonging medication - the use of concomitant medications that might lead to QT 
prolongation is prohibited and requires the discontinuation of the patient prior to starting the 
respective QT prolonging medication. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
RAD001 is expected. However, drug-drug interaction studies between macrolide antibiotics and 
warfarin have produced mixed outcomes and the disparity in these findings has led to the 
conclusion that multiple factors may alter the clearance of warfarin. The co-administration of 
RAD001 and oral anticoagulants is possible but should be subject to verification of coagulation 
(INR) once steady state is reached (after one week’s treatment). 
Examples are provided in Table 6-9. A comprehensive list of cytochrome P450 isoenzymes and 
CYP3A4 inhibitors, inducers, and substrates can be found at http://medicine.iupui.edu/flockhart.  
This website is continually revised and should be checked frequently for updates. 


 
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Table 6-9 Examples of clinically relevant drug interaction: substrates, inducers and inhibitors of 
isoenzyme CYP3A.  
Substrates (competitive inhibition) 
 
Antibiotics1: 
 
clarithromycin* 
 
erythromycin  
 
telithromycin* 
Anti-arrhythmics: 
 
quinidine 
Benzodiazepines: 
 
alprazolam 
 
diazepam 
 
midazolam 
 
triazolam 
Immune Modulators: 
 
cyclosporine 
 
tacrolimus (FK506) 
HIV Protease Inhibitors: 
 
indinavir* 
 
ritonavir* 
 
saquinavir* 
Prokinetic: 
 
cisapride 
Antihistamines: 
 
astemizole 
 
chlorpheniramine61 
Calcium Channel Blockers: 
 
amlodipine 
 
diltiazem 
 
felodipine 
 
nifedipine 
 
nisoldipine 
 
nitrendipine 
 
verapamil 
HMG CoA Reductase Inhibitors2:  
 
atorvastatin 
 
cerivastatin 
 
lovastatin 
 
simvastatin 
Miscellaneous: 
 
aprepitant 
 
buspirone 
 
haloperidol 
 
methadone 
 
pimozide  
 
quinine 
 
sildenafil 
 
tamoxifen 
 
trazodone 
 
vincristine 
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin* 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Cimetidine 
Clarithromycin 
Delaviridine 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Sevilla orange 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and 
polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104.  and 
[http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 13, 2006] 
* asterisk denotes strong inhibition/ induction  
Please note: 
- 
strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in clearance of sensitive 
CYP substrates 
- 
moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% decrease in clearance  
of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions). 
1. Macrolide antibiotics: Azithromycin is not a CYP3A substrate. It may therefore be employed where 


 
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antibiotherapy with a macrolide is desirable in a patient being treated with RAD001 
2. Statins: Atorvastatin and pravastatin may be associated with RAD001, since a PK interaction study has shown that 
there is no relevant PK interaction.  
6.9 
Study drug discontinuation 
Patients experiencing unacceptable toxicity (AE grade 3 or higher) that the investigator considers 
directly attributable to the study drug should have their dose adjusted as per dose modification 
guidelines in Table 6-2. If a patient has already decreased 2 dose levels, no further dose 
reduction is permitted, and the patient will be permanently discontinued from treatment. A delay 
of more than 21 days in resuming study drug due to treatment-emergent adverse event will result 
in the withdrawal of the patient from the study (non-treatment related delay of more than 21 days 
but no more than 28 consecutive days may be allowed to resume therapy after discussion with 
the overall PI). Patient so withdrawn should undergo the required end of study procedures 
follow-up post treatment discontinuation. 
Premature patient withdrawal/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 may be withdrawn from the study if any of the following occur: 
 Disease progression or lack of efficacy 
 Uncontrolled diabetes mellitus (DM) 
 Pregnancy 
 Adverse event(s)  
 Abnormal laboratory value(s) 
 Abnormal test procedure result(s) 
 
QT-related discontinuation criteria  
 
Confirmed QTcF >480msec and discontinuation recommended by a cardiologist 
 
New occurrence of clinically significant/symptomatic bradycardia  
 
Increased risk of QT prolongation by use of QT prolonging medication 
 
Hypokalemia (<3.5 mmol/L) or hypomagnesaemia (<0.7 mmol/L) confirmed by repeat 
testing that is either a new finding or accompanied by vomiting or diarrhea and not corrected 
by treatment 
 Protocol violation 
 Subject withdrew consent 
 Lost to follow-up 
 Administrative problems 
 Death 
 Disease progression 
 Treatment duration completed as per protocol 


 
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7 
Visit schedule and assessments 
Table 7-1 lists all of the assessments and indicates the visits at which they are to be performed 
with an “X”. All data obtained from these assessments must be supported in the patient’s source 
documentation. To accommodate scheduling challenges, the required assessments may be 
performed within +/- 2 days of the specified scheduled dates. 
Hepatitis Screening 
A detailed assessment of hepatitis B/C medical history and risk factors must be done for all 
patients at screening.  Patients with positive hepatitis B and/or hepatitis C test results are 
ineligible for the study. Testing for hepatitis B viral load and serologic markers: HBV-DNA, 
HBsAg, HBs Ab, and HBc Ab and HCV RNA PCR are required at screening for all patients in 
the following risk categories:  
o All patients who currently live in (or have lived in) Asia, Africa, Central and South America, 
Eastern Europe, Spain, Portugal, and Greece.  
[http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/hepatitis-b.aspx#849] 
o Patients with any of the following risk factors:  
• known or suspected past hepatitis B infection,  
• blood transfusion(s) prior to 1990,  
• current or prior IV drug users,  
• current or prior dialysis,  
• household contact with hepatitis B infected patient(s),  
• current or prior high-risk sexual activity,  
• body piercing or tattoos,  
• mother known to have hepatitis B 
• history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper quadrant 
pain. 
o Additional patients at the discretion of the investigator  
 
Testing for hepatitis C should be performed using quantitative RNA-PCR at screening for all 
patients in the following risk categories: 
o known or suspected past hepatitis C infection (including patients with past interferon 
‘curative’ treatment),  
o blood transfusions prior to 1990,  
o current or prior IV drug users,  
o current or prior dialysis,  
o household contact of hepatitis C infected patient(s),  
o current or prior high-risk sexual activity,  
o body piercing or tattoos,  
o At the discretion of the investigator, additional patients may also be tested for hepatitis C.  


 
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Table 7-1 Schedule of Events and Assessments 
Patient assessments and the visits at which they are to be performed are indicated with an “X”. All data obtained from these assessments must be supported in the patient’s 
source documentation.  
In order to accommodate scheduling challenges, the required assessments may be performed within +/- 2 days of the specified scheduled dates. 
Examination 
Screening/ 
Baseline 
 
Pasireotide i.m. 
Everolimus p.o 
End of 
Study 
Follow-up 
Visit number 
1 
C1D1 
 
C1D22* 
C2D1 
C2D22* 
C3D1 
 
C3D22* 
C4D1 
C5D1 
C6D1 
C7D1$  
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
History/ current 
medical conditions 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X# 
X 
X 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and stage 
of cancer  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and ongoing 
therapy 
Xa 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam  
X 
X 
 
X 
 
X 
 
X 
X 
X 
X# 
X 
 
Vital signs  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X# 
X 
 
ECG  
X* 
X 
X* 
 
 
 
X* 
 
 
X* 
 
 
 
Gallbladder 
ultrasound  
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X# 
X 
 
Hematology 
X 
X& 
 
X 
 
X 
 
X 
X 
X 
X# 
X 
 
Glycosylated 
hemoglobin 
Xc 
X& 
 
 
 
 
 
 
 
 
 
 
 
PT, PTT 
X 
X& 
 
 
 
 
 
 
 
 
 
 
 
CMP including 
fasting cholesterol 
and triglyceride@ 
X 
X& 
 
X 
 
X 
 
X 
X 
X 
X# 
X 
 


 
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Table 7-1 Schedule of Events and Assessments 
Patient assessments and the visits at which they are to be performed are indicated with an “X”. All data obtained from these assessments must be supported in the patient’s 
source documentation.  
In order to accommodate scheduling challenges, the required assessments may be performed within +/- 2 days of the specified scheduled dates. 
Examination 
Screening/ 
Baseline 
 
Pasireotide i.m. 
Everolimus p.o 
End of 
Study 
Follow-up 
LFT assessment+  
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X# 
X 
 
Hepatitis screening 
X% 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Markers: 
Medullary: Free 
T4, TSH, CEA, 
Calcitonin and 
chromogranin A; 
Differentiated: 
TSH, free T4, 
thyroglobulin, 
thyroglobulin 
antibodies. 
X 
 
 
 
 
X 
 
 
X 
 
X# 
 
 
Biomarker Samples 
(IGF-1, optional 
PBMC) 
Xd 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Urinalysis 
X 
X& 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
X& 
 
 
 
 
 
 
 
 
 
 
 
Archival tissue 
collection 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
MRI/CT Scan 
Xf 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Study Drug 
Administration 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Response 
Assessment 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Adverse events 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
$ cycle 7 and beyond  


 
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& need not be repeated if within normal institutional reference limits and obtained within 7 days of C1D1 
@ Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, magnesium, potassium, total protein, SGOT, SGPT, sodium, bicarbonate, total 
protein, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, urea/BUN γ-GT, fasting blood glucose, phosphorous, [at screening and as clinically 
indicated: CPK, HbA1c, LDH lipase, α-amylase and uric acid]. If the total bilirubin concentration is increased above 1.5 times the upper normal limit (UNL), 
total bilirubin should be differentiated into the direct and indirect reacting bilirubin (patient may be treated if direct bilirubin is < 1.5 x ULN) 
# repeat visit every other cycle until progression or withdrawal from study; cholesterol and triglyceride only for patients on everolimus 
* Day 22 assessments only applicable to patients on pasireotide; EKG to be obtained only for patients on pasireotide at the following timepoints 
 
 
Baseline (before pasireotide LAR injection) 
• 
21 days after 1st pasireotide LAR injection  
• 
21 days after 3rd pasireotide LAR injection 
• 
Cycle 6 (before pasireotide LAR injection) 
• 
Every 3 cycles after Cycle 6 
• 
ECG should be done at any time when clinically indicated 
% All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C infection using clinical history as detailed in the 
subsection on hepatitis screening. Patients with viral hepatitis C risk factors should be screened for HCV RNA-PCR. Patients on antiviral prophylaxis treatment 
or positive HBV antibodies should be tested for HBV-DNA on Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for re-activation. If 
re-activation is confirmed, everolimus must be interrupted or discontinued according to the guidance in Tables 6-7 and 6-8. Patients with positive HCV RNA-
PCR results at screening and/or a history of past infection (even if treated and considered ‘cured’) should have HCV RNA-PCR testing performed on Cycle 1 
Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for reactivation. Everolimus must be discontinued if HCV reactivation is confirmed 
according to the guidance in Table 3-4. 
+: For patients receiving pasireotide, liver function tests [ALT, AST, total bilirubin, (fractionate to direct/indirect bilirubin if total bilirubin is > 2.0x ULN), Alb, 
PT (INR), Alkaline Phosphatase, and GGT] must be assessed at screening, baseline (C1D1), Day 22 (C1D22) after the first injection, Day 29 (C2D1), Day 50 
(C2D22), Day 57 (C3D1) and Day 85 (C4D1). After Day 85, monitoring should follow the regular CMP schedule. The Day 22 and Day 50 LFTs must be 
available and assessed prior to dosing on Day 29 (2nd injection) and Day 57 (3rd LAR injection). 
a:  not more than 1 prior systemic  therapy for patients’s current cancer allowed; prior radiation therapy is allowed. 
b: obtain only if clinically indicated; patient found with symptomatic gallstones are excluded; patients with asymptomatic incidental gall stone may be allowed at 
the discretion of the PI  
c: repeat as necessary if patient is a known diabetic or if baseline values elevated 
d: obtain peripheral blood sample for IGF-1 at the end of every even number cycle (up to end of cycle 6) as part of restaging evaluation  
e: if archival tissue cannot be obtained, upto-20 unstained slides may be collected if available. 
f: same modality should be used for each restaging; other imaging studies may be obtained in addition as necessary for clinical management. Baseline scan must 
be obtained not later 30 days of initiation of drug administration.  


 
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7.1 
Information to be collected on screening failures 
All clinical information and results of study related procedures should be collected in the CRF 
for all patients who signed informed consent but later found ineligible at screening.  
7.2 
Patient demographics/other baseline characteristics 
The study will be open to adult patients of all ethnicities, race, gender or social status who meet 
the eligibility criteria set forth in the protocol. Patient demographic information will be entered 
in the CRF at the time of enrolment. 
7.3 
Treatments 
All current medication used to treat diabetes mellitus should be documented. 
All medications, including over-the-counter medication, taken prior to study drug administration 
and which continue during the course of the study must be documented  
Compliance will be assessed by the investigator and/or study personnel at each visit. Records of 
study medication used, treatment administered, and intervals between visits will be kept during 
the study. Drug accountability will be noted. Patients will be asked to return all used medication 
ampoules at each visit and the end of the study. 
7.4 
Efficacy 
Primary efficacy assessment 
The primary endpoints of this study are response rate (RR) and progression free survival (PFS). 
Interim analysis for the RR primary endpoint will be performed after 18 evaluable patients have 
been enrolled for each arm of treatment. Any arm not meeting the pre-specified efficacy RR 
(specified in Section 10.1 under statistical analysis) will be closed to further accrual. Tumor 
response assessment will be performed after every two cycles of therapy using cross-sectional 
imaging according to the RECIST 1.1 criteria. 
 
All patients who completed at least 2 cycles of therapy will be deemed evaluable for the efficacy 
endpoint. In the event of study discontinuation prior to completing two treatment cycles for 
reasons other than disease progression, the affected subject will be considered inevaluable for 
efficacy and will be replaced by another subject (comparable as per stratification criteria) to be 
enrolled on the same arm of the study.  
Patients who discontinue treatment due to drug-related toxicity prior to obtaining a restaging 
scan would be considered inevaluable and would be replaced.  
Patients who discontinue treatment for symptomatic disease progression prior to a restaging scan 
would be deemed to have progressed as of the time of treatment discontinuation and will not be 
replaced.  
Patients who are lost to follow-up will be censored as of the last official contact date for efficacy 
and survival outcome analysis. If the event occured prior to the first restaging scan such patients 
will be deemed inevaluable for RR efficacy endpoint and will therefore be replaced by another 


 
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patient. They will, however, remain evaluable for overall safety assessment provided they have received 
at least one dose of the study drug.. 
 
Secondary efficacy assessments 
 Assessment for other secondary and exploratory endpoint will be performed at study conclusion. 
 
Patient will be evaluable for overall toxicity and safety endpoint determination if they received 
any dose of the investigational agent.  
Any patient deemed inevaluable for efficacy assessment as a result of treatment discontinuation 
due to treatment-related toxicity may still be evaluated for overall safety profile assessment. 
Notwithstanding this provision, however, only patients who are evaluable for the primary 
efficacy endpoint may be included in the safety assessment conducted for the sole of picking a 
winning arm for the trial. 
 
The investigational agents in this trial have not been previously studied in thyroid cancer, 
therefore we are unable to accurately determine the patient drop-off rate. Nonethelss, we have 
estimated that approximately 5% of all enrolled patients will be deemed inevaluable for safety 
and or efficacy assessment due to various factors listed above.


 
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Tumor response 
Response assessment will be based on the RECIST 1.1 criteria. Only patients with measurable 
disease at baseline should be included in the study. 
Definitions 
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 ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan. 
Non-measurable Lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and: 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
Clinical lesions will only be considered measurable when they are superficial (e.g., 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.  
Methods of Measurement   
• 
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 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen and 
pelvis. Head and neck tumors and those of extremities usually require specific protocols. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
• 
Since clinical benefit rate is one of the primary endpoints of the study, 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 to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 


 
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• 
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. 
• 
Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases 
(e.g., after treatment to differentiate between residual benign lesions and residual malignant 
lesions in tumor types such as germ cell tumors). 
Baseline documentation of “Target” and “Non-Target” Lesions 
• 
All measurable lesions up to a maximum of two lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline.  
• 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging techniques 
or clinically).  
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported 
as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize 
the objective tumor. 
• 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
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 LD of target lesions, 
taking as reference the baseline sum LD 
* Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started or the appearance of 
one or more new lesions 


 
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* Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started 
Evaluation of Non-Target Lesions 
* Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level 
* Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) 
or/and maintenance of tumor marker level above the normal limits 
* Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions (1)  
Although a clear progression of “non target” lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail and the progression status should be 
confirmed later on by the review panel (or study chair). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for 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. 
Table 7-2: Response Assessment by RECIST 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response 
/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


 
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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”. Every effort should be made to document the objective progression 
even after discontinuation of treatment.  
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 complete response 
status. 
Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate.  
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol  
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started.          
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for disease progression are met, 
taking as reference the smallest measurements recorded since the treatment started.  
Response Review 
For trials where the response rate is the primary endpoint it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion.  
Simultaneous review of the patients’ files and radiological images is the best approach. A central 
review of all responses is planned for the end of the study. Nonetheless, decision regarding 
treatment continuation will be based on the treating physician’s assessment with the concurrence 
of the PI in cases where there is differences of opinion. 
Reporting of Results 


 
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All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). 
All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered as failing to respond to 
treatment (disease progression).  Thus, an incorrect treatment schedule or drug administration 
does not result in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific. 
All conclusions should be based on all eligible patients. 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, these subanalyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported. 
7.5 
Safety 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations. 
These assessments should be performed within ±2 days of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study. Safety and 
tolerability 
will 
be 
assessed 
according 
to 
the 
NIH/NCI 
CTCAE 
version 
4.0 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf. 
7.5.1  Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
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: 


 
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1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the study drug(s) (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 medication taken; non-drug 
therapy given; hospitalization/prolonged hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
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, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the [Investigators’ Brochure]. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
7.5.1.1 
Serious adverse events 
A serious adverse event is an undesirable sign, symptom or medical condition 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 (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 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 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
 after the patient has provided informed consent and until 4 weeks after the patient has 
stopped study treatment/participation 
 after the patient is randomized and until 4 weeks after the patient has stopped study treatment 


 
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 after the patient begins taking study drug and until 4 weeks after the patient has stopped 
study treatment 
 after protocol-specified procedures begin (e.g., placebo run-in, washout period, double-blind 
treatment, etc.) and until 4 weeks after the patient has stopped study treatment 
 after the start of any period in which the study protocol interferes with the standard medical 
treatment given to a patient (e.g., treatment withdrawal during washout period, change in 
treatment to a fixed dose of concomitant medication) and until 4 weeks after the patient has 
stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. Any SAEs 
experienced after this 4-week period should only be reported to Novartis if the investigator 
suspects a causal relationship to the study drug. Recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event. 
The investigator must assess and record the relationship of each SAE to each specific study drug 
(if there is more than one study drug), complete the SAE Report in English, and send the 
completed, signed form by fax (1-877-778-9739) within 24 hours to the Novartis Clinical Safety 
and Epidemiology Department. 
The original copy of the SAE Report and the fax confirmation sheet must be kept within the 
Trial Master File 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 Clinical Safety and 
Epidemiology 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. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in accordance 
with Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
7.5.1.2 
Novartis instructions for rapid notification of serious adverse 
events 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, 
and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E). 


 
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All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
All events must be reported, by FAX (1-877-778-9739), to Novartis Pharmaceuticals CS&E 
Department within 24 hours of learning of its occurrence. This includes serious, related, 
labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths 
during treatment or within 30 days following completion of active protocol therapy must be 
reported within 24 hours of learning of the occurrence. 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the period 
in which the study protocol interferes with the standard medical treatment given to a patient (e.g. 
treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant 
medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
7.5.1.3 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
 
7.5.1.4 Adverse Event and Serious Adverse Event reporting from other participating sites 
The coordinating center at Emory University WINSHIP CANCER INSTITUTE would 
ultimately be responsible for reporting AEs and SAEs to the study supporter, NOVARTIS and 
the FDA as outlined above. All other participating sites are required to transmit details of any 
suspected AE and SAE at their centers to the coordinating center for the attention of: 
Vanessa H. Phelan, BS 
Regulatory & Compliance Specialist 
Winship Cancer Institute-Emory University 
1256 Briarcliff Road, Bldg. A, 421W-A 
Atlanta, GA 30306 
Ph. 404.778.2918 | Fax. 404.778.4004 
Email: vanessa.h.phelan@emory.eduOr  
 
Kim T. Nguyen 


 
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Assistant Director of Regulatory Affairs 
Clinical Trials Office 
Emory University/Winship Cancer Institute 
1256 Briarcliff Road, Room 423W 
Atlanta GA, 30306 
404-778-5680(p) 
404-778-4004 (f) 
kim.t.nguyen@emory.eduThe Emory sponsor-investigator will review the adverse events and 
determine whether it meets Serious Adverse Event reporting requirements based on 
expectedness, relatedness, frequency,  severity and outcome. 
 
7.5.2 
Vital signs 
Body weight, body temperature, supine blood pressure, and supine pulse rate will be assessed. 
Height will be noted during the screening/baseline period. 
7.5.3 
Performance status 
Performance status will be assessed and graded using the ECOG scale at screening and prior to 
initiation of every new cycle (See appendix A). 
 
7.5.4 
Laboratory evaluations 
Patients are to fast overnight for 8 hours prior to all biochemistry samples being taken. Blood 
samples are to be taken as early in the day as possible. Water is allowed during this time. 
Laboratory samples will be analyzed locally at the clinical sites, unless indicated otherwise. 
Albumin, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, magnesium, 
potassium, total protein, SGOT, SGPT, sodium, bicarbonate, total protein, total cholesterol, LDL 
cholesterol, HDL cholesterol, triglycerides, urea/BUN γ-GT, fasting blood glucose, phosphorous. 
[at screening and as clinically indicated: CPK, HbA1c, LDH lipase, α-amylase and uric acid]. If 
the total bilirubin concentration is increased above 1.5 times the upper normal limit (UNL), total 
bilirubin should be differentiated into the direct and indirect reacting bilirubin (patient may be 
treated if direct bilirubin is < 1.5 x ULN) 
7.5.4.1 Thyroid function tests 
Free T4 and TSH will be assessed.  
7.5.4.2 Hormone assessments 
IGF-1 will be assessed.  


 
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7.5.4.3 Urinalysis 
Specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and blood will be assessed. 
7.5.4.4 Hepatitis B Virus testing 
Prior to randomization (or starting study drug in non-randomized trials), the categories of 
patients listed in Section 7 should be tested for hepatitis B serologic markers and viral load: 
HBV-DNA HBsAg, HBc Ab, and HBs Ab.  
HBV DNA monitoring should be done depending on results from serologic markers and viral 
load as listed in Table 6-6. 
7.5.4.4.Hepatitis C Virus  testing 
Patients with hepatitis C risk factors and additional patients at the discretion of the investigator 
should be tested for HCV RNA-PCR test at baseline. For a list of hepatitis C risk factors, refer to 
Section 7.  
Follow-up testing will be performed, as per the visit schedule, only if the patient has a history or 
is positive at baseline, or both.  
 
7.5.5 Pregnancy test 
Study drug treatment should be withdrawn in the event of pregnancy. To ensure patient safety 
each pregnancy must also be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and the presence or absence of any birth defects, congenital 
abnormalities or maternal and newborn complications. Any SAE experienced during pregnancy 
must be reported on the SAE Report Form. 
7.5.6 Gallbladder ultrasound 
A gallbladder ultrasound will be performed as clinically indicated at baseline and during the 
course of the study. Patients with a history of symptomatic cholelithiasis are excluded from 
participating in the study.  
7.5.7 Electrocardiogram (ECG) 
A 12-lead electrocardiogram (ECG) and rhythm strip will be performed at baseline for all 
enrolled patients. Due to concern with prolonged QT interval, all patients treated with pasireotide 
will have repeat EKGs performed as follows: 
  
Baseline (before pasireotide LAR injection) 
• 
21 days after 1st pasireotide LAR injection  
• 
21 days after 3rd pasireotide LAR injection 
• 
Cycle 6 (before pasireotide LAR injection) 


 
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• 
Every 3 cycles after Cycle 6 
Note that ECG may be done at any time when clinically indicated 
 
If a clinically significant abnormality is detected, the electrocardiogram will be repeated at the 
discretion of the Investigator until the abnormality has been resolved.  
7.6 
Pharmacokinetics 
Pharmacokinetic analysis will not be performed during this study. 
 
7.7 
Exploratory biomarker assessments 
7.7.1 
Sample collection  
Refer appendix B for details of sample collection, handling, preservation and shipping 
Blood Sample Collection: 
Blood samples will be collected at the indicated times into heparinized green top tubes (7 mls for 
PBMC collection - optional), red top tube (7 mls to obtain serum sample for ELISA assay). 
PBMC will be purified using standard Ficoll-Paque gradient centrifugation according to the 
instructions of the manufacturer (Amersham Pharmacia, Uppsala, Sweden). All samples must be 
stored away within 2 hours of collection by refrigeration at -70 to -80oC until ready for assay.  
Paraffin-Embedded Tissue  
Archival paraffin embedded tissue collected at the time of patient screening will be shipped to 
the lab of Shi-Yong Sun, PhD at the Winship Cancer Institute. If the entire paraffin block cannot 
be submitted, 15-20 slides of 4-5 micron sections cut from the block should be submitted. The 
patient ID # should be provided with the specimens. 
ELISA Assay  
ELISA detection and quantification of the cytokines of interest will be performed using 
previously published methods. Samples will be loaded onto a 96-well microtiter plate coated 
with monoclonal antibody specific for the cytokine of interest. After a blocking step, samples 
will be diluted into a buffer and incubated with the primary antibody. After a washing step, 
antisera specific for the cytokine is added followed by additional incubation. Another washing 
step will be performed to be followed by the addition of peroxidase-conjugated secondary 
antibody. The concentrations of the respective cytokines will be determined in triplicate for each 
serum samples using an ELISA plate reader. A set of calibrators and assay controls will be run 
with each assay.  


 
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Immunohistochemistry (IHC) for mTOR pathway proteins and somatostatin receptor 
expression 
Immunohistochemical detection of the mTOR pathway proteins will be carried out with the 
avidin-biotin technique using specific monoclonal antibodies targeting the proteins of interest. 
The IHC will be performed in collaboration with, Shi-Yong Sun, PhD and on a fee-for-service 
basis using the personnel and resources provided by the Pathology Core facility at Emory 
Winship Cancer Institute. Semiquantitative scoring of protein expression will be performed by 
Dr. Owonikoko (prior pathology training) in collaboration with Anthony Gal, MD a staff 
anatomic pathologist with Emory University Hospital. 
 
8 
Data Review and Data Management 
8.1 
Data Monitoring Committee 
The institution data safety monitoring committee will review the outcome of the study at regular 
intervals as mandated by institutional policy or more frequently if deemed necessary by the 
Principal Investigator. The Data Monitoring Committee (DMC) will be composed of medical, 
ethics and statistical experts and will meet to review the efficacy and safety data and determine a 
risk/benefit analysis in this subject population. The purpose of the DMC is to advise on serious 
safety considerations, lack of efficacy and any other considerations within the charge to the 
Committee. The DMC may request additional meetings or safety reports as deemed necessary 
upon discussion with Novartis and its representatives. The DMC may stop the study following 
review of results from each interim analysis. Appropriate efficacy and safety data summaries will 
be provided to the DMC after each interim analysis. 
In addition, the principal investigator will review the toxicities as they occur and/or are reported. 
The approval of the principal investigator or designee is necessary for accrual of all patients. 
The Data Coordinating Center will review responses and toxicity and report these to the 
regularly scheduled meetings of the Data Safety Monitoring Committee of the Emory Winship 
Cancer Institute 
Each participating site is expected to have its own data monitoring and safety plan (DMSP) with 
regard to forwarding information to their IRBs. If the data reveals a change in the risk/benefit 
ratio, the investigator will notify the IRB and the PI.  The principal investigator and co-
investigators will review the data and forward any changes or protocol amendments to the IRBs.  
All serious adverse events will be reported promptly or periodically to the IRB according to the 
requirements specified in the IRB policy and guidelines. All study participant information will be 
kept in a confidential manner by the assigning of a random number to each study participant. All 
data will be kept confidential as per institutional guidelines and policies. Any breach of 
confidentiality is a serious matter and conflicts with institutional policies and will be reported to 
the IRB. A cumulative summary of all adverse events occurring on this study and a report of the 


 
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data safety and monitoring plan will be submitted to the IRBs with the annual renewal reports. 
Enter information concerning the data monitoring board 
 
8.2 
Data Collection and Management 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations. 
Investigators must enter study data onto CRFs or other data collection system. The Investigator 
will permit study-related audits by Novartis or its representatives, IRB/EC review, and regulatory 
inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the facilities where the study 
took place, to source documents, to CRFs, and to all other study documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the 
subject’s records (e.g., medical records, office charts, hospital charts, and study related charts) 
for source data verification. The data collection must be completed prior to each visit and be 
made available to the Novartis representative so that the accuracy and completeness may be 
checked. 
 
8.3 
Overall Study Monitoring for Collaborating Sites 
The coordinating center for this multicenter study is the Clinical Trials Office of the Winship 
Cancer Institute of Emory University. Monitoring plan for this study will therefore follow the 
established Data Safety and Monitoring Plan for all investigator-initiated phase II trials at the 
Winship. The Emory University WINSHIP CANCER INSTITUTE monitoring team will have 
primary responsibility to coordinate, conduct and/or oversee all study auditing. The study will be 
audited at least annually in addition to the reporting requirement established by the IRB. If the 
Monitoring Committee determined that an external audit should be conducted, the committee 
shall be responsible for appointing the external auditors. The scope and conduct of the audit will 
be established by the committee and support for the audit will be provided by the Emory 
WINSHIP CANCER INSTITUTE Monitoring Office.  
Monitoring Committee: The committee members shall consist of faculty members, a research 
nurse, the Clinical Trials Director and/or Associate Director, the Medical Director of Clinical 
Trials, the Director of the Phase I program and the Regulatory and Compliance Manager. The 
Monitoring Committee reviews all auditing, DSMB composition and reports, and recommends 
corrective action if needed to the PI.  
The committee will: 
Review all SAEs from all sites at the time of report to the WINSHIP CANCER INSTITUTE 


 
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Review risk/benefit ratio and report to Emory IRB at the time of continuing review 
Review the protocol, amendments, informed consent documents and IRB submissions 
Meet with the PI for clarification of objectives and collection tools for these objectives. 
 
The Monitoring Office: This office consists of auditors and support staff and is administered by 
the Regulatory and Compliance Manager. The Clinical Trials Medical Director is available for 
ongoing consultation. Auditing will be performed by a qualified auditor who has access to the 
Medical Director of Clinical Trials, or a designee if he is involved in the study, for guidance and 
resolution of medical questions. The Emory WINSHIP CANCER INSTITUTE Monitoring 
Office will audit data integrity and safety information for all participating sites according to the 
approved schedule in the Winship DSMC Standard Operating Procedures and Policies.  
 
The following will be inspected during the monitoring visit 
i. 
Review of data integrity  
ii. 
Documentation of the qualifications, training and experience of the PI and other study 
staff 
iii. 
Eligibility of consented/enrolled patients 
iv. 
Informed consent document and process 
v. 
Verification that the local PI and staff are performing trial functions in accordance 
with protocol 
vi. 
Accuracy, completeness and timeliness of data 
vii. 
Accuracy and completeness of all source documentation 
viii. 
Response evaluation: verify that responses are identified according to the protocol 
definition of response for any response that is a major endpoint 
ix. 
Toxicity 
x. 
Appropriate reporting of all AEs and SAEs as required by GCP, the protocol, IRB 
regulations, sponsor’s SOPs and other regulatory requirements 
The monitor shall meet with RN/Coordinator assigned to the trial to: 
provide an itemized review of the deficiencies to the RN/Coordinator and remove items from 
itemized review which are corrected during this meeting 
review and document corrections; the RN/coordinator should indicate any remaining deficiencies 
and provide corrective action plan for resolution 


 
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prepare summary report for PI and Monitoring Committee to include summary of systematic 
deficiencies, significant protocol deviations, summary of remaining deficiencies and 
RN/coordinator corrective action plan, recommendations for data collection, protocol revision 
for clarity 
The Monitor shall meet with the overall PI to discuss the report and document the PI’s responses 
prior to submitting final report to the Monitoring Committee 
The final Monitoring Committee review of audit report and PI response and PI summary of 
protocol to date will be included in the annual renewal submission. 
Egregious data insufficiencies that may impact the scientific integrity of the trial are reported to 
the Medical Director and Clinical Trial Review Committee. 
 
Please see the attached supplementary Emory University WINSHIP CANCER INSTITUTE data 
safety monitoring plan policy document for a complete detail of the monitoring plan.   
9 
Statistical methods and data analysis 
All treated subjects will be included in the analysis of efficacy and safety. 
Demographic and baseline characteristics will be summarized using descriptive statistics.  The 
toxicities will be tabulated by organ system.  Time to disease progression and overall survival 
will be evaluated using the Kaplan-Meier method.  
Correlative analysis will be exploratory in the context of this Phase II screening trial.  
Post treatment correlatives will be collected on a limited number of patients who progress on the 
single agent arm. These will allow us to explore whether biological mechanisms postulated to be 
specific to the investigational agents is involved, and if dynamic changes in putative targets 
distinguish between responders and non-responders in this limited subset of patients. 
Analysis of baseline measurements obtained on all patients: Three types of analysis are planned: 
(a) Conditional analysis: does the correlate have an impact on response rate if the patient is 
treated with the specific investigational agent? (b) Marginal analysis: does the correlate have an 
impact when combining the two agents? and (c) Interaction: does the correlate have an impact 
differing by the treatment arm?  
Due to the variability in the baseline expression of correlative endpoints such as somatostatin 
receptor and mTOR protein, the limited sample-size and response rate, and pre-determined 
sample-size, no formal power calculation is presented for this exploratory research. 
9.1 
Objective RR and PFS as endpoints 
 
Within Arm: Using a Simon’s 2-stage MinMax design, 18 patients will be enrolled into stage I. 
At least one objective response is required to proceed to stage II accrual of 10 additional patients 
for a total of 28 patients per arm. If 3 or more patients achieve objective response following total 


 
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accrual, the particular treatment arm will be deemed worthy of further clinical evaluation in this 
disease. For response determination, any patient who progress prior to satisfying the objective 
response criteria will not be replaced but will be deemed evaluable for response evaluation and 
classified as a non-responder.  
 
Between Arms: Any treatment arm closed to accrual after the first stage interim analysis will be 
considered an inferior arm and will be excluded from comparison for the winner of trials. 
The arm with the best overall RR at the end of full enrolment will be adjudged the winner to be 
considered for further development provided there are at least 3 objective responses. Only in the 
event of identical RR between 2 or more arms or if none of the arms met the RR criterion (less 
than 3 objective responses after full patient enrolment) would the 1-yr PFS rate be employed to 
determine a winner. Based on recent clinical trials of targeted agents in similar patient 
population, 90% of patients were alive at 1 year and median progression free survival ranged 
between 9 and 18 months.8-10 We assume a conservative estimate that only 20% of the patients 
will be progression free at 1 year if the treatment is ineffective while 50% or more of the patients 
will be progression free at the same time point with an effective regimen. For this purpose, a 1-
year PFS rate of 50% or greater will be considered sufficient activity to justify further evaluation 
of the treatment in this disease. Assuming a 20% or lower 1-year PFS rate with an inactive 
regimen and a 50% or greater rate with an active regimen, 28 patients enrolled onto each arm 
will classify the treatment as having sufficient activity for further evaluation with a probability of 
0.95 (power against the alternative hypothesis p = 0.05).In this respect, the arm with the highest 
1-yr PFS rate will be judged the winner. In the event of a tie between the arms for both the RR 
and 1-yr PFS rate, the arm with the best profile in terms of safety and tolerability will be 
considered the overall winner to be selected for further evaluation in this disease. The power 
calculation for PFS assessment assumes full enrolment of 28 patients to the treatment arm, 
therefore any arm closed to further accrual following the initial interim analysis will not be 
eligible for the PFS endpoint assessment. The investigational agents in this trial have not been 
previously studied in thyroid cancer; therefore we are unable to accurately determine the drop-
off rate. Nonetheless, all patients  
9.2 
CBR as endpoints 
Any treatment arm that was closed to accrual after the first stage analysis will be considered to 
be an inferior arm. The CBR rates of all arms with complete accrual of 28 evaluable patients will 
be estimated and used as additional reference for the determination of the winner arm to be 
considered for further study.  
 
9.3 
Other Endpoints: 
Preclinical evidence show that mTOR inhibitor resistance may be due to increased survival 
pathway signaling activity with resultant addiction of the tumor cells to this pathway. The trial 
will explore the potential benefit of sequential versus concurrent initiation of mTOR inhibitor 
and Pasireotide. For this purpose, patients randomized to the single agent arms will be allowed to 
receive the 2-drug combination at the time of disease progression. Such patients may, however, 
remain on treatment only if they achieve disease stabilization or objective response at the end of 


 
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the first 2 cycles of 2-drug combination using the last imaging scan obtained while on the single 
agent therapy as the new baseline.  
9.4 
Correlative Study Analyses:  
The expression of somatostatin receptor and mTOR pathway protein (S6, pS6, 4E-BP1, p-4E-
BP1, eIF4e, Akt, pAkt, raptor, rictor, PRAS40, mSin1, FKBP38, IGF-R, IRS-1 and HIF1-α) in 
archival tissue and in fresh tumor biopsy obtained at the time of progression will be determined 
by immunohistochemistry and quantified by immunoscore as previously described.52 Differences 
in mean expression between the 3 treatment arms will be compared with ANOVA or Chi-Square 
test. Longitudinal analyses will also be conducted to investigate the association between the 
treatment arm and changes in circulating IGF-1 using ELISA assay and immunoscore of the 
listed proteins in progressing patients. The MIXED procedure of SAS will be used for the 
analyses. 
 
10 
Protocol amendments, or changes in study conduct 
10.1 Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 
or 
can 
be 
accessed 
via 
the 
website 
of 
the 
World 
Medical 
Association 
at 
http://www.wma.net/e/policy/17-c_e.html. 
10.2 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Novartis standard operating procedures and: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996.  
Directive 91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 
 
 
10.3 Protocol Modification 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Novartis and the investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB at each study center.  A 


 
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copy of the written approval of the IRB must be provided to Novartis. Examples of amendments 
requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients 
included in the trial.  If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons Novartis must be notified and the IRB at the 
center must be informed immediately. Amendments affecting only administrative aspects of the 
study do not require formal protocol amendments or IRB approval but the IRB must be kept 
informed of such administrative changes. Examples of administrative changes not requiring 
formal protocol amendments and IRB approval include: 
1. 
changes in the staff used to monitor trials  
2. 
minor changes in the packaging or labeling of study drug. 
 
11 
Regulatory Considerations 
11.1 Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards. 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the IRB/IEC/REB 
must be given to Novartis before study initiation. Any amendments to the protocol, other than 
administrative ones, must be reviewed by Novartis approved by this committee. 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study. The approval will be obtained prior to the 
initiation of the study. 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval. The Investigator is also responsible for notifying the 


 
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IRB/EC of any serious deviations from the protocol, or anything else that may involve added risk 
to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
11.2 Informed consent 
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedures as per GCPs as set forth in the CFR and ICH guidelines. 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents. The original 
consent form signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files. 
The investigator must explain to each subject (or legally authorized representative) the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. If the subject cannot read or sign the 
documents, oral presentation may be made or signature given by the subject’s legally appointed 
representative, if witnessed by a person not involved in the study, mentioning that the patient 
could not read or sign the documents. No patient can enter the study before his/her informed 
consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval. 
 
11.3 Subject confidentiality 
Novartis affirms the subject’s right to protection against invasion of privacy. In compliance with 
United States federal regulations, Novartis requires the Investigator to permit representatives of 
the sponsor and, when necessary, representatives of the FDA or other regulatory authorities to 
review and/or copy any medical records relevant to the study in accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 


 
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11.4 Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately to 
ensure their confidentiality. The information provided by Novartis to the investigator may not be 
disclosed to others without direct written authorization from Novartis, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the trial. 
 
11.5 Study records requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the protocol therapy, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; SAE reports, pharmacy 
dispensing records; recorded data from automated instruments; copies or transcriptions certified 
after verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; documents regarding subject 
treatment and drug accountability; original signed informed consents, etc.]) be retained by the 
Investigator for as long as needed to comply with national and international regulations 
(generally 2 years after discontinuing clinical development or after the last marketing approval). 
The Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 
11.6 Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and prior to any outside submission.  Novartis must receive copies of any 
intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the scientific 
content and conclusions of such publications or presentations.  Principal Investigation/Institution 
shall have the final authority to determine the scope and content of its publications, provided 
such authority shall be exercised with reasonable regard for the interests of Novartis and, in 
accord with the trial contract and shall not permit disclosure of Novartis confidential or 
proprietary information. 
11.7 Premature discontinuation of study 
The Principal Investigator, institution and Novartis have the right to discontinue this study at any 
time for reasonable medical or administrative reasons. Possible reasons for termination of the 
study could be but are not limited to: 
Unsatisfactory enrollment with respect to quantity or quality.  


 
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Inaccurate or incomplete data collection.  
Falsification of records.  
Failure to adhere to the study protocol.  
Any possible premature discontinuation would be documented adequately with reasons being 
stated, and information would have to be issued according to local requirements (e.g., IRB/EC, 
regulatory authorities, etc.). 
 
 


 
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12 
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signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. 
Leuk Res 2007;31:673-82. 
37. 
Wanner K, Hipp S, Oelsner M, et al. Mammalian target of rapamycin inhibition induces 
cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to 
rituximab. Br J Haematol 2006;134:475-84. 
38. 
Tuncyurek P, Mayer JM, Klug F, et al. Everolimus and mycophenolate mofetil sensitize 
human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to standard 
chemotherapy? Eur Surg Res 2007;39:380-7. 
39. 
Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian cancer cell 
proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer 
model. Clin Cancer Res 2007;13:4261-70. 


 
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40. 
Mabuchi S, Altomare DA, Connolly DC, et al. RAD001 (Everolimus) delays tumor onset 
and progression in a transgenic mouse model of ovarian cancer. Cancer Res 2007;67:2408-13. 
41. 
Treeck O, Wackwitz B, Haus U, Ortmann O. Effects of a combined treatment with 
mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer cells. 
Gynecol Oncol 2006;102:292-9. 
42. 
Sieghart W, Fuereder T, Schmid K, et al. Mammalian target of rapamycin pathway 
activity in hepatocellular carcinomas of patients undergoing liver transplantation. 
Transplantation 2007;83:425-32. 
43. 
Haritunians T, Mori A, O'Kelly J, Luong QT, Giles FJ, Koeffler HP. Antiproliferative 
activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell 
lymphoma. Leukemia 2007;21:333-9. 
44. 
Tanaka C, O'Reilly T, Kovarik JM, et al. Identifying optimal biologic doses of 
everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical 
pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008;26:1596-602. 
45. 
Tabernero J, Rojo F, Marimon I, et al. Phase I pharmacokinetic and pharmacodynamic 
study of weekly 1-hour and 24-hour infusion BMS-214662, a farnesyltransferase inhibitor, in 
patients with advanced solid tumors. J Clin Oncol 2005;23:2521-33. 
46. 
Wang X, Hawk N, Yue P, et al. Overcoming mTOR inhibition-induced paradoxical 
activation of survival signaling pathways enhances mTOR inhibitors' anticancer efficacy. Cancer 
Biol Ther 2008;7:1952-8. 
47. 
Sun SY, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E survival pathways 
by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2005;65:7052-8. 
48. 
Wang X, Yue P, Kim YA, Fu H, Khuri FR, Sun SY. Enhancing mammalian target of 
rapamycin (mTOR)-targeted cancer therapy by preventing mTOR/raptor inhibition-initiated, 
mTOR/rictor-independent Akt activation. Cancer Res 2008;68:7409-18. 
49. 
Sun S-Y, Rosenberg LM, Wang X, et al. Activation of Akt and eIF4E Survival Pathways 
by Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition. Cancer Res 
2005;65:7052-8. 
50. 
Chan JAR, D.P; Fuchs, C; Zhu, A.X; Abrams, A; Wolpin, B.M; Casey, C; Regan, E; 
Cavanaugh, K; Kulke, M. Phase I study of pasireotide (SOM230) in combination with 
everolimus (RAD001) in patients (pts) with advanced neuroendocrine tumors (NET). Meeting: 
ASCO 2010 Gastrointestinal Cancers Symposium 2010:Abstract 238. 
51. 
Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive 
lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 2008;148:519-28. 


 
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52. 
Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the 
mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic 
study in patients with advanced solid tumors. J Clin Oncol 2008;26:1603-10. 
 


 
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13 
APPENDICES 
 
13.1 
APPENDIX A- Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely 
disabled, 
hospitalization 
indicated.  Death not imminent. 
4 
100% 
bedridden. 
 
Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 


 
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13.2 
APPENDIX B – Blood sample collection and processing  
Pharmacodynamic Studies 
Plasma samples will be obtained in green-topped vacutainer tubes; PBMCs will be prepared and 
stored for future use at each time for which blood is sampled.  
Sample collection and processing 
Careful attention should be paid to the types of tubes required for each day’s sample acquisition. 
Samples for pharmacodynamic and PBMC preparation will be performed at the beginning of 
each odd numbered cycle 1, 3, 5 through the end of cycle  6. Does not need to be repeated with 
cycle 1 if already collected as part of screening. 
Venous blood will be collected in 4-ml heparinized green-topped vacutainer tubes. When 
obtained, each tube should be inverted several times to mix the heparin anticoagulant with blood. 
All samples will be sent to Dr. Owonikoko’s lab in batches to attention, Guojing Zhang. Lab 
should be notified prior to sample packaging and shipping.  
Sample Processing 
Microtainer tubes shall be inverted several times to mix blood with heparin and then centrifuged 
at approximately 300 x g in a refrigerated tabletop centrifuge so as to produce plasma. The 
resulting plasma should be aspirated from the tubes, placed into appropriately-labeled 
microcentrifuge tubes, and stored at -70°C. Blood samples for IGF-1 ELISA should be collected 
in red topped tubes to obtain the serum.  
 
PBMC - Collect blood in CPT or heparinized tube. Centrifuge at 1500g (approximately 
2800rpm) for 30 minutes. Discard supernatant (plasma). Remove the thin white layer of WBC 
(Buffy coat and transfer to a clean 15 ml centrifuge tube. Wash cells by filling the tube with 
PBS. Centrifuge at 300g (approximately1200rpm) for 5 minutes. Discard supernatant, resuspend 
cells in small quantity of PBS and transfer into two cryotubes tubes. Store at -70oC until ready 
for shipment. 
 
Serum: Collect whole blood in SST tube. Allow to clot by leaving it undisturbed at room 
temperature for 15-30 minutes. Centrifuge at 1500 g (approximately 2800rpm) for 10 minutes in 
a refrigerated centrifuge. Immediately transfer the supernatant serum into clean cryotubes and 
store as 0.5 - 1 ml aliquots at –70°C until ready for shipment. 
 


 
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13.3 
APPENDIX C - Medication Diary 
 
Study Title 
A 3-Arm Randomized Phase II Trial Evaluating Single Agent and Combined 
Efficacy of Pasireotide and Everolimus in Adult Patients with Radioiodine-
Refractory Differentiated and Medullary Thyroid Cancer 
Medication Diary  
 
 
 
 
Subject Initials 
 
Subject ID 
 
Cycle # 
 
Research Coordinator 
Name: 
Phone: 
Pager: 
e-mail: 
Cohort# 
Original Everolimus Dose 
…………………… 
Original Pasireotide Dose 
……………………. 
# of Dose Reductions  
 
Current Everolimus Dose: 
……………….. 
Current Pasireotide Dose: 
……………… 
Instructions:  
 
1. Please take the prescribed medications as instructed 
 
2. Please record the date and time you take your medications. On visit days, medications should be taken in 
the clinic unless otherwise instructed 
 
3. Please bring medication and pill diary to each study visit. 
Day 
Date 
Everolimus (Y/N) 
Pasireotide (Y/N) 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 


 
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16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Patient Signature 
 
…………………………………… 
Date: 
This section to be completed by a Research Personnel (Investigator, Research Nurse/Coordinator) 
Dosing Cycle Start Date: 
Dosing Cycle End Date: 
Everolimus Lot 
Number: ………… 
#  of Bottles / # of Tablets Dispensed :  
 ____5mg     ____10mg 
 
 
Any Interruptions?  
(Yes/No) 
Pasireotide Lot Number 
….……… 
#  of Bottles / # of Injections Dispensed :  
 ____ 
Any Interruptions?  
(Yes/No) 
Length of Dose Interruption: Everolimus …………………… 
 Pasireotide ……………………………. 
Reason for Interruption 
 
Reason for Dose Reduction 
 
Additional Comments: 


 
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13.4 Attached Supplement – Emory Winship DSMP Policy 
Emory Winship Cancer Institute Data Safety Monitoring Plan Policy attached as a supplement