Clinical trial NCT00767819
Conditions: Progressive Sarcoma
Keywords: progressive GIST progressive sarcoma
Sponsor: Novartis Pharmaceuticals
Start date: 2008-03-31; Completion date: 2017-05-17
Enrollment: 71 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this multicenter, three-arm, exact binomial single-stage, phase II trial is to determine the preliminary efficacy and safety of RAD001 in patients with histological evidence of progressive or metastatic bone or soft tissue sarcoma.

Detailed description:

Arms: arm 1: Progressive or metastatic bone or soft tissue sarcomas arm 2: Progressive gastrointestinal stromal tumors (GIST) after failure of prior imatinib and sunitinib 1st and 2nd line arm 3: Progressive or metastatic alveolar soft part sarcoma (ASPS)
Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: 2.5 and 5 mg tablets taken orally and starting dose was 10 mg daily for all patients

Protocol documents:
Prot_000.pdf: 
Clinical Development 
RAD001 
CRAD001C24114 / NCT00767819
Multicenter, triple-arm, single-stage, phase II trial to 
determine the preliminary efficacy and safety of RAD001 in 
patients with histological evidence of progressive or 
metastatic bone or soft tissue sarcomas 
Author(s): 
 
Document type: 
Amended Protocol Version 
EUDRACT number : 
2007-005294-60 
Development phase: 
II  
Version No. 
07  Amended Protocol Version 
Release date: 
 2013-08-27 
Property of Novartis Pharma  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Novartis approval signatures for: 
Amendment No. 7 to Clinical Study Protocol CRAD001C24114 
 
 
 
 
 
 
 
  
 
 
Signature 
 Date 
 
 
 
 
  
 
 
  
  
 
Signature 
 Date 
 
 
 
 
  
 
 
  
  
 
Signature 
 Date 
 


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Investigator approval signatures for: 
Amendment No. 7 to Clinical Study Protocol CRAD001C24114 
 
Investigator signature 
I have read the protocol amendment and agree to conduct this trial in accordance with all 
stipulations of the protocol as amended, with applicable laws and regulations and in 
accordance with the ethical principles outlined in the Declaration of Helsinki. 
 
 
 
 
 
 
  
Investigator 
 
Signature 
 Date 
 
Affiliation: 


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Table of contents 
 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
Amendment 6 ............................................................................................................................. 9 
Amendment rationale ................................................................................................................. 9 
Changes to the protocol .............................................................................................................. 9 
Changes to Section 3 Objectives ......................................................................................... 9 
Changes to Section 7 ......................................................... Error! Bookmark not defined. 
IRB/IEC/REB Approval .................................................................................................... 10 
1 
Background and introduction ............................................................................................ 11 
1.1 
Soft tissue sarcomas ............................................................................................... 11 
1.1.1 
Treatment .............................................................................................. 11 
1.1.2 
Active drugs .......................................................................................... 12 
1.2 
mTOR pathway and cancer ................................................................................... 13 
1.3 
Overview of RAD001 ............................................................................................ 13 
1.3.1 
Preclinical studies of RAD001 .............................................................. 14 
1.3.2 
RAD001 pharmacokinetics ................................................................... 14 
1.3.3 
RAD001 Phase I Studies ....................................................................... 15 
1.3.4 
RAD001 Phase II / III Studies .............................................................. 15 
1.4 
Rationale ............................................................................................... 15 
2 
Study purpose .................................................................................................................... 16 
3 
Objectives .......................................................................................................................... 16 
Primary objective ............................................................................................................... 16 
Secondary objective(s) ...................................................................................................... 17 
4 
Study design ...................................................................................................................... 17 
Screening for hepatitis B ................................................................................................... 18 
Screening for hepatitis C ................................................................................................... 18 
5 
Population .......................................................................................................................... 19 
5.1 
Inclusion/exclusion criteria .................................................................................... 19 
5.2 
Premature patient withdrawal ................................................................................ 22 
6 
Treatment ........................................................................................................................... 22 
6.1 
Treatment assignment ............................................................................................ 22 
6.2 
Investigational drug ............................................................................................... 23 
6.3 
Treating the patient ................................................................................................ 23 


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6.3.1 
Instructions for prescribing and taking the study drug .......................... 23 
6.3.2 
RAD001 dose adjustments .................................................................... 23 
6.3.3 
Management of RAD001 toxicities ...................................................... 24 
Management of Hepatitis reactivation ............................................................................... 28 
Monitoring for hepatitis C ................................................................................................. 30 
6.3.4 
Follow-up for toxicities while receiving RAD001 ................................ 31 
6.3.5 
Other concomitant medications ............................................................. 31 
Inhibitors of CYP3A4 and/or PgP ..................................................................................... 31 
Inducers of CYP3A4 and/or PgP ....................................................................................... 32 
6.3.6 
Study drug discontinuation ................................................................... 33 
7 
Visit schedule and assessments ......................................................................................... 34 
7.1 
Information to be collected on screening failures .................................................. 34 
7.2 
Patient demographics/other baseline characteristics ............................................. 36 
7.3 
Treatments ............................................................................................................. 37 
7.4 
Efficacy .................................................................................................................. 37 
7.5 
Safety ..................................................................................................................... 37 
7.5.1 
Adverse events ...................................................................................... 37 
7.5.2 
Physical examination ............................................................................ 39 
7.5.3 
Vital signs.............................................................................................. 39 
7.5.4 
Performance status ................................................................................ 39 
7.5.5 
Laboratory evaluations .......................................................................... 39 
7.5.6 
ECG ....................................................................................................... 40 
7.5.7 
Pregnancy test ....................................................................................... 40 
8 
Safety monitoring .............................................................................................................. 41 
8.1 
Serious adverse event reporting ............................................................ 41 
8.1.1 
Safety assessments ................................................................................ 41 
8.2 
Pregnancies ........................................................................................... 41 
9 
Data review and database management ............................................................................. 42 
9.1 
Site monitoring ...................................................................................... 42 
9.2 
Data collection ...................................................................................... 42 
9.3 
Database management and quality control ........................................... 43 
10 Data analysis ...................................................................................................................... 43 
10.1 
Populations for analysis ......................................................................................... 44 
10.2 
Patient demographics/other baseline characteristics ............................................. 44 
10.3 
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance) ............................................................................................................ 44 
10.4 
Analysis of the primary objective(s) ...................................................................... 45 


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10.4.1 
Variable ................................................................................................. 45 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 45 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 45 
10.4.4 
Supportive analyses ............................................................................... 45 
10.5 
Analysis of secondary objectives ........................................................................... 45 
10.5.1 
Efficacy (secondary) ............................................................................. 45 
10.5.2 
Safety ..................................................................................................... 46 
10.5.3 
Tolerability ............................................................................................ 46 
10.5.4 
Resource utilization ............................................................................... 46 
10.6 
Sample size calculation .......................................................................................... 46 
10.7 
Power for analysis of critical secondary variables ................................................ 47 
11 References ......................................................................................................................... 47 
Appendix 1: Administrative procedures ............................................................................ 50 
Post-text supplement 1: Response Evaluation Criteria in Solid Tumors (RECIST) ................ 52 
 List of tables 
 
Table 4-1 
Schematic of study design ..................................................................... 17 
Table 6-1 
RAD001 Dose levels for dose adjustment ............................................ 23 
Table 6-2 
Criteria for dose-modification in case of suspected RAD001 
toxicity and re-initiation of RAD001 treatment .................................... 24 
Table 6-3 
Management of non-infectious pneumonitis ......................................... 27 
Table 6-4 
Action to be taken for positive baseline hepatitis B results .................. 28 
Table 6-5 
Guidelines for management of hepatitis B ............................................ 29 
Table 6-6 
Guidelines for management of hepatitis C ............................................ 31 
Table 6-7 
Clinically relevant drug interactions: substrates, inducers, and 
inhibitors of isoenzyme CYP3A ........................................................... 32 
Table 6-8 
Clinically relevant drug interactions mediated by PgP ......................... 32 
Table 7-1 
Assessment schedule ............................................................................. 35 
Table 10-1 
Design features for exact binomial single-stage designs ...................... 47 
Table Appendix 1: 
Response criteria for target lesions ....................................................... 54 
Table Appendix 2: 
Response criteria for non-target lesions ................................................ 54 
Table Appendix 3: 
Overall lesion response at each assessment .......................................... 55 
 


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List of abbreviations 
AE 
adverse event 
ALT / GPT 
alanine aminotransferase / glutamic pyruvic transaminase 
ASPS 
alveolar soft part sarcoma 
AST / GOT 
aspartate aminotransferase / glutamic oxaloacetic transaminase 
AUC 
area under the curve; area under the drug concentration time curve 
b.i.d. 
bis in die / twice a day 
CRF 
case report/record form 
Cmax 
maximum concentration 
CNS 
central nervous system 
CS&E 
clinical safety and epidemiology 
CR 
complete response 
CRO 
contract research organization 
CT 
computer tomography 
CTC 
Common Toxicity Criteria 
CYP 
human cytochrome P450 
ECG 
electrocardiogram 
CRF 
case report/record form 
EGF 
epidermal growth factor 
GI 
gastrointestinal 
GRF 
growth hormone releasing factor 
Hb 
hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization of technical requirements for 
registration of pharmaceuticals for human use 
IEC 
Independent Ethics Committee 
i.v. 
intravenous(ly) 
IGF-1 
insulin-like growth factor 1 
i.m. 
intramuscular 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
mTOR 
mammalian target of rapamycin 
NET(s) 
neuroendocrine tumor(s) 
ORR 
objective response rate 
OS 
overall survival 
PBMC(s) 
peripheral blood mononuclear cell(s) 
PI3K 
phosphatidylinositol 3-kinase 
p.o. 
per os / by mouth (orally) 
PD 
pharmacodynamics (or progressive disease in the context of tumor response) 
PFS 
progression free survival 
PK 
pharmacokinetics 
PR 
partial response 
q.d. 
quaque die / once a day 


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REB 
Research Ethics Board 
RECIST 
response evaluation criteria in solid tumors 
SD 
stable disease 
SAE 
serious adverse event 
SOP 
standard operating procedure 
STI 
signal transduction inhibitors 
STS 
Soft Tissue Sarcoma 
TTP 
time to progression 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
VIP 
vasoactive intestinal peptide 
 


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Amendment 7  
Amendment rationale 
 
This study was designed as a three-armed phase II trial to evaluate the preliminary efficacy 
and safety of RAD001 in patients with advanced bone or soft tissue sarcomas. Enrollment of 
patients with progressive or metastatic bone or soft tissue sarcomas [except gastrointestinal 
stromal tumors (GIST) and alveolar soft part sarcoma (ASPS)] in arm I, enrollment of patients 
with progressive GIST after failure of prior imatinib and sunitinib treatment in arm II and 
enrollment of patients with progressive or metastatic alveolar soft part sarcoma (ASPS) in arm 
III were already completed. 
As on 23 July 2013, one patient in arm II and one patient in arm III are ongoing and receive 
study drug. To ensure drug supply to both patients with RAD001 (everolimus), this 
amendment implements the use of Afinitor® (everolimus) as study drug. 
Changes to the protocol 
 
Additions to the study protocol are shown in red and deletions are shown in strike-out mode. 
Comments and instructions for changes are shown in italics.  
Changes to Section 6 Treatment 
The section was amended as follows: 
6.2 Investigational drug 
RAD001 is formulated as tablets of 5mg strength, blister-packed under aluminum foil in units 
of 10 tablets. In addition RAD001 will also be delivered as Afinitor® (everolimus) tablets 
formulated as tablets of 5 mg strength, blister-packed  in units of 30 tablets per pack. 
RAD001/everolimus are dosed on a daily basis.  
6.3.5 Other concomitant medications 
Inducers of CYP3A4 and/or PgP 
If patient requires co-administration of strong CYP3A4 inducers (i.e., phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s worth), an increase in the dose 
of everolimus up to twice the currently used daily dose should be considered, using 5 mg 
increments every other day 5 mg increments daily. 
 


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IRB/IEC/REB Approval 
A copy of this amendment will be sent to the Institutional Review Board (IRB) / Independent 
Ethics Committee (IEC) / Research Ethics Board (REB).  
The changes described in this amendment require IRB/IEC/REB approval prior to 
implementation. In addition, sites are required to update and submit for approval a revised 
informed consent that takes into account the changes to the protocol described herein. 
  


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1 
Background and introduction 
1.1 
Soft tissue sarcomas 
Soft tissue sarcomas (STS) are rare tumours with an incidence of 2-3/100.000. Overall, STS 
account for approximately 1% of all malignancies, while they give rise to 2% of the total 
cancer-related mortality. Sarcomas constitute a heterogeneous group of rare tumours arising 
from cells of connective tissues (Clark MA et al, 2005). The gender distribution is equal. STS 
arise from mesodermal or ectodermal tissues and therefore occur at any site of the extremities, 
trunk, retroperitoneum or head and neck. There are multiple histological subtypes of STS. At 
present all these subtypes are usually grouped under the heading of STS for the purpose of 
treatment, although an increasing number of new treatment options are expected to be directed 
more specifically at individual histological subtypes. 
Currently, more than half of all patients die within 5 years of primary diagnosis, mostly due to 
metastatic disease involving the lungs. About 10% of the patients present with metastatic 
disease at the time of diagnosis, whereas 40-60% of patients with localized, high-grade soft 
tissue sarcoma will develop metastases, predominantly in the lungs, despite local control of 
the tumour. Median survival from the time of diagnosis of metastatic disease is 8 to 12 
months. According to the EUROCARE data (Ref.) the 5-year survival in Europe of adult STS 
(excluding visceral ones) averages 60%, with substantial geographic variations. Thus further 
improvements in the treatment outcome of these rare tumours are needed. 
1.1.1 
Treatment 
Local surgery is usually the first line of management. Standard treatment is generally a wide 
surgical excision of the primary tumour combined with adjuvant radiotherapy, whenever 
feasible, or in some cases radical surgery, i.e. compartmental resection or amputation of the 
extremity. 
Partly because of the presence of a misleading pseudo membrane and a multifocal origin of 
the tumour, surgery was initially followed by a very high incidence of local recurrence. 
Nowadays, the addition of post-operative radiotherapy appears to reduce the rate of local 
recurrence significantly. However, even an optimal local treatment does not prevent the 
occurrence of distant metastases in some of the patients – especially those with high-grade 
tumours. Although the effect adjuvant chemotherapy has been studied by several groups, they 
did not allow any final conclusions. A recent international meta-analysis indicated an effect 
on progression free survival but no effect on overall survival. 
STS metastasise primarily to the lungs but also to bone, liver and other organs depending on 
the subtype. The median survival is generally less than 12 months, though long term survival 
may follow optimal response to chemotherapy in a limited number of patients. Chemotherapy 
is widely used in the treatment of advanced disease, basically with a palliative intent, but with 
the present knowledge its effect is clearly inadequate. 
Only few drugs have shown single-agent activity above 15% with the most active being 
doxorubicin, epirubicin and ifosfamide resulting in response rates of 18-29% in first-line 
treatment. Combination chemotherapy consisting of anthracyclines and ifosfamide results in 


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response rates of 40-50% with up to 10% complete remissions, however at the cost of 
increased toxicity. Whereas complete remissions lead to prolonged survival, sometimes even 
cure, overall survival superiority of combination chemotherapy over single-agent doxorubicin 
has not been established yet. 
In second-line treatment after anthracycline failure, ifosfamide plays a major role with 
response rates of up to 30%. Even after pre-treatment with standard doses of ifosfamide, high-
dose ifosfamide represents an active treatment option. 
Based on the understanding of molecular mechanisms and experience from clinical trials, it 
has become increasingly clear that distinct histological subtypes have a completely different 
clinical behaviour and response to systemic therapy. Hormonal therapy is very active in low-
grade endometrial stromal tumours. Taxanes have shown interesting activity in 
angiosarcomas, though being inactive in soft tissue sarcoma in general. Topoisomerase I – 
inhibitors lead to response rates of 0 to 10% with some additional proportion of disease 
stabilisation in leiomyosarcomas. Gemcitabine was used in several trials and responses were 
reported in up to 18% of patients. The combination of Gemcitabine and Docetaxel resulted in 
a response rate of 53%, predominantly in uterine leiomyosarcomas. This combination was 
found to be significantly superior to Gemcitabine alone for progression-free survival and 
overall survival, being the first trial at all, to show superiority in overall survival. 
There is a wide variety of DNA alternations observed in sarcoma, including translocations, 
gene amplifications, kinase mutation, gene deletion, loss of p53 and/or Rb and gross 
chromosomal rearrangements, often define nosological entities (e.g. Ewing sarcoma, synovial 
sarcoma and GIST). The proteins encoded by these mutated genes differ vary between 
histological sub-types, ranging from transcription factor. IN recent years, systemic treatment 
of sarcomas have evolved from a relatively uniform approach (doxorubicin + ifosfamide 
regiments) towards individualized strategies selecting cytotoxics and targeted treatment for 
specific histotypes and molecular subtypes (Cassier et al. 2007) 
1.1.2 
Active drugs 
Doxorubicin appears to be the most active drug in the treatment of STS. During the last 
decade more than a thousand patients have been treated with the drug in connection with 
several reported studies. The cumulative response rate in non-pre-treated patients is 23%. 
Activity has also been noted in pre-treated patients in an EORTC trial. Doxorubicin treatment 
is limited because of cumulative cardiotoxicity, but unfortunately none of the tested 
anthracycline analogs has shown superiority or comparability to doxorubicin in terms of 
therapeutic activity with less toxicity. 
A second active drug in the treatment of STS is ifosfamide. The initial non-randomized 
studies had shown response rates of 38-67%. The EORTC Soft Tissue and Bone Sarcoma 
Group (STBSG) performed a randomized phase II trial comparing cyclophosphamide with 
ifosfamide. In this trial the activity of ifosfamide was confirmed with a 25% response rate in 
non-pre-treated patients. In a recent study also by the EORTC STBSG, ifosfamide 3g/m2, 
given over 4 hours on 3 consecutive days showed better activity than ifosfamide 5g/m2 over 
24 hours schedule. 


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The third drug with known moderate activity is DTIC (Dacarbazine), which achieved a 
response rate of 17% in 53 patients. Because the response rate of the combination of 
doxorubicin plus DTIC was much higher as compared with either one of these two drugs 
alone, DTIC was not studied further as a single agent, until the EORTC STBSG confirmed the 
activity of the drug in second line. 
Doxorubicin and ifosfamide have been studied in second line treatment after pre-treatment 
with the respective other drug. Activity was comparable to first line therapy. After pre-
treatment with the combination of doxorubicin and ifosfamide, there is currently no standard 
treatment available. 
Therefore, there is a need to identify other active agents against this disease. 
1.2 
mTOR pathway and cancer 
The target of RAD001 is mTOR (mammalian target of rapamycin), a serine-threonine kinase 
which is a member of the larger PI3K (phosphatidylinositol 3-kinase) family and present in all 
cells. The main known functions of mTOR include (Bjornsti and Houghton, 2004):  
• mTOR functions as a sensor of mitogens, growth factors, energy and nutrient levels, 
facilitating cell-cycle progression from G1 to S phase in appropriate growth conditions. 
• The PI3K (mTOR) pathway itself is frequently deregulated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors. 
• The mTOR pathway is involved in the production of pro-angiogenic factors (e.g. VEGF) 
and inhibits endothelial cell growth and proliferation directly. 
• Through inactivating eukaryotic initiation factor 4E binding proteins and activating the 
40S ribosomal S6 kinases (e.g. p70S6K1), mTOR regulates protein translation. 
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). 
The pathway is known to be deregulated in numerous proliferate disorders including cancer. 
Molecular epidemiological studies have also shown that activation of the PI3/AKT/mTOR 
pathway is frequently associated with worsening prognosis through resistance to treatment, 
disease extension and disease progression. A variety of preclinical models have confirmed the 
role of this pathway in tumor development. It has also been demonstrated that constitutional 
activation of kinases such as AKT can lead to inexorable development of cancers resembling 
those which in patients are characterized by frequent activation of the same kinases. This is 
complemented by the demonstration of the antitumour activity of kinase inhibitors acting on 
the pathway in in vitro and in vivo preclinical models. 
1.3 
Overview of RAD001 
RAD001 (everolimus) is a derivative of rapamycin. It is commercialized as Certican® as an 
immunosuppressant in solid organ transplantation. 
 


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1.3.1 
Preclinical studies of RAD001 
At the cellular and molecular level RAD001 acts by selectively inhibiting mTOR (mammalian 
target of rapamycin). Various in vitro and in vivo experiments were performed in order to 
identify the cell signaling pathways through which RAD001 acts in cancer and identify 
molecular markers which may predict cellular response. A significant positive correlation was 
observed between the antiproliferative activity of RAD001 and levels of phosphorylated AKT 
(Serine 473) and phosphorylated S6 (Serines 240 and 244). Hence, phospho-AKT/phospho-S6 
levels may be useful indicators of pathway activation and sensitivity to RAD001. 
[Investigators’ Brochure, 2006] 
In vivo studies investigating the antitumour activity of RAD001 against experimental animal 
tumor models showed that RAD001 monotherapy typically reduced tumor cell growth rates 
rather than producing regressions or stable disease. These effects occurred within the dose 
range of 2.5-10mg/kg p.o. daily. 
The antiangiogenic activity of RAD001 was also confirmed in animal experiments. RAD001 
selectively inhibited VEGF-dependent angiogenic response at doses that were well tolerated 
(see IB 4.1.2.6.), and both primary and metastatic tumors from RAD001-treated mice 
demonstrated a significant reduction in blood vessel density compared to controls. 
In humans, studies suggested that 70S6K1 level in peripheral blood mononuclear cells 
(PBMCs) could be a useful pharmacodynamic marker of RAD001 inhibitory effects on the 
mTOR pathway. Preclinical and clinical studies have been (and are being) conducted to 
further evaluate which are the best indications and combination partners for RAD001, and 
which potential molecular markers can predict response to treatment. 
Based on findings of safety pharmacology studies, the potential of RAD001 to affect vital 
functions in patients is considered to be low. All significant adverse effects observed in 
preclinical toxicology studies of RAD001 in mice, rats, monkeys and minipigs were 
consistent with its anticipated pharmacological action as an antiproliferative and 
immunosuppressive agent and were 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. 
[Investigators’ Brochure, 2006] 
1.3.2 
RAD001 pharmacokinetics 
RAD001 is formulated for oral administration. It is rapidly absorbed with a median tmax of 1-2 
hours and a bioavailability estimated at 11% or more. The AUC is dose-proportional over the 
range of doses tested while Cmax becomes less than dose-proportional at doses above 20mg. 
The coefficient of variation between patients is approximately 50%. In whole blood, 
approximately 80% of the drug is sequestered in cells. Of the remaining 20% in plasma, 
approximately a quarter is unbound. Metabolism and excretion are essentially hepatic. In vitro 
studies showed that RAD001 is a competitive inhibitor of CYP3A4, P-gp and CYP2D6 
substrates, potentially increasing the concentrations of medicinal products eliminated by these 
enzymes. Thus, caution should be exercised when co-administering RAD001 with CYP3A4 
and CYP2D6 substrates with a narrow therapeutic index. The elimination half-life is 
approximately 30 hours. [Investigators’ Brochure, 2006] 


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1.3.3 
RAD001 Phase I Studies 
RAD001 has been evaluated in phase I studies involving 147 patients with advanced cancers 
using both a weekly regimen (up to 70mg/wk) and a daily regimen (10mg/d) [Investigators’ 
Brochure, 2006]. The most frequent adverse drug reactions in the oncology setting have been 
rash, stomatitis, fatigue and, to a lesser extent, gastrointestinal disorders (nausea, anorexia, 
diarrhea, vomiting) and headache. The adverse events are mild-moderate (CTC grade 1-2) in 
the majority of patients. Severe (grade 3), suspected drug-related, dose-limiting events 
occurred in 19% of patients, mainly stomatitis (often apthous ulcers), and occasionally severe 
fatigue, hyperglycemia and neutropenia. Reduced blood counts, hyperlipidemia (mainly 
hypercholesterolemia) and hyperglycemia are relatively frequent laboratory findings. 
Infections have not been frequent. 
The dose and schedule of 10mg p.o. q.d. has been selected for most phase II studies based on 
assessment of both pharmacodynamic and safety studies. Molecular pharmacodynamic studies 
using immunohistochemistry assays on tumor biopsies have shown target inhibition at both 
daily dosage (5-10mg) and weekly dosage (50-70mg) with satisfactory tolerability in most 
patients. 
Conventional cytotoxic agents were empirically evaluated in in vitro and in vivo 
pharmacology studies as combination partners for RAD001 and have shown that RAD001 is 
additive or synergistic in combination with other anticancer agents, including cytotoxics and 
other signal transduction inhibitors (STIs) as well as endocrine therapy. In many cases, a 
potentiation of cell death by the drug combination was observed. RAD001 has also been 
evaluated in several phase I studies in combination with other anticancer drugs. Interactions 
have required dose reduction of RAD001 when given in combination with some drugs (e.g. 
Gleevec, Xeloda) but not others (e.g. paclitaxel, letrozole). Please refer to Investigator 
Brochure for more information. 
1.3.4 
RAD001 Phase II / III Studies 
RAD001 is currently investigated in different Phase III trials in renal cell carcinoma (Jac et 
al., ASCO 2007, abstract 5107), in neuroendocrine tumors (Yao et al., ASCO 2007, abstract 
4503), and in lymphoma. 
Phase II trials are ongoing in many different tumor entities, such as breast cancer (Ellard et 
al., ASCO 2007, abstract 3513), non small lung cancer, small lung cancer, colorectal cancer, 
lymphoma (Johnston et al., ASCO 2007, abstract 8055), GIST (van Oosterom et al., ASCO 
2005, abstract 9033), and melanoma (Rao et al., ASCO 2007, abstract 8530). 
In a Phase II study with the mTOR inhibitor CCI-779 in patients with soft tissue sarcoma it 
was shown that this concept of treatment has acceptable toxicity profile (Okuna et al, 2006).  
1.4 
Rationale 
The systemic treatment of locally advanced or metastatic soft tissue sarcoma (STS) is 
unsatisfactory with few drugs showing signs of activity. Treatment is toxic, yet usually given 
with palliative intent. 


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PET responses and improvement of symptoms have been described in sarcoma patients with 
AP23573, an intravenous mTOR inhibitor (
) 
tested in a phase II trial (Sankhala et al., ASCO 2005, abstract 9028). 
Recent data with this mTOR inhibitor AP23573 demonstrate a single-agent activity in a broad 
range of sarcoma tumor types in a phase I/II trial. In this trial the patients were enrolled 
according to their histological subtype of the tumor. Totally, 212 patients were enrolled of 
which over 90% had a progression at the time of study entry. 79% had 2 prior 
chemotherapies. The overall clinical benefit rate was 29% and the median OS was 40,1 
weeks. In the subset of patients achieving a clinical benefit response, the OS was 67,6 weeks. 
(Chawla, ASCO 2007, abstract 10076). 
The experiences with this mTOR inhibitor are a rational to test RAD001 in patients with soft 
tissue and bone sarcoma. 
RAD001 is a macrolide, a new derivative of rapamycin. It is orally available and acts as an 
mTOR inhibitor. TOR is a ubiquitous protein kinase implicated in cell cycle control and 
specifically in the progression of cells from the G1 to S phase. It is considered to be 
downstream of PI3-AKT. RAD001 is being developed as an antiproliferative drug with 
applications as an immunosuppressant and anticancer agent. It is already registered in the 
transplantation setting as Certican. 
In a phase I study in 33 patients with advanced solid tumors, RAD001 has been given at doses 
of 20mg, 50mg and 70mg weekly, or 5mg and 10mg daily. Dose limiting toxicities have been 
stomatitis, neutropenia and hyperglycemia. The recommended dose for further phase II 
evaluation is 10mg daily (Tabernero et al., ASCO 2005, abstract 3007). 
2 
Study purpose 
The purpose of this multicenter, triple-arm, exact binomial single-stage, phase II trial is to 
determine the preliminary efficacy and safety of RAD001 in patients with histological 
evidence of progressive or metastatic bone or soft tissue sarcoma. 
3 
Objectives 
Primary objective 
• To evaluate preliminary efficacy of RAD001 in progressive or metastatic bone and soft 
tissue sarcoma (except for GIST). Efficacy is defined as the proportion of patients 
showing complete response, partial response or stable disease at 16 weeks. 
• To evaluate preliminary efficacy of RAD001 in patients with gastrointestinal stromal 
tumor (GIST) after failure or intolerance of treatment with imatinib or sunitinib in 1st and 
2nd line. Efficacy is defined as the proportion of patients showing complete response, 
partial response or stable disease at 16 weeks. 
• To evaluate preliminary efficacy of RAD001 in progressive or metastatic alveolar soft part 
sarcoma (ASPS). Efficacy is defined as the proportion of patients showing complete 
response, partial response or stable disease at 16 weeks. 
 


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Secondary objective(s) 
The following secondary objectives will be evaluated in three arms separately: 
• To evaluate the tolerability and safety profile of RAD001 in these patient populations. 
• To evaluate the objective tumor response rate based on RECIST-criteria (complete 
response [CR] and partial response [PR]) at 16 weeks. 
• To evaluate duration of response. 
• To evaluate progression-free survival (PFS) at 16 weeks. 
• To evaluate overall survival (OS). 
• To evaluate PFS at month 12 for patients with data available from follow-up observation 
(optional). 
• To evaluate OS at 12 months for patients with data available from follow-up observation 
(optional). 
4 
Study design 
This is a non-randomized, multicenter, triple-arm, phase II trial evaluating the treatment of 
RAD001 in the following three arms: in patients with progressive or metastatic bone or soft 
tissue sarcoma (except for GIST), in patients with progressive or metastatic GIST after failure 
or intolerance of treatment with imatinib or sunitinib in 1st and 2nd line and in patients with 
progressive or metastatic alveolar soft part sarcoma (ASPS) (see Table 4-1). 
It is anticipated to achieve an estimated total sample size of 10 subjects in arm III. No interim 
analysis is planned. 
A 12-month recruitment phase is anticipated to achieve an estimated total sample size of 36 
subjects in arm I, a total sample size of 24 subjects in arm II and in arm III, respectively, in a 
single stage. No interim analysis is planned. All 5 patients with alveolar soft part sarcoma 
(ASPS) included in the arm I of the study will be transferred to and analyzed in the arm III. 
Table 4-1 
Schematic of study design 
Arm I: 
Patients with progressive or metastatic bone or soft tissue sarcoma (except 
for GIST) 
 
Starting dose: RAD001 10 mg/day 
 
36 patients to be accrued in a single stage 
Arm II: 
Patients with progressive GIST after failure or intolerance of treatment with 
imatinib or sunitinib in 1st and 2nd line 
 
Starting dose: RAD001 10 mg/day  
 
24 patients to be accrued in a single stage 
Arm III: Patients with progressive or metastatic alveolar soft part sarcoma (ASPS) 
 
Starting dose: RAD001 10 mg/day 
 
10 patients to be accrued in a single stage 
 


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Studies with other mTOR-inhibitors have shown a significant clinical benefit in patients with 
soft tissue sarcoma. Therefore, the 10mg daily dose of RAD001 has been selected as the 
treatment regimen for this study. 
 
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 (Loomba et al. 2008). 
Screening for hepatitis B 
Prior to starting study drug the following three categories of patients should be tested for 
hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBs Ab, and HBc 
Ab:   
1. 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 ] 
2. 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. 
3.  Additional patients at the discretion of the investigator  
The management guidelines, in Section 6.3.3, are provided according to the results of the 
baseline assessment of viral load and serological markers for hepatitis B. 
  
Screening for hepatitis C 
Patients with any of the following risk factors for hepatitis C should be tested using 
quantitative RNA-PCR 
• known or suspected past hepatitis C infection (including patients with past interferon 
‘curative’ treatment),  
• blood transfusions prior to 1990,  
• current or prior IV drug users,  
• current or prior dialysis,  


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• household contact of hepatitis C infected patient(s),  
• current or prior high-risk sexual activity,  
• body piercing or tattoos,  
At the discretion of the investigator, additional patients may also be tested for hepatitis C.   
The management guidelines, in Section 6.3.3, are provided according to the results of the 
baseline assessment of hepatitis C viral load. 
 
5 
Population 
The study population will consist of adult patients with bone and soft tissue sarcoma. 
In phase II trials of novel cytotoxics, it has been usual practice to include patients who have 
received 2 lines of single agent chemotherapy or 1 line of combination treatment. Given the 
novel mechanism of action of this agent, such a restriction is illogical. Therefore, there will be 
no restriction on the number of lines of prior chemotherapy, provided the patients have 
adequate performance status and organ function and have failed standard treatment. 
5.1 
Inclusion/exclusion criteria  
The investigator must ensure that all patients who meet the following inclusion and exclusion 
criteria are offered enrollment in the study. No additional exclusion parameters can be applied 
by the investigator, in order that the study population will be representative of all eligible 
patients. 
Inclusion criteria 
• Histological evidence of progressive or metastatic bone or soft tissue sarcoma. 
The following tumor types are included: 
 alveolar soft part sarcoma (ASPS) 
 malignant fibrous histiocytoma; 
 liposarcoma; 
 synovial sarcoma; 
 malignant paraganglioma; 
 fibrosarcoma; 
 leiomyosarcoma; 
 angiosarcoma including haemangiopericytoma; 
 malignant peripheral nerve sheath tumor; 
 STS, not otherwise specified; 
 miscellaneous sarcoma including mixed mesodermal tumors of the uterus; 
 osteosarcoma; 
 Ewing’s sarcoma; 
 rhabdomyosarcoma; 


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 gastrointestinal stromal tumor (only after failure or intolerance of imatinib or sunitinib 
in 1st and 2nd line) 
Objective progression of disease may be documented by RECIST criteria. Any of the 
following would be sufficient according to RECIST:  
 a 20% increase in the sum of unidimensionally measured target lesions; 
 a new lesion; 
 unequivocal increase in non-measurable disease. 
• At baseline, a CT or MRI scan must demonstrate measurable disease by RECIST criteria, 
i.e. the presence of at least one measurable lesion. Measurable disease lesions must be 
accurately measured in at least one dimension with longest diameter ≥ 20mm using 
conventional techniques or ≥ 10mm with spiral CT scan (with minimum lesion size no 
less than double the slice thickness). (see post-text supplement 1). 
• At least one measurable lesion outside of the field of any prior radiation therapy 
(according to RECIST criteria). Prior radiotherapy to a single index lesion is not allowed. 
• Adult male or female patients (≥18 years of age). In countries outside Germany patients at 
the age of ≥ 16 can also be included into the trial. 
• Patients must have disease not amenable to surgery, radiation, or combined modality 
therapy with curative intent. 
• Adequate bone marrow function as shown by: absolute neutrophil count (ANC) > 
1,500/µl, Platelets ≥ 100,000/µl, Hb > 9g/dL. 
• Adequate renal function as shown by: a serum creatinine value < 1.5 x upper limit of 
normal (ULN). 
• Adequate liver function as shown by:  
• serum bilirubin ≤ 1.5 x ULN; 
• INR < 1.3 x ULN (or < 3 on anticoagulants); 
• ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases). 
• ECOG performance status 0 – 2. 
• Fully recovered from any previous surgery, prior chemotherapy or radiation therapy (at 
least 4 weeks since major surgery or prior myelosuppressive chemotherapy). Prior 
radiotherapy to a single index lesion is not allowed. With the exception of alopecia, 
patients must have resolution of all acute toxic effects of any prior surgery, radiotherapy, 
or chemotherapy to NCI CTC (Version 3.0) grade ≤ 1. 
• 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. 
Exclusion criteria 
• Anticancer therapy within 3 weeks of enrollment including chemotherapy, hormonal 
therapy, immunotherapy, or radiotherapy. 
• The following tumor types will not be included: 


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 gastrointestinal stromal tumor (except for patients after treatment with imatinib or 
sunitinib in 1st and 2nd line); 
 chondrosarcoma; 
 malignant mesothelioma; 
 neuroblastoma. 
• Prior therapy with RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus). 
• neurotoxicity ≥ grade 2 CTC. 
• Radiation of the lung. 
• Patients taking drugs known to inhibit or induce isoenzyme CYP3A (Table 6-4) are 
excluded unless the drugs are medically necessary and no substitutes are available. If there 
are no acceptable substitutes, special precautions should be taken in these patients (section 
6.3.5). 
• Patients with any concurrent major medical condition liable to compromise the patient's 
participation in the study (e.g. known HIV infection, uncontrolled diabetes, serious cardiac 
dysrhythmia or condition, New York Heart Association classification of III or IV, 
congestive cardiac failure, myocardial infarction within 6 months, unstable angina, 
chronic or acute renal or liver disease, uncontrolled serious infections including abscess or 
fistulae, etc.). 
• Patients with a history of another malignancy prior to study entry, except curatively 
treated non-melanotic skin cancer or carcinoma in-situ cervical cancer unless in complete 
remission or no evidence of disease and off all therapy for that disease for a minimum of 5 
years. 
• No symptomatic brain metastasis. Patients with asymptomatic brain metastases can be 
entered, if this is deemed to be in the best interest of the patient by the responsible 
physician. Previously radiated brain lesions will be defined non evaluable for response. 
• Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer. 
• History of hypersensitivity to any of the study drugs or to drugs with similar chemical 
structures. 
• Patients committed to an institution by order of the authorities or court decision. 
• Female patients who are pregnant or breast feeding or patients of reproductive potential 
not employing an effective method of birth control. Because oral, implantable or 
injectable contraceptives may be affected by cytochrome P450 interactions, an appropriate 
method of birth control should be used throughout the trial in both sexes. Women of 
childbearing potential (WOCBP) must have a negative serum pregnancy test within 48 
hours prior to the administration of study medication. 
Definition of women of child-bearing potential (WOCBP): all women physiologically capable of 
becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes 
intercourse with a male partner and women whose partners have been sterilized by vasectomy or 
other means, UNLESS they meet the following definition of post-menopausal: 12 months of 
natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH 
levels > 40mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy 
OR are using one or more of the following acceptable methods of contraception: Acceptable 


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methods of contraception may include total abstinence at the discretion of the investigator in 
cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. 
Appropriate contraception is defined as surgical sterilization (e.g. bilateral tubal ligation, 
vasectomy), hormonal contraception (implantable, patch, oral), and double-barrier methods (any 
double combination of: IUD, male or female condom with spermicidal gel, diaphragm, sponge, 
cervical cap).Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Reliable contraception 
should be maintained throughout the study and for 30 days after study drug discontinuation. 
5.2 
Premature patient withdrawal 
Patients must be withdrawn from the study for any of the following reasons: 
• Withdrawal of informed consent 
• Pregnancy 
• Study drug discontinuation  
• Progression of tumor 
• Unacceptable toxicity 
• Patients also should be withdrawn at any time if the investigator concludes that it 
would be in the patient’s best interest for any reason. 
The reason for premature patient withdrawal from the study must be  recorded on the Study 
Completion CRF. 
Protocol violations should not lead to patient withdrawal unless they indicate a significant risk 
to the patient’s safety. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, or fail to return for visits, or 
become lost to follow up for any other reason. 
For patients who are lost to follow-up (i.e. those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show “due diligence” by documenting in the source documents steps taken to contact the 
patient, e.g. dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the core study will be replaced by an equal 
number of newly enrolled patients. 
6 
Treatment 
6.1 
Treatment assignment 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by the sponsor to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the 
investigator. At each site the first patient is assigned patient number 1, and subsequent 
patients are assigned consecutive numbers (e.g. the second patient is assigned patient number 
2, the third patient is assigned patient number 3). Once assigned to a patient, a patient number 


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will not be reused. If the patient fails to be started on treatment for any reason, the reason for 
not being treated will be entered on the Screening Log. 
6.2 
Investigational drug 
RAD001 is formulated as tablets of 5 mg strength, blister-packed under aluminum foil in units 
of 10 tablets. In addition RAD001 will also be delivered as Afinitor® (everolimus) tablets 
formulated as tablets of 5 mg strength, blister-packed in units of 30 tablets per pack. 
RAD001/everolimus are dosed on a daily basis.  
6.3 
Treating the patient 
6.3.1 
Instructions for prescribing and taking the study drug 
RAD001 will be dispensed by the study center personnel on an outpatient basis. Patients will 
be provided with an adequate supply of RAD001 for self-administration at home.  
RAD0001 will be dosed starting on Week 1 Day 1. Patients will be instructed to take two 
tablets of RAD001 orally with a glass of water, once daily at the same time each day, in a 
fasting state or after no more than a light, fat-free meal. If vomiting occurs, no attempt should 
be made to replace the vomited dose. Patients should be requested to bring their unused 
medication, including the empty blister packs, to the clinic at each visit. Compliance should 
be verified by the investigator’s staff through counting the number of tablets consumed 
between visits. 
The investigator (or his/her designee) will document dosage administration and all dose 
changes during the study in the CRF. The site must maintain an overall drug accountability 
log for the study, as well as individual accountability records for each patient. The dose, 
amount dispensed, amount received, and amount remaining unused must be recorded in the 
source document. Drug accountability will be noted by the field monitor during site visits and 
at the completion of the study. The patient will be asked to return all unused RAD001 at the 
end of study treatment. 
Patients will be treated with RAD001 until progression of tumor, the occurrence of 
unacceptable toxicity, or until the investigator or patient decides that continuation is not in the 
best interest of the patient. Interruption for toxicity should follow the instructions in Table 6.2.  
6.3.2 
RAD001 dose adjustments 
For patients who are unable to tolerate the protocol-specified RAD001 dosing schedule, dose- 
adjustment guidelines are given below. Three RAD001 dose levels are defined for dose 
adjustment: 10mg daily, 5mg daily, and 5mg every other day. (Table – 1) 
Table 6-1 
RAD001 Dose levels for dose adjustment 
Dose level 
Dose and schedule 
0 (starting dose) 
10mg daily 
Decrease 1 dose level 
5mg daily 
Decrease 2 dose levels 
5mg every other day 
Toxicity will be assessed using the NCI-CTC for Adverse Events, version 3.0 (CTCAE v3.0, 


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(http://ctep.cancer.gov/forms/CTCAEv3.pdf)). 
6.3.3 
Management of RAD001 toxicities 
Known Undesirable Side Effects of RAD001 
Adverse events most frequently observed with RAD001 are rash, stomatitis/oral mucositis, 
fatigue, headache, anorexia, nausea, vomiting, diarrhea, ocular toxicity and infections. Non-
infectious pneumonitis has also been observed. Overall, the most frequently observed 
laboratory abnormalities include neutropenia, thrombocytopenia, hypercholesterolemia, 
and/or hypertriglyceridemia. The majority of these AEs have been of mild to moderate 
severity (CTC grade 1-2). 
Table 6-2 
Criteria for dose-modification in case of suspected RAD001 toxicity 
and re-initiation of RAD001 treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2 (except pneumonitis, refer to Table 6.3) 
If the toxicity is tolerable to the patient, maintain 
the same dose. If the toxicity is intolerable to 
patient, interrupt RAD001 until recovery to grade ≤ 
1. 
Then reintroduce RAD001 at same dose. 
If event returns to grade 2, interrupt RAD001 until 
recovery to grade ≤ 1. Then reintroduce RAD001 
at the lower dose level. 
Grade 3 (except hyperlipidemia) 
Interrupt RAD001 until recovery to grade ≤ 1. 
Then reintroduce RAD001 at the lower dose level. 
For pneumonitis, consider the use of a short 
course of corticosteroids (see table 6.3). 
Grade 3 hyperlipidemia (hypercholesterolemia 
and/or hypertriglyceridemia) 
Should be managed using standard medical 
therapies. 
Grade 4 
Discontinue RAD001. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia 
(platelets < 75, ≥ 50x109/L)  
Interrupt RAD001 until recovery to grade ≤ 1 
(platelets ≥ 75x109/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 Thrombocytopenia 
(platelets < 50, ≥ 25x109/L)  
Interrupt RAD001 until recovery to grade ≤ 1 
(platelets ≥ 75x109/L). 
Then resume RAD001 at one dose level lower. 
If grade 3 thrombocytopenia recurs, discontinue 
RAD001. 
Grade 4 Thrombocytopenia 
(platelets < 25x109/L) 
Discontinue RAD001. 


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Grade 3 Neutropenia 
(neutrophils (< 1, ≥ 0.5x109/L) 
Interrupt RAD001 until recovery to grade ≤ 1 
(neutrophils ≥ 1.5x109/L). 
Then resume RAD001 at the initial dose. If ANC 
again returns to Grade 3, hold RAD001 until the 
ANC ≥ 1.5x109/L. 
Then resume RAD001 dosing at the lower dose 
level. Discontinue patient from study therapy for a 
third episode of grade 3 neutropenia. 
Grade 4 Neutropenia 
(neutrophils (< 0.5x109/L) 
Interrupt RAD001 until recovery to grade ≤ 1 
(neutrophils ≥ 1.5x109/L). 
Then resume RAD001 at the lower dose level. 
If grade 3 or grade 4 neutropenia occurs despite 
this dose reduction, discontinue RAD001. 
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. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue RAD001. 
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 3 weeks 
Discontinue RAD001. 
Monitoring of RAD001 suspected toxicities  
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value suspected to be related to RAD001 must be followed at least 
weekly via telephone until the adverse event or abnormal laboratory value resolves or returns 
to grade 1. If a patient requires a dose delay of > 21 days from the intended day of the next 
scheduled dose, then the patient must be discontinued from the study. 
Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to RAD001 should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral toxicities 
associated with RAD001 as mouth ulcers, rather than mucositis or stomatitis. If your 
examination reveals mouth ulcers rather than a more general inflammation of the mouth, 
please 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, 


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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 RAD001 metabolism, 
thus leading to higher RAD001 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 3.0. 
Management of 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. Grade 2 or 
higher hypercholesterolemia (> 300mg/dL or 7.75mmol/L) or grade 2 or higher 
hypertriglyceridemia (> 2.5 x ULN) should be treated with a statin or appropriate lipid-
lowering medication, in addition to diet. Patients should be monitored clinically and through 
serum biochemistry for the development of rhabdomyolysis and other adverse events as 
required in the product label/data sheets for HMG-CoA reductase inhibitors. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated 
with an increased risk of a rare but serious skeletal muscle toxicity manifested by 
rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, acute 
renal failure and sometimes death. The risk versus benefit of using this therapy should be 
determined for individual patients based on their risk of cardiovascular complications of 
hyperlipidemia. 
Grade 3 hyperglycemia has been observed in patients receiving RAD001 therapy. In many 
cases the affected patients had an abnormal fasting glucose at baseline. Based on this finding, 
it is recommended that optimal glucose control is achieved before starting a patient on 
RAD001. Study patients should have their glucose levels monitored during RAD001 therapy. 
Management of skin disorders 
In prior phase I clinical studies with RAD001 alone, rash and/or erythema was the most 
frequent AE experienced by approximately 40% of patients. For patients with grade 1 
toxicity, no specific supportive care is usually needed or indicated. The rash should be 
reported as an AE. Patients with grade 2 supportive toxicity may be treated with supportive 
measures, including the following at the discretion of the investigator: oral minocycline, 
topical tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, oral 
predinisolone (short course) or pimecrolimus. 


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Management of gastrointestinal disorders  
Nausea, vomiting and diarrhea have been seen in approximately 15-55% of patients treated 
with RAD001. The symptoms have in general been mild to moderate (CTC grade 2). 
Appearance of grade 1-2 diarrhea should lead to supportive care such as loperamide, initiated 
at the earliest onset (4mg orally followed by 2mg orally every 2 hours until resolution of 
diarrhea). In patients who have emesis and are unable to retain the medication, every attempt 
should be made to control symptoms of nausea and vomiting with the best available 
supportive care. However, no attempt should be made to replace the vomited dose. Patients 
experiencing diarrhea leading to hospitalisation will have their drug administration interrupted 
or changed according to the procedures described in table 6.2. 
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. 
Since disease control for tumor measurement includes bimonthly CT of the lung or chest x-
ray, no additional CT/x-ray is required to monitor for asymptomatic (grade 1) non-infectious 
pneumonitis. 
Additional chest x-rays or 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 6.3. 
Table 6-3 
Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
RAD001 Dose Adjustment 
Grade 1 
CT scans with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat a 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 includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
each subsequent cycle until 
return to baseline. Consider 
a 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. 


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Grade 3 
CT scan with lung windows 
and pulmonary function 
testing includes: spirometry, 
DLCO, and room air O2 
saturation at rest. Repeat 
each subsequent cycle until 
return to baseline. 
Bronchoscopy is required 
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. 
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 required. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Discontinue treatment. 
The investigator should promote compliance by instructing the patient to take the study drug 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and 
the validity of the study. The patient should be instructed to contact the investigator if he/she 
is unable for any reason to take the study drug as prescribed. 
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
 
Management of Hepatitis reactivation 
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 4 provides details of monitoring and prophylactic therapy according to the baseline 
results of viral load and serologic markers testing. 
Table 6-4 
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 - 
+ 
- 


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Study No. CRAD001C24114 
 
Test 
Result 
Result 
Result 
Result 
Result 
Recommendation 
Prophylaxis treatment 
should be started 1-2 
weeks prior to first dose 
of  study drug 
Monitor HBV-DNA 
approximately every 4-8 
weeks 
No prophylaxis 
Monitor HBV-DNA 
approximately every 4 
weeks 
 
No specific 
action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study 
drug.  
For patients who have already been randomized and 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 5 Guidelines for 
management of hepatitis B.  
Table 6-5 
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.  (see Table 1 – Study 
drug dose reductions) 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 
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. (see Table 1 – Study 
drug dose reductions) 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 


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Ab]  
-------------------------------
------ 
reactivation is defined as: 
New appearance of 
measurable HBV-DNA 
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. 
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 3.0 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 3.0 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 4–8 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 
Guidelines for management of hepatitis C. 


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Table 6-6 
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 v 3.0 
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 3.0 Metabolic Laboratory/Other: Viral Re-activation).  
 
6.3.4 
Follow-up for toxicities while receiving RAD001 
Patients who interrupt or permanently discontinue RAD001 due to an adverse event or 
abnormal laboratory value must be followed at least weekly via telephone for 28 days after 
the last dose of RAD001, and subsequently at monthly intervals until resolution or 
stabilization of the event, whichever comes first. If a patient requires a 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 RAD001. 
6.3.5 
Other concomitant medications 
Inhibitors of CYP3A4 and/or PgP 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) 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 everolimus to half the currently used 
dose. Additional dose reductions to every other day may be required to manage toxicities. If 


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the inhibitor is discontinued the everolimus dose should be returned to the dose used prior to 
initiation of the moderate CYP3A4/PgP inhibitor. 
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. Concomitant 
use should be avoided. 
Inducers of CYP3A4 and/or PgP 
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 worth), an increase in the dose of everolimus up to twice the currently used daily dose 
should be considered, using 5 mg increments every other day – 5 mg increments daily. 
Enzyme induction usually occurs within 7-10 days, therefore everolimus dose should be 
increased by one increment 7 days after the start of the inducer therapy.  If no safety concerns 
are seen within the next 7 days, the dose can be increased again one additional increment up 
to a maximum of twice the daily dose used prior to initiation of the strong CYP3A4 inducer.   
This dose adjustment of everolimus 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 everolimus dose 
should be returned to the dose used prior to initiation of the strong CYP3A/PgP inducer. 
Table 6-7 
Clinically relevant drug interactions: substrates, inducers, and 
inhibitors of isoenzyme CYP3A 
INDUCERS 
Barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, 
troglitazone, efavirenz, nevirapine, topiramate 
INHIBITORS 
Strong inhibitors:  
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir,  
mibefradil, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
troleandamycin, voriconazole, 
Posaconazole (Krishna et al, 2009) 
 
Moderate inhibitors:  
aprepitant, atazanavir, cimetidine, ciprofloxacin, darunavir, diltiazem, erythromycin, 
fluconazole, grapefruit juice, imatinib,  tofisopam, verapamil,  
Table 6-8 
Clinically relevant drug interactions mediated by PgP 
PgP Substrates 
PgP Inhibitors in vivo 
PgP Inducers 
digoxin, fexofenadine,  
indinavir, vincristine, 
colchicine, topotecan, 
paclitaxel 
amiodarone, azithromycin, 
captopril, carvedilol, 
clarithromycin, conivaptan, 
cyclosporine, diltiazem, 
elacridar, erythromycin, 
felodipine, (GF120918), 
rifampin, St John’s wort 


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PgP Substrates 
PgP Inhibitors in vivo 
PgP Inducers 
itraconazole, 
ketocoanzole, lopinavir, 
(LY335979), mibefradil, 
nifedipine, nitrendipine, 
(PSC833), quinidine, 
ranolazine, ritonavir, 
talinolol, valspodar, 
verapamil 
Reference: 
Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Dec. 2, 2009, which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies, the University of Washington’s Drug Interaction Database, and Indiana 
University School of Medicine's Drug Interaction Table. " 
**This list of clinically relevant drug interactions is updated as of December 02, 2009** 
 
6.3.6 
Study drug discontinuation 
Study drug must be discontinued for a given patient if the investigator determines that 
continuing it would result in a significant safety risk for that patient. Patients who, in the 
opinion of the investigator, require alternative medical therapy, will be discontinued from the 
study. Patients with a progression will be discontinued from the study. Patients who become 
pregnant during the study must be withdrawn. If the treatment has to be interrupted for more 
than 21 consecutive days for any reason, the patient will be discontinued from the study 
unless otherwise discussed with the study coordinator. In case of patient’s discontinuation, the 
end of study evaluation will be completed as soon as possible. End of study evaluations will 
include adverse events, concomitant medications and therapies, physical examination, vital 
signs, ECOG performance status, biochemistry, hematology and tumor measurement. 
Patients who discontinue prematurely due to significant AE should continue to be followed-up 
until resolution of the AE, and the relevant sections of the CRF should be completed as 
appropriate. Patients who are discontinued due to clinically significant abnormalities in 
clinical laboratory results should continue to be evaluated until the abnormality resolves or is 
judged to be permanent. 
It will be documented whether or not each patient completed the clinical study. If, for any 
patient, the study treatment was discontinued the reason will be recorded. Reasons that a 
patient may discontinue participation in a clinical study are considered to constitute one of the 
following: 
1. 
Adverse event(s) 
2. 
Abnormal laboratory value(s) 
3. 
Abnormal test procedure result(s) 
4. 
Unsatisfactory therapeutic effect 
5. 
Subject's condition no longer requires study treatment 


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6. 
Protocol violation which affect the safety of the patient 
7. 
Subject withdraws consent 
8. 
Lost to follow-up 
9. 
Administrative problems 
10. 
Death 
Progressive disease is defined as unsatisfactory therapeutic effect. 
For patients who are lost to follow-up, the investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. 
It is agreed that for reasonable cause, either the investigator or Novartis may terminate this 
study, provided a written notice is submitted at a reasonable time in advance of the intended 
termination. 
A Study Drug Discontinuation form should be completed, giving the date and primary reason 
for stopping the study drug. 
Study treatment will be continued until progression. Patients will be followed until 
progression.  
The overall survival will be documented on the survival information page for all patients 
except for those who withdrew consent or are lost to follow-up. 
7 
Visit schedule and assessments 
7.1 
Information to be collected on screening failures 
Information on screening failures will be kept in the Novartis Screening Failure Log. No CRF 
has is needed for screening failures. 
All data obtained from the assessments listed in Table 1 and described in detail in the 
subsections below must be supported in the patient’s source documentation. Assessments that 
generate data for database entry and which are recorded on CRFs are listed using the CRF 
name. Assessments that are transferred to the database electronically (e.g. laboratory data) are 
listed by test name. 
The final examination (visit 6 respectively EOS) will be performed for all patients included in 
this trial (i.e. who signed an informed consent form and received study treatment), whether 
they discontinued study treatment prematurely or completed the study treatment. Patients who 
discontinue study drug before completing the core study, and those who prematurely 
withdraw from the core study for any reason, should be scheduled for the End-of-study-visit 
as soon as possible, at which time all of the assessments listed for the EOS-visit will be 
performed. 
During the follow-up period, the treatment regimen as taken during the study should be 
maintained. However, changes in the regimen based on each patient’s clinical needs and the 
investigators’ experience and discretion will be possible at any time. In the Follow-Up-Phase 


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the End-of-Follow-Up-Visit is the corresponding visit to the End-of-Study-Visit in the Core 
Phase.  
For all visits of the Core Study a tolerance of 3 days in both directions is acceptable. For all 
visits of the Follow Up Phase a tolerance of 1 week in both directions is acceptable. 
Table 7-1 
Assessment schedule 
 
Base-
line1 
Core study 
Follow-up12 
Visit No. 
1 
2 
3 
4 
5 
6 
EOS 
 
 
 
 
End of 
FUP  
 
 
 
 
 
 
 
 
FUP 1 - X 
 
Day  
-14 
1 
 
 
 
 
  
  
 
 
 
 
Week 
  
  
4 
8 
12 
16 
  
28 
40 
52 
X 
 
Demographics1 
x 
  
  
  
  
  
  
  
  
  
  
  
Informed 
consent 
x 
  
  
  
  
  
  
  
  
  
  
  
In-/exclusion 
criteria 
x 
  
  
  
  
  
  
  
  
  
  
  
HBV-DNA, 
HBsAg, HBs Ab, 
HBc Ab, HCV-
RNA-PCRX 
x 
 
 
 
 
 
 
 
 
 
 
 
HBV DNA, HCV 
RNA-PCRXX 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 5 
x 
  
  
  
  
  
  
  
  
  
  
  
Medical history 
x 
  
  
  
  
  
  
  
  
  
  
  
Extent of cancer 
x 
  
  
  
  
  
  
  
  
  
  
  
Prior anti-
neoplastic 
treatment 
x 
  
  
  
  
  
  
  
  
  
  
  
Vital signs 2  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height  
x 
  
  
  
  
  
  
  
  
  
  
  
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 6 
x 
  
  
  
  
  
x 
  
  
  
  
x 
Physical 
examination 1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG PS 3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology 4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Biochemistry 4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinanalysis 4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CT / MRI  
x 
  
  
x 
  
x 
x 
x 
x 
x 
x 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-ray 9 
x 
  
  
x 
  
x 
  
x  
x  
 x 
x  
  
PET optional 
(not in Germany) 7 
x 
  
x  
  
  
 
  
  
  
  
  
  


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Base-
line1 
Core study 
Follow-up12 
Visit No. 
1 
2 
3 
4 
5 
6 
EOS 
 
 
 
 
End of 
FUP  
 
 
 
 
 
 
 
 
FUP 1 - X 
 
Day  
-14 
1 
 
 
 
 
  
  
 
 
 
 
Week 
  
  
4 
8 
12 
16 
  
28 
40 
52 
X 
 
Tumor 
evaluation 
(RECIST) 7 
x 
  
  
x 
  
x 
x 
x 
x 
x 
x 
  
Study drug 
administration 
  
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
  
Adverse events 
8 
x 
ongoing data capture 
ongoing data capture 
Prior medication 
x 
  
  
  
  
  
  
  
  
  
  
  
Concomitant 
medication 
x 
ongoing data capture 
ongoing data capture 
Survival-
information 10 
  
  
  
  
  
  
  
  
  
  
  
x 
Comments 
  
ongoing data capture 
ongoing data capture 
1Described in Section 7.2; 7.5.2 
2Described in Section 7.5.3 
3Described in Section 7.5.4 
4Described in Section 7.5.5 
5Described in Section 7.5.7; 8.2  
6Described in Section 7.5.6 
7Described in Section 7.4 
8Described in Section 8.1.1 
9Chest x-ray only in cases where no CT/MRI thorax is available 
10Survival information for patients who discontinued earlier  
11 Baseline assessment can be done between day-14 and day 1 together with visit 2  
12 During the follow up period patients will continues to be followed every 3 months until progression 
X All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C.  It 
is highly recommended that patients positive HBV-DNA or HBsAg are treated prophylactically with an antiviral 
for 1-2 weeks prior to receiving study drug. The antiviral treatment should continue throughout the entire study 
period and for at least 4 weeks after the last dose of study drug. Patients with viral hepatitis C risk factors should 
be screened for HCV RNA-PCR. 
XX Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-DNA 
according to study visit schedule. Patients with positive HCV-RNA PCR or a history of past infection, even if 
treated and considered ‘cured’ – should be followed by HCV-RNA PCR according to visit schedule. 
 
7.2 
Patient demographics/other baseline characteristics 
Demographic data include: Date of birth, sex, and race. 
Baseline characteristics include: Medical history/current medical condition, prior medication, 
tumor history, baseline tumor assessment, relevant prior tumor therapy, ECOG, vital signs 
(height, weight, blood pressure, pulse), result of pregnancy test, hematology and 
biochemistry. 
 


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HBV testing 
Prior to starting study drug, the categories of patients listed in Section 4 Changes to Study 
design 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 4. 
HCV 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 4 Changes to Study design.  
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.  
 
7.3 
Treatments 
Study drug administration will be documented. Dose modifications and interruptions will be 
documented ongoing. 
7.4 
Efficacy 
Tumor evaluation 
Disease status will be based on CT/MRI scans and/or chest x-ray performed maximum ca. 2 
weeks before baseline, thereafter after week 8, 16, 28, 40, 52 and X, respectively at final visit. 
If medically indicated, unscheduled CT/MRI examinations and/or chest x-ray will be 
performed at the investigator’s discretion. Response status will be evaluated using RECIST 
criteria (please see Post-text supplement 1). The evaluation of the central radiologist will be 
used. 
At baseline and 1st comparative FDG-PET assessment at visit 5 can be carried out optional in 
non-German-centers in order to provide this additional perspective on changes in tumor 
activity induced by the therapy and give data on correlation of PET as an indicator for 
progression or response. Although 18FDG-PET functional imaging may be valuable as a 
complement to standard anatomical imaging (CT or MRI) in any tumor assessment 
(identification of new lesions or of newly active foci in otherwise inactive lesions), the 
primary variable for efficacy assessment will be that obtained by standard anatomical 
imaging. 
7.5 
Safety 
7.5.1 
Adverse events 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after date of signed informed consent even if the event is not 
considered to be related to study drug. Study drug includes the investigational drug under 
evaluation that is given during any phase of the trial. Medical conditions/diseases present 
before date of signed informed consent are only considered adverse events if they worsen 


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after date of signed informed consent. Abnormal laboratory values or test results constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy (e.g. any hematologic abnormality that requires transfusion or 
cytokine treatment). In addition, abnormal laboratory values that cause study discontinuation 
or constitutes in and of itself a Serious Adverse Event (SAE) should be recorded on the 
Adverse Events CRF. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 3.0 (http://ctep.cancer.gov/forms/CTCAEv3.pdf). If CTCAE 
grading does not exist for an adverse event, the severity of mild, moderate, severe, and life-
threatening, OR grades 1 – 4, will be used. CTCAE grade 5 (death) will not be used in this 
study; rather, this information will be collected in the End of Treatment or Survival 
Information CRF page. Adverse event monitoring should be continued for at least 4 weeks 
following the last dose of study drug. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine: 
1. the severity grade (CTCAE Grade 1 – 4) or mild, moderate, severe, life-threatening if 
CTCAE grading does not exist for an adverse event, 
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), 
and 
5. whether it is serious, where a serious adverse event (SAE) is defined as one which: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (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 an 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 


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In contrast to routine safety assessments, SAE are monitored continuously and have 
special reporting requirements; see Section 8.1 “Serious adverse event reporting”. 
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 Investigator's Brochure or will be communicated between IB updates in the form 
of Investigator Notifications. This information will be included in the patient informed 
consent form and should be discussed with the patient during the study as needed. 
7.5.2 
Physical examination 
A routine physical examination will be performed according to the visit schedule.  
A full physical examination is to be performed once a month during the first five months of 
the study and every two months thereafter. It should comprise a total body examination 
(general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and basic nervous system). 
Information about the physical examination must be present in the source documentation at 
the study site. Significant findings that are present prior to signing informed consent (or 
therapy) must be included in the Relevant Medical History / Current Medical Conditions 
CRF. Significant findings made after signing informed consent which meet the definition of 
an adverse event must be recorded on the Adverse Event CRF. 
7.5.3 
Vital signs 
Pulse, blood pressure (measured after at least 3 minutes in the sitting position), temperature 
and weight will be measured at every visit.  Height will be measured at baseline only. 
Patients should be weighed and monitored regularly for signs and symptoms of fluid 
retention. An unexpected rapid weight gain should be carefully investigated and appropriate 
treatment provided. 
7.5.4 
Performance status 
The patient’s performance status should be estimated using the ECOG scale / Karnofsky 
scale, and recorded in the CRF. Post-text supplement 2 shows the grading scale for reference 
(Karnofsky, 1948). 
7.5.5 
Laboratory evaluations 
Blood and urine samples will be analyzed in the local laboratory. The laboratory details will 
be provided in writing to Novartis prior to the screening of the first patient at the site. In 
particular, the name, address and contact details of the lab must be provided, together with the 
lab normal ranges, and a copy of the latest lab certificate. Unless prior agreement is given by 


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Novartis to the site, the site must use the same lab(s) for all samples from a given patient, and 
all patients at that site. 
The following assessments should be made: 
Hematology 
Total white blood cell (WBC (total)), red blood cells (RBC), Hemoglobin, Hematocrit, 
platelets. 
Differential counts of the following should be made also: neutrophils, lymphocytes, 
eosinophils, basophils, monocytes. Results should be provided as absolute or percentage 
values (not both). The same units used for the screening visit assessment should be used for 
all samples for a particular patient. 
Blood chemistry 
Urea or BUN (depending on what is commonly used at the site), creatinine, sodium, 
potassium, glucose, uric acid, LDH, total protein, albumin, total bilirubin, SGOT, SGPT, 
alkaline phosphatase, cholesterol, triglycerides y-GT, Lipase, CRP, Quick, PTT. 
. 
Urine measurements 
Glucose, protein, bilirubin, ketones, leukocytes, erythrocytes, specific gravity, pH, 
microscopic analysis. 
7.5.6 
ECG 
A standard 12 lead ECG must be carried out at baseline for screening purposes and to provide 
a pretreatment comparison for an on-treatment ECG performed at the End of Study visit and 
at the end of follow-up. 
7.5.7 
Pregnancy test 
Any pregnancy that occurs during study participation should be reported using a Clinical Trial 
Pregnancy Form. 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. Instructions about completing initial and follow-up Clinical Trial Pregnancy 
Forms and sending them to Novartis are given in Section 8.2. “Instructions for rapid 
notification of pregnancies”. 


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8 
Safety monitoring 
8.1 
Serious adverse event reporting 
8.1.1 
Safety assessments 
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 
participation (end of treatment) must be reported to Novartis within 24 hours of learning of its 
occurrence. Any SAE 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. 
Information about all SAE is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess the relationship to study drug, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the local 
Novartis Clinical Safety & Epidemiology Department. The telephone and telefax number of 
the contact persons in the local department of Clinical Safety and Epidemiology, specific to 
the site, are listed in the Investigator Folder provided to each site. The original copy of the 
SAE Report Form and the fax confirmation sheet must be kept with the CRF documentation 
at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, 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 & 
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. 
Safety assessments will consist of monitoring and recording all adverse events, including 
serious adverse events, the regular monitoring of hematology, blood chemistry and urine 
values, regular monitoring of vital signs, physical condition and body weight. 
8.2 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 


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and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Clinical Safety & Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship of any pregnancy outcome to the Novartis study drug. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
If the father is taking the study drug, informed consent to report information regarding 
pregnancy outcome needs to be obtained from the mother. 
9 
Data review and database management 
9.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study drug is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the CRFs, which will be documented as being the source 
data. The investigator must also keep the original informed consent form signed by the patient 
(a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAE, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed. 
9.2 
Data collection 
Designated investigator staff must enter the information required by the protocol onto the 
Novartis CRFs that are printed on 3-part, non-carbon-required paper. Field monitors will 
review the CRFs for completeness and accuracy and instruct site personnel to make any 
required corrections or additions. The CRFs are forwarded to the Data Management of 
Novartis or to the designated CRO by field monitors, one copy being retained at the 
investigational site; a further copy may be used as a working copy for the field monitors. 


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Once the CRFs are received by Novartis, their receipt is recorded and they are forwarded for 
data entry. 
9.3 
Database management and quality control 
Data from the CRFs are entered into the study database using double data entry with 
electronic verification. Text items (e.g. comments) are entered once and checked manually 
against the CRF. 
Subsequently, the entered data are systematically checked by Data Management staff, using 
error messages printed from validation programs and database listings. Obvious errors are 
corrected by Novartis personnel. Other errors or omissions are entered on Data Query Forms, 
which are returned to the investigational site for resolution. The signed original and resolved 
Data Query Forms are kept with the CRFs at the investigator site, and a copy is sent to 
Novartis so the resolutions can be entered into the database. Quality control audits of all key 
safety and efficacy data in the database are made prior to locking the database. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
10 
Data analysis 
This is a non-randomized, multicenter, triple-arm, phase II trial evaluating the treatment of 
RAD001 in the following three arms: in patients with progressive or metastatic bone or soft 
tissue sarcoma (except for GIST), in patients with progressive or metastatic GIST after failure 
or intolerance of treatment with imatinib or sunitinib, and in patients with progressive or 
metastatic alveolar soft part sarcoma (ASPS) respectively. 
The study is designed to assess the activity, safety, and tolerability of the therapy with 
RAD001 in progressive bone or soft tissue sarcoma in the three arms each. 
The data will be analyzed by Novartis and/or by the designated CRO. Any data analysis 
carried out independently by the investigator(s) should be submitted to Novartis before 
publication or presentation. It is planned that the data from participating centers in this 
protocol will be combined within each of the arms, so that an adequate number of patients 
will be available for analysis. 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and pharmacokinetic 
measurements. Categorical data will be presented as absolute frequencies and percentages. 
For continuous data, N, mean, standard deviation, median, minimum, and maximum will be 
presented. 
It is planned that the data of each arm will be analyzed independently of the other arm once 
the number of patients needed for analysis was reached. 
For simplification, populations for analysis, and the analysis of patient demographics/other 
baseline characteristics, treatment, primary and secondary efficacy variables, and safety will 


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be described without referring to a specific arm. As mentioned above, the methods of analysis 
will be applied to each arm separately. 
In a period of 46 months, so far 8 patients have been enrolled in arm III of this trial. It is 
deemed very unlikely, that a further extension of the enrollment period will result in the 
required number of patients in arm III of this trial. Therefore, enrollment in arm III 
will be stopped. However, patients already enrolled into arm III will continue to be 
treated and observed as foreseen by the protocol. The final analysis of arm III will be 
done when all patients have completed the study or discontinued prematurely. Since the 
sample size required for the decision algorithm will not be reached, data for arm III will 
be summarized descriptively, and results will be interpreted purely exploratively. 
10.1 
Populations for analysis 
The Safety Population will consist of all patients who received at least one dose of study drug 
and had at least one post-baseline safety assessment. Patients will be analyzed according to 
treatment received. Of note, the statement that a patient had no adverse events also constitutes 
a safety assessment. 
The intent-to-treat (ITT) population will consist of all patients who received at least one dose 
of study drug and have at least one post-baseline assessment of the primary efficacy variable 
(assessment according to RECIST). Patients without any post-baseline assessment of tumor 
will be included if they are defined as progressive disease based on clinical evaluation. 
The per-protocol (PP) population (i.e. the efficacy-analyzable population) consists of all 
patients of the intent-to-treat population who show no major protocol violations. As major 
protocol violations are considered those that may have an impact on the study outcome. 
Criteria that are assumed to have such an impact will be defined in a Review Meeting before 
database lock. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and background information will be summarized for the safety, the ITT, and the 
PP population, using frequency distributions for categorical variables and descriptive statistics 
of mean, standard deviation, minimum, median and maximum for continuous variables. 
Background information includes prior medication, past/current medical conditions, diagnosis 
and extent of cancer, ECOG performance status and tumor evaluation at baseline. 
Medical history will be coded using MedDRA and will be presented by system organ class, 
MedDRA preferred term and treatment group. Separate tables will be provided for past 
medical condition and current medical condition. Prior medication will be coded according to 
WHO Drug Reference List. 
10.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
Duration (days) of application of study medication will be summarized descriptively. Dosage 
averages will be calculated including and excluding zero doses for periods of temporary 
interruption of treatment regardless of whether this was due to safety reasons or patients’ non-
compliance. Daily dose levels will be summarized descriptively. Frequency of dose reduction 


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(including temporary dose interruption) for safety reasons as per protocol guidelines as well 
as average daily dose will be presented by visit. Reasons for dose adjustments (including 
temporary dose interruption) will be presented by frequency distribution. Permanent treatment 
discontinuations will be analyzed by frequencies. These analyses will be performed for the 
ITT and the PP population. 
10.4 
Analysis of the primary objective(s) 
10.4.1 
Variable 
The primary variable is defined as the proportion of patients in whom a complete (CR) or 
partial (PR) response or stable disease (SD) was observed at 16 weeks according to RECIST. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
Response rate will be presented with the appropriate 95% confidence interval for the PP 
population. The absolute number of patients showing a response will be determined to 
conclude preliminary activity or non-activity of the study drugs in this patient population 
according to the rules outlined in section 10.2. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Not applicable, only efficacy-analyzable patients (PP population) will be analyzed. 
10.4.4 
Supportive analyses 
Additionally, absolute and relative frequencies together with their appropriate 95% 
confidence interval will be presented for each category (CR/PR/SD/PD/UNK) for PP 
population. 
10.5 
Analysis of secondary objectives 
10.5.1 
Efficacy (secondary) 
Objective response rate (ORR) is defined as the proportion of patients in whom a complete 
(CR) or partial (PR) response was observed at week 12 according to RECIST. Absolute and 
relative frequencies of patients in whom an objective response (CR/PR) was observed at week 
12 will be presented together with the 95% confidence interval for the ITT and PP population. 
Duration of response is defined as the time from onset of response (CR/PR) to progression or 
death from any cause. Patients, not experiencing progression or death at 16 weeks will be 
censored with the date of their last assessment. Duration of response will be explored 
graphically by presenting the Kaplan-Meier curve. 
Progression-free survival (PFS) is defined as the time from first study drug administration to 
objective tumor progression or death from any cause. Observations from patients not 
experiencing tumor progression or death at 16 weeks will be censored with the date of their 
last assessment. PFS will be explored graphically by presenting the Kaplan-Meier curve. 
Additionally, the Kaplan-Meier curve will be presented for PFS at 12 months. 


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Overall survival (OS) is defined as the time from first study drug administration to death from 
any cause. Patients, not experiencing death at 16 weeks will be censored with the date of their 
last assessment. OS will be explored graphically by presenting the Kaplan-Meier curve. 
10.5.2 
Safety 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
electrocardiogram, vital signs, and special tests) will be considered as appropriate. 
10.5.2.1 Adverse events 
Adverse events will be summarized by presenting for the safety population the number and 
percentage of patients having any adverse event, having an adverse event in each body system 
and having each individual adverse event. Any other information collected (e.g. severity or 
relatedness to study medication) will be listed as appropriate. 
10.5.2.2 Laboratory values 
Laboratory data will be summarized by presenting shift tables using extended normal ranges 
(baseline to most extreme post-baseline value), by presenting summary statistics of raw data 
and change from baseline values (means, medians, standard deviations, ranges) and by the 
flagging of notable values in data listings. 
Data from other tests (e.g. electrocardiogram or vital signs) will be listed, notable values will 
be flagged, and any other information collected will be listed as appropriate. Any statistical 
tests performed to explore the data will be used only to highlight any interesting comparisons 
that may warrant further consideration. 
10.5.3 
Tolerability 
Not applicable. 
10.5.4 
Resource utilization 
Not applicable. 
10.6 
Sample size calculation 
The study follows an exact binomial single-stage design in each arm. (A’Hern 2001). Values 
of P0 and P1 follow the recommendation of the EORTC Soft Tissue and Bone Sarcoma Group 
previous publication evaluating PFS in STS patients treated with 2nd line active and inactive 
compounds. In arm I (patients with bone and soft tissue sarcoma except for GIST), the study 
requires 36 evaluable subjects to decide whether the proportion responding, P, is less than or 
equal to P0 = 20% or greater than or equal to P1 = 40% (Table 10-1). In arm II or III (patients 
with GIST after failure or intolerance of 1st and 2nd line treatment with imatinib or sunitinib, 
and patients with progressive or metastatic alveolar soft part sarcoma (ASPS), respectively), 
the study requires 24 evaluable subjects to decide whether the proportion responding, P, is 
less than or equal to P0 = 20% or greater than or equal to P1 = 40%. 


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If the number of responses in arm I is 11 or more, the hypothesis that P is less than or equal to 
20% is rejected with a target type I error rate of 10% and an actual error rate of 8.9% (Table 
10-1). If the number of responses in arm I is 10 or less, the hypothesis that P is greater than or 
equal to 40% is rejected with a target type II error rate of 10% and an actual error rate of 9%. 
If the number of responses in arm II or arm III, respectively, is 8 or more, the hypothesis that 
P is less than or equal to 20% is rejected with a target type I error rate of 10% and an actual 
error rate of 8.9%. If the number of responses in arm II is 7 or less, the hypothesis that P is 
greater than or equal to 40% is rejected with a target type II error of 20% and an actual error 
rate of 19.2%. 
The designs were estimated with NCSS Trial and PASS 2002. 
Table 10-1 
Design features for exact binomial single-stage designs 
 
Arm I 
Arm II 
Arm III 
P0 (maximum response proportion of an inactive drug) 
20% 
20% 
20% 
P1 (minimum response proportion of an active drug 
40% 
40% 
40% 
Type I error (one-sided test) 
10% 
10% 
10% 
Type II error (one-sided test) 
10% 
20% 
20% 
Sample size 
36 
24 
24 
Accept inactivity at the end if  
≤ 10 responders 
≤ 7 responders 
≤ 7 responders 
Reject inactivity at the end if 
≥ 11 responders 
≥ 8 responders 
≥ 8 responders 
Actual type I error level 
8.9% 
8.9% 
8.9% 
Actual type II error level 
9.0% 
19.2% 
19.2% 
The type I error is the probability of rejecting that P is lower or equal to P0 when this is true. The type 
II error is the probability of rejecting that P is greater or equal to P1 when this is true. 
10.7 
Power for analysis of critical secondary variables 
Not applicable. 
11 
References 
A'Hern, RP: Sample size tables for exact single-stage phase II designs. Statist. Med. 2001; 
20:859 – 866 
Bjornsti MA, Houghton PJ, The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 
2004 May;4(5):335-48. 
Cassier PA, Dufresne A, Fayette J, Alberti L, Ranchere D, Ray-Coquard I Blay JY Emergine 
drungs for the treatment of soft tissue sarcomas. Expert opin Emerg Drugs. 2007; 12(1): 139-
53. 
Clark MA, Fisher C, Judson I, Thomas JM: Soft tissue sarcoma in adults. N Engl J Med. 
2005; 353:701-11. 
Investigators’ Brochure RAD001, Edition 5. 2006 


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Jac J, Giessinger S, Khan M et al: A phase II trial of RAD001 in patients (Pts) with metastatic 
renal cell carcinoma (MRCC). Journal of Clinical Oncology. ASCO Annual Meeting 
Proceedings Part I. 2007; Vol 25, No. 18S (June 20 Supplement): 5107  
Yao JC, Phan A, Chang DZ et al., Phase II study of RAD001 (everolimus) and depot 
octreotide (sandostatin LAR) in advanced low grade neuroendocrine carcinoma (LGNET). 
Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I. 2007: Vol 25, No. 
18S (June 20 Supplement): 4503 
Ellard S, Gelmon KA, Chia S et al: A randomized phase II study of two different schedules of 
RAD001C in patients with recurrent/metastatic breast cancer. Journal of Clinical Oncology, 
2007: ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement): 
3513 
Johnston PB, Ansell SM, Colgan JP et al: Phase II trial of the oral mTOR inhibitor everolimus 
(RAD001) for patients with relapsed or refractory lymphoma, Journal of Clinical Oncology, 
2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement): 
8055  
van Oosterom A, Reichardt P, Blay JY et al.: A phase I/II trial of the oral mTOR-inhibitor 
Everolimus (E) and Imatinib Mesylate (IM) in patients (pts) with gastrointestinal stromal 
tumor (GIST) refractory to IM: Study update. Journal of Clinical Oncology, 2005 ASCO 
Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement): 9033 
Rao RD, Allred JB, Windschitl HE et al: N0377: Results of NCCTG phase II trial of the 
mTOR inhibitor RAD-001 in metastatic melanoma. Journal of Clinical Oncology, 2007 
ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement): 8530 
Sankhala KK, Chawla SP, Iagaru A et al:  Early response evaluation of therapy with AP23573 
(an mTOR inhibitor) in sarcoma using [18F]2-fluoro-2-deoxy-D-glucose (FDG) positron 
emission tomography (PET) scan; Journal of Clinical Oncology, 2005 ASCO Annual Meeting 
Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 9028 
Chawla SP, Tolcher AW, Staddon AP et al: Survival results with AP23573, a novel mTOR 
inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: Update of phase II trial. 
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 
18S (June 20 Supplement), 2007: 10076 
Okuno SH, Mahoney MR, Bailey HH et al (2006) A multicenter phase 2 consortium (P2C) 
study of mTOR inhibitor in advanced soft tissue sarcomas (STS). Journal of Clinical 
Oncology, 2006 ASCO Annual Meeting Proceedings Part I. 2006;  24: 9504 
Tabernero J., Rojo F., Burris H., et al: A phase I study with tumor molecular 
pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor 
Everolimus (RAD001) in patients (pts) with advanced solid tumors Journal of Clinical 
Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 
Supplement), 2005: 3007 
Oken, MM et al, Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol 1982;5:649-655.  
 


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Karnofsky DA, Abelmann WH, Craver LF, et al, Cancer 1948; 1:634-656. 
 
Loomba R, Rowley A, Wesley R, et al (2008). Systematic review: the effect of preventive 
lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 148(7): 519-28.  
 
Krishna G, Moton A, Lei Ma L, Savant I, Martinho M, Seiberling M, McLeod J. Effects of 
oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: A 
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2009;  31: 286-98. 
 
 


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Appendix 1: Administrative procedures 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the ICH Harmonized 
Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), 
and with the ethical principles laid down in the Declaration of Helsinki. 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a properly constituted 
Institutional Review Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB) before study 
start. A signed and dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis before study initiation. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to monitors, auditors, Clinical Quality Assurance representatives, IRBs/IECs/REBs, and regulatory 
authorities as required. If an inspection of the clinical site is requested by a regulatory authority, the investigator 
must inform Novartis immediately that this request has been made. 
Informed consent  
Eligible patients may only be included in the study after providing written, IRB/IEC/REB-approved informed 
consent, or, if incapable of doing so, after such consent has been provided by a legally acceptable representative 
of the patient. In cases where the patient’s representative gives consent, the patient should be informed about the 
study to the extent possible given his/her understanding. If the patient is capable of doing so, he/she should 
indicate assent by personally signing and dating the written informed consent document or a separate assent 
form. Informed consent must be obtained before conducting any study-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should be documented in the 
patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form that complies 
with the ICH GCP guideline and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed to by Novartis before 
submission to the IRB/IEC/REB and a copy of the approved version must be provided to the Novartis monitor 
after IRB/IEC/REB approval. 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that must be approved 
by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only amendments that are required for 
patient safety may be implemented prior to IRB/IEC/REB approval. Notwithstanding the need for approval of 
formal protocol amendments, the investigator is expected to take any immediate action required for the safety of 
any patient included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC/REB at the study site should be informed within 10 
working days. 
Study drug supply and resupply, storage, and tracking 
Study drugs must be received by a designated person at the study site, handled and stored safely and properly, 
and kept in a secured location to which only the investigator and designated assistants have access. Upon receipt, 
all study drugs should be stored according to the instructions specified on the drug labels. Clinical supplies are to 
be dispensed only in accordance with the protocol. 


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Medication labels will be in German or in the local language and comply with the legal requirements of 
Germany or the respective country. They will include storage conditions for the drug, but no information about 
the patient except for the randomization number. 
The investigator must maintain an accurate record of the shipment and dispensing of study drug in a drug 
accountability ledger. Monitoring of drug accountability will be performed by the field monitor during site visits 
and at the completion of the trial. Patients must return all unused study drug and packaging at the end of the 
study or at the time of study drug discontinuation. 
At the conclusion of the study and as appropriate during the course of the study, the investigator will return all 
used and unused study drug, packaging, drug labels, and a copy of the completed drug accountability ledger to 
Novartis. 


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Post-text supplement 1: Response Evaluation Criteria in Solid 
Tumors (RECIST) 
RECIST criteria for evaluation of tumor response 
Eligibility 
Only patients with measurable disease at baseline should be included in the study: 
• 
Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
• 
Measurable lesions - lesions that can be accurately measured in at least one dimension 
with longest diameter ≥ 20mm using conventional techniques or ≥ 10mm with spiral CT 
scan (with minimum lesion size no less than double the slice thickness). 
• 
Non-measurable lesions - all other lesions, including small lesions (longest diameter  
< 20mm with conventional techniques or < 10mm with spiral CT scan), i.e. bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by 
imaging techniques, and cystic lesions. 
Methods of tumor measurement 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 14 days before the beginning of the treatment. 
• The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• CT and MRI: CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. Conventional CT and MRI 
should be performed with cuts of 10mm or less in slice thickness contiguously. Spiral CT 
should be performed using a 5-8mm contiguous reconstruction algorithm. This applies to 
tumors of the chest, abdomen and pelvis. 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 


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• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e. after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response or stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e. skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions up to a maximum of five lesions per organ and 10 
lesions in total, representative of all involved organs should be identified as target lesions 
and recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). A sum of the longest diameter 
for all target lesions will be calculated and reported as the baseline sum of the longest 
diameter. The baseline sum of the longest diameter will be used as reference by which to 
characterize the objective tumor response. 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Measurements of these lesions are not 
required, but the presence or absence or worsening of each should be noted throughout the 
study. 
Evaluation of target and non-target lesions 
To assess tumor response, the sum of the longest diameter for all target lesions will be 
calculated (at baseline and throughout the study). At each assessment response is evaluated 
first separately for target (Table 1) and non-target lesions (Table 2). These evaluations are 
then used to calculate the overall lesion response considering both, the target and non-target 
lesions together (Table 3). 


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Table Appendix 1: 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response 
(CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum longest diameter. 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of the longest diameter of target 
lesions, taking as reference the smallest sum of longest diameter 
recorded since the treatment started or the appearance of one or more 
new lesions. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of the longest 
diameter since the treatment started. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a less sensitive 
method than baseline. 
Table Appendix 2: 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response 
(CR): 
Disappearance of all non-target lesions 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) 
Progressive Disease 
(PD): 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.1 
Unknown (UNK) 
Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a less 
sensitive method than baseline. 
Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the 
opinion of the treating physician does prevail and the progression status should be confirmed later on 
by the review panel (or study chair). 
The response for non-target lesions is CR only if all non-target lesions which were evaluated 
at baseline are now all absent. If any of the non-target lesions is still present, the response can 
only be ‘Incomplete response/Stable disease’ unless any of the lesions was not assessed (in 
which case response is UNK) or worsened (in which case response is PD). 
Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below in 
Table 3. 


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Table Appendix 3: 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion 
response 
CR 
CR 
No 
CR1 
CR 
Incomplete response/SD 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1 This overall lesion response also applies when there are no non-target lesions at baseline 
2 Once confirmed PR was achieved, all these assessments are considered PR. 
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed not less than 4 weeks after the criteria for 
response are first met. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression. 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR). 
• SD = at least one SD assessment > 6 weeks after start of treatment (and not qualifying for 
CR or PR). 
• PD = progression or death due to underlying cancer ≤ 16 weeks after start of treatment 
(and not qualifying for CR, PR or SD). Patients with symptoms of rapidly progressing 
disease without radiologic evidence will be classified as progression only when clear 
evidence of clinical deterioration is available and patient discontinued due to ‘Disease 
progression’. 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 16 weeks) 


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Overall lesion responses of CR must stay the same until progression sets in, with the 
exception of a UNK status. A patient who had a CR can not subsequently have a lower status, 
e.g. PR or SD, as this would imply that one or more lesions reappeared, in which case the 
status would become a PD. 
Overall lesion responses of PR must stay the same or improve over time until progression sets 
in, with the exception of a UNK status. However, if a patient has a PR (≥ 30% reduction of 
tumor burden compared to baseline) at one assessment, followed by a < 30% reduction from 
baseline at the next assessment (but not > 20% increase from previous smallest sum), the 
objective status at that assessment should be SD. Once a confirmed PR was seen, the overall 
lesion response should be considered PR (or UNK) until progression is documented. 
If the patient progressed but continues study medication, further assessments are not 
considered for the determination of best overall response. 
The best overall response for each patient will be determined based on investigator 
assessments (‘Investigator best overall lesion response’). 
Post-text supplement 2: ECOG Performance Status Scale 
Criteria for Estimation of Performance Status 
GRADE 
SCALE 
0 
Fully active, able to carry out all pre-disease performance without restriction. 
(Karnofsky 90-100%) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g. light housework, office work. (Karnofsky 70-80%) 
2 
Ambulatory and capable of all self-care, but unable to carry out work activities. Up and 
about more than 50% of waking hours (Karnofsky 50-60%) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. (Karnofsky 30-40%) 
 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
(Karnofsky 10-20%) 
5 
Dead (Karnofsky 0%) 
Sources: 
Oken, MM et al, Am J Clin Oncol 5:649-655, 1982 
Karnofsky, DA et al, Cancer 1:634-656, 1948 

SAP_001.pdf: 
Clinical Development 
RAD001 
CRAD001C24114 / NCT00767819
Multicenter, triple-arm, single-stage, phase II trial to 
determine the preliminary efficacy and safety of RAD001 in 
patients with histological evidence of progressive or 
metastatic bone or soft tissue sarcomas 
RAP Module 3 – Detailed statistical methodology 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Final 1.0 
Release date: 
07-Jul-2011
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Novartis approval signatures for: 
RAP Module 3 – Detailed statistical methodology 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
Signature 
 
Date 
 


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1 
Data analysis 
This was a non-randomized, multicenter, triple-arm, phase II trial evaluating the treatment of 
RAD001 in the following three arms: in patients with progressive or metastatic bone or soft 
tissue sarcoma (except for GIST), in patients with progressive or metastatic GIST after failure 
or intolerance of treatment with imatinib or sunitinib, and in patients with progressive or 
metastatic alveolar soft part sarcoma (ASPS), respectively. 
The study was designed to assess the activity, safety, and tolerability of the therapy with 
RAD001 in progressive bone or soft tissue sarcoma in the three arms each. 
The data were analyzed by Novartis. Any data analysis carried out independently by the 
investigator(s) was recommended to be submitted to Novartis before publication or 
presentation. It was planned that the data from participating centers in this protocol were 
combined within each of the arms, so that an adequate number of patients was available for 
analysis. 
Data were summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and pharmacokinetic 
measurements. Categorical data were presented as absolute frequencies and percentages. For 
continuous data, N (the number of valid observations), N miss. (the number of missing 
observations), mean, standard deviation, median, minimum, and maximum were presented. 
It was planned that the data of each arm were to be analyzed and reported independently of 
the other arm once the number of patients needed for analysis was reached. However, the 
methods described in this analysis plan apply for all three arms, if not otherwise indicated. 
For simplification, populations for analysis, and the analysis of patient demographics/other 
baseline characteristics, treatment, primary and secondary efficacy variables, and safety were 
described without referring to a specific arm. As mentioned above, the methods of analysis 
were applied to each arm separately. 
Changes from the analysis pre-planned in the protocol: 
1. Although planned in the protocol, the central radiologic review was only incompletely 
performed due to a variety of reasons (no images submitted from local to central 
radiologist, when already the first tumor assessment resulted in an overall lesion 
response of ‘progressive disease’; or images were not assessable according to the 
central radiologist). An incomplete sequence of central assessments cannot be used to 
derive the primary and secondary efficacy variables. Thus, the trial will be analyzed 
based on local tumor assessments only. 
2. The intention-to-treat (ITT) set will be used for the primary efficacy analysis rather 
than the per-protocol (PP) set, since this is what is recommended by RECIST criteria 
(version 1.0, see Therasse et al. 2000: ‘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. [...]All conclusions should be based on all eligible 
patients.’) 


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1.1 
Populations for analysis 
The safety set consisted of all patients who received at least one dose of study drug and had at 
least one post-baseline safety assessment. Patients were analyzed according to treatment 
received. Of note, the statement that a patient had no adverse events also constituted a safety 
assessment. 
The intent-to-treat (ITT) set consisted of all patients who received at least one dose of study 
drug and had at least one post-baseline assessment of the primary efficacy variable 
(target/non-target lesion assessment according to RECIST). Patients without any post-baseline 
assessment of tumor were included if they were defined as progressive disease based on 
clinical evaluation. 
The per-protocol (PP) set consisted of all patients of the intent-to-treat population who did 
not show any major protocol violations. As major protocol violations were considered those 
that may have an impact on the study outcome. Criteria that were assumed to have such an 
impact were defined in a Review Meeting before database lock. 
1.2 
Patient demographics/other baseline characteristics 
Demographic and background information were summarized for the ITT set, using frequency 
distributions for categorical variables and descriptive statistics of mean, standard deviation, 
minimum, median and maximum for continuous variables. Background information included 
prior medication, past/current medical conditions, diagnosis and extent of cancer, ECOG 
performance status and tumor evaluation at baseline. 
Medical history was coded using MedDRA and was presented by system organ class, and 
MedDRA preferred term. Separate tables were provided for past medical condition and 
current medical condition. Prior medications (including prior antineoplastic medications and 
radiotherapy) were coded according to WHO Drug Reference List (WHO-DRL). Prior 
medications  were summarized by ATC class and preferred term. 
1.3 
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance) 
Study drug and concomitant therapies were analyzed for the safety set. 
Study drug 
Duration of exposure to study drug was defined as the time from start of treatment to the last 
end date documented in the Study Drug Administration CRF. Duration of exposure was 
summarized descriptively. 
Mean daily doses of study drug were calculated including and excluding zero doses for 
periods of temporary interruption of treatment regardless of whether this was due to safety 
reasons or patients’ non-compliance. Mean daily doses were summarized descriptively.  
The number of dose changes/patients with dose changes (including temporary dose 
interruption) was presented by reason for dose change by frequency distribution. Permanent 
treatment discontinuations were analyzed by frequencies. 


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Concomitant medications 
Concomitant medications were coded according to WHO-DRL and summarized by ATC class 
and preferred term using frequency tables. 
1.4 
Analysis of the primary objective(s) 
1.4.1 
Variable 
The primary variable is defined as the proportion of patients in whom a best overall response 
of complete (CR) or partial (PR) response or stable disease (SD) was observed at 16 weeks 
according to RECIST (version 1.0, Therasse et al. 2000) based on local radiologic 
assessments. 
The best overall response for each patient was determined from the sequence of overall 
(lesion) responses at Visit 4/Week 8 and Visit 6/Week 16, respectively, according to the 
following rules (see Post-text supplement 1 to the study protocol): 
• CR = at least two determinations of CR at least 4 weeks apart before progression. 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR). 
• SD = at least one SD assessment > 6 weeks after start of treatment (and not qualifying for 
CR or PR). 
• PD = progression or death due to underlying cancer ≤ 16 weeks after start of treatment 
(and not qualifying for CR, PR or SD). Patients with symptoms of rapidly progressing 
disease without radiologic evidence will be classified as progression only when clear 
evidence of clinical deterioration is available and patient discontinued due to ‘Disease 
progression’. Furthermore, patients without radiologic evidence for progression who were 
prematurely discontinuing from the study for ‘unsatisfactory therapeutic effect’, ‘new 
cancer therapy’ or ‘death’ (from any reason) will be classified as progression. 
• UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 16 weeks) 
1.4.2 
Statistical hypothesis, model, and method of analysis 
The best overall response rate (CR/PR/SD/PD/UNK) was presented together with the 
appropriate two-sided confidence interval for the ITT set. Since the one-sided alpha was set to 
10%, two-sided 80% confidence intervals were presented. Exact confidence intervals were 
computed according to the method of Clopper and Pearson. 
The absolute number of patients showing a best overall response of CR, PR or SD was 
determined to conclude preliminary activity or non-activity of the study drugs in this patient 
population according to the rules outlined in CSP section 10.2. Furthermore, the lower limit of 
the confidence interval was used to support the decision in favor of p0 or p1: if the lower limit 
of the confidence interval overlapped p0, the hypothesis that p is greater than or equal to p1 
could be rejected; on the other side, if the lower limit of the confidence interval excluded p0, 
the hypothesis that p is greater than or equal to p1 could be accepted. 


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1.4.3 
Handling of missing values/censoring/discontinuations 
The derivation of the primary efficacy variable from the sequence of overall lesion responses 
recorded at each assessment followed the Novartis guidance ‘Guidelines for Response, 
Duration of Overall Response, TTF, TTP, Progression-Free Survival and Overall Survival 
(based on RECIST)’. Subjects not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks were classified as ‘UNK’ for 
their best overall response. 
1.4.4 
Supportive analyses 
The number and percentage of patients showing a best overall response of CR, PR or SD as 
well as the number and percentage of patients for each category (CR/PR/SD/PD/UNK) was 
additionally presented for the per-protocol (PP) set. 
Additionally, for patients who entered the follow-up period starting after Visit 6/Week 16, the 
best overall response was determined using all available local tumor assessments. 
1.5 
Analysis of secondary objectives 
1.5.1 
Efficacy (secondary) 
Secondary efficacy variables were analyzed for the ITT set. 
Objective response rate (ORR) was defined as the proportion of patients in whom a 
complete (CR) or partial (PR) response was observed at Visit 6/Week 16 according to 
RECIST (version 1.0) based on central radiologic review. Absolute and relative frequencies 
were presented together with the appropriate exact confidence interval. 
Duration of stable disease (CR, PR or SD) applied only to those patients whose best overall 
response was CR, PR or SD based on local radiologic assessments and was defined as the 
time from start of treatment to progression or death from underlying disease. Patients not 
experiencing progression or death at 16 weeks were censored with the date of their last tumor 
assessment. Duration of response was explored using the Kaplan-Meier method. The Kaplan-
Meier estimate for median duration of response as well as the Kaplan-Meier curve was 
displayed. Although duration of response (CR or PR) was planned to be analyzed within the 
protocol, this was changed to reach a more valuable analysis since no patient reached a best 
overall response of CR or PR. 
Progression-free survival (PFS) was defined as the time from the date of start of treatment 
to the date of event defined as the first documented progression or death from any cause. If a 
patient had not had an event, PFS was censored at the date of the last adequate tumor 
assessment, which was the date of Visit 6 for the core study phase and the last available tumor 
assessment for the follow-up phase. PFS was explored by using the Kaplan-Meier method. 
The Kaplan-Meier estimate for median PFS as well as the Kaplan-Meier curve was displayed. 
Time to progression (TTP) was defined as the time from the date of start of treatment to the 
date of event defined as the first documented progression or death from underlying disease. If 
a patient had not had an event, TTP was censored at the date of the last adequate tumor 
assessment, which was the date of Visit 6 for the core phase and the last available tumor 


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assessment for the follow-up phase. TTP was explored by using the Kaplan-Meier method. 
The Kaplan-Meier estimate for median TTP as well as the Kaplan-Meier curve was displayed. 
Overall survival (OS) was defined as the time from the date of start of treatment to death 
from any cause. If a patient was not known to have died, OS was censored at the date of the 
last contact, which was the date of Visit 6 for the core phase and the last available visit for the 
follow-up phase. OS was explored by using the Kaplan-Meier method. The Kaplan-Meier 
estimate for median OS as well as the Kaplan-Meier curve was displayed. 
1.5.2 
Safety 
The assessment of safety was based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. 
electrocardiogram, vital signs, and special tests) were considered as appropriate. 
1.5.2.1 
Adverse events 
Adverse events (AE) were summarized by presenting the number and percentage of patients 
having any adverse event, having an adverse event in each body system and having each 
individual adverse event. Furthermore, the incidence of AE was summarized by maximum 
severity, for AE with suspected drug relation, for serious AE, for AE leading to permanent 
discontinuation of study drug, and for significant AE. As significant (S)AE were defined 
those (S)AE who 
• were suspected to be drug related, 
• lead to dose adjustment or temporary interruption, 
• lead to permanent discontinuation, 
• required concomitant medication/non-drug therapy, and  
• Deaths 
Any other information collected (e.g. severity or relatedness to study medication) was listed 
as appropriate. 
1.5.2.2 
Laboratory values 
Laboratory data were summarized by presenting summary statistics of raw data and changes 
from baseline value by visit. Although foreseen in the protocol, notable values were not 
analyzed since no notable ranges were defined in the protocol. Any statistical tests performed 
to explore the data were used only to highlight any interesting comparisons that may warrant 
further consideration. 
Data from other tests (e.g. electrocardiogram or vital signs) were planned to be listed, notable 
values were recommended to be flagged (if appropriate), and any other information collected 
was planned to be listed as appropriate. 
1.5.3 
Tolerability 
Not applicable. 


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1.5.4 
Resource utilization 
Not applicable. 
1.6 
Sample size calculation 
The study followed an exact binomial single-stage design in each arm. (A’Hern 2001). Values 
of P0 and P1 followed the recommendation of the EORTC Soft Tissue and Bone Sarcoma 
Group’s previous publication evaluating PFS in STS patients treated with 2nd line active and 
inactive compounds. 
In arm I (patients with bone and soft tissue sarcoma except for GIST), the study required 36 
evaluable subjects to decide whether the proportion responding (best overall response of CR, 
PR or SD), p, was less than or equal to p0 = 20% or greater than or equal to p1 = 40% (Table 
10-1). In arm II or III (patients with GIST after failure or intolerance of 1st and 2nd line 
treatment with imatinib or sunitinib, and patients with progressive or metastatic alveolar soft 
part sarcoma (ASPS), respectively), the study required 24 evaluable subjects to decide 
whether the proportion responding best overall response of CR, PR or SD), p, was less than or 
equal to p0 = 20% or greater than or equal to p1 = 40%. 
If the number of responses in arm I was 11 or more, the null hypothesis that p is less than or 
equal to 20% was to be rejected with a target type I error rate of 10% and an actual error rate 
of 8.9%. If the number of responses in arm I was 10 or less, the alternative hypothesis that p is 
greater than or equal to 40% was to be rejected with a target type II error rate of 10% and an 
actual error rate of 9%. 
If the number of responses in arm II or arm III, respectively, was 8 or more, the null 
hypothesis that p is less than or equal to 20% was to be rejected with a target type I error rate 
of 10% and an actual error rate of 8.9%. If the number of responses in arm II was 7 or less, the 
alternative hypothesis that p is greater than or equal to 40% was to be rejected with a target 
type II error of 20% and an actual error rate of 19.2%. 
The designs were estimated with NCSS Trial and PASS 2002. 
Table 10-1 
Design features for exact binomial single-stage designs 
 
Arm I 
Arm II 
Arm III 
p0 (maximum response proportion of an inactive drug) 
20% 
20% 
20% 
p1 (minimum response proportion of an active drug 
40% 
40% 
40% 
Type I error (one-sided test) 
10% 
10% 
10% 
Type II error (one-sided test) 
10% 
20% 
20% 
Sample size 
36 
24 
24 
Accept inactivity at the end if  
≤ 10 responders 
≤ 7 responders 
≤ 7 responders 
Reject inactivity at the end if 
≥ 11 responders 
≥ 8 responders 
≥ 8 responders 
Actual type I error level 
8.9% 
8.9% 
8.9% 
Actual type II error level 
9.0% 
19.2% 
19.2% 
The type I error is the probability of rejecting the hypothesis that p is lower or equal to p0 when this is 
true. The type II error is the probability of rejecting the hypothesis that p is greater or equal to p1 when 
this is true. Response was defined as a best overall response of CR, PR or SD. 


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1.7 
Power for analysis of critical secondary variables 
Not applicable.