Clinical trial NCT00936858
Conditions: Thyroid Cancer
Keywords: radioiodine refractory thyroid cancer RAD001
Sponsor: Dana-Farber Cancer Institute
Start date: 2009-07-01; Completion date: 2020-02-27
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Since thyroid cancer becomes refractory to radioactive iodine, treatment options are very limited. Tyrosine kinase inhibitors such as sorafenib have recently shown promise. This trial seeks to expand treatment options for this disease with a new, oral drug called RAD001. It is an inhibitor of the mTOR pathway and has shown activity in neuroendocrine cancers of the gastrointestinal tract and has been approved for the treatment of metastatic renal cell cancer.

Detailed description:
* RAD001 will be taken once a day in the morning starting on Day 1 and continue until the participant is no longer participating in the study treatment.
* A history and physical exam will be performed the first day of the study and then once a month. Blood tests including coagulation studies, and thyroid studies will be performed monthly. A urine sample will need to be provided on the first day of treatment and then every 2 months. Imaging consisting of a CT or MRI of the neck, chest and abdomen will be done every 8 weeks after starting RAD001.
* Participants will remain on this research study for up to 24 months. However, if the participants doctor feels that they are benefiting from the study drug and they do not have severe side effects, they may be given the option to continue taking RAD001.

Arms: arm 1: RAD001 will be administered orally as once daily dose of 10 mg (one 10mg tablet or two 5mg tablets) continuously from study day 1 until progression of disease or unacceptable toxicity.
Interventions: intervention 1: RAD001
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
 
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A phase II trial using RAD001 for patients with radioiodine 
refractory thyroid cancer  
 
Sponsor Study # CRAD001CUS74T
 
 
 
Author(s): 
Jochen H. Lorch, M.D., M.S. 
Dana Farber Cancer Institute 
450 Brookline Avenue 
Boston MA 02215 
Phone: (617) 632 3090 
Email: Jochen_Lorch@dfci.harvard.edu 
Site Principal 
Investigator(s) :  
Lori Wirth, M.D. 
Massachusetts General Hospital 
Center for Head and Neck Cancers 
55 Fruit Street, Yawkey Building 
Boston, MA 02114 
Phone: 617-724-4000 
Email: lwirth@partners.org 


 
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Naifa Busaidy, M.D. 
University of Texas-MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 1461 
Houston, TX 77054 
Phone: 713-792-2841 
Email: nbusaidy@mdanderson.org 
 
 
Krzysztof Misiukiewicz, MD 
Mount Sinai School of Medicine 
One Gustave L.Levy Place,  
P.O Box 1079, 
New York, NY-10029 
Phone: 212-241-6772 
Email: krzystof.misiukiewicz@mssm.edu 
 
 


 
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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 4 
1 
Introduction ......................................................................................................................... 7 
1.1 
RAD001 (everolimus) ............................................................................................. 7 
1.1.1 
mTOR pathway and mechanism of action ............................................. 7 
1.1.2 
Preclinical studies ................................................................................... 8 
1.1.3 
Clinical experience ............................................................................... 10 
2 
Study objectives ................................................................................................................. 15 
3 
Investigational plan ........................................................................................................... 15 
3.1 
Overall study design .............................................................................................. 15 
3.2 
Study population .................................................................................................... 16 
3.2.1 
Patient population ................................................................................. 16 
3.2.2 
Inclusion and exclusion criteria ............................................................ 16 
3.2.3 
Interruption or discontinuation of treatment ......................................... 19 
3.2.4 
Monitoring of RAD001 suspected toxicities ........................................ 21 
3.2.5 
Known Side Effects of RAD001 .......................................................... 21 
3.2.6 
Management of Side Effects of RAD001……………………………..23 
       3.3 
Treatments ............................................................................................ 29 
3.3.1 
RAD001 Administration....................................................................... 29 
3.3.2 
Treatment assignment ........................................................................... 30 
3.3.3 
Concomitant therapy ............................................................................. 30 
3.3.4 
Treatment compliance .......................................................................... 33 
3.4 
Visit schedule and assessments ............................................................................. 33 
3.4.1 
Visit schedule ....................................................................................... 33 
3.4.1.4 
Study Procedures……………………………………………………...38 
3.4.2 
Efficacy assessments ............................................................................ 39 
3.4.3 
Safety assessments ................................................................................ 40 
3.4.4 
Novartis and FDA instructions for rapid notification of SAEs………41 
3.4.5 
IRB instructions for notification of serious adverse events…42 
 
3.4.1.5 
Pregnancies……………………………………………………………42 
4 
Protocol amendments, or changes in study conduct .......................................................... 43 
5 
Correlative Studies ............................................................................................................ 43 
6 
Data management .............................................................................................................. 44 
6.1 
Data collection ....................................................................................................... 44 


 
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6.1.1 Data Safety………………………………………………………...............44 
7 
Statistical methods ............................................................................................................. 44 
7.1 
Statistical methods ................................................................................................. 44 
8 
References ......................................................................................................................... 46 
9 
Procedures and instructions ............................................................................................... 49 
9.1.1 
Publication of results ............................................................................ 49 
9.1.2 
Disclosure and confidentiality .............................................................. 49 
9.1.3 
Discontinuation of study ....................................................................... 49 
9.2 
Ethics and Good Clinical Practice ......................................................................... 49 
9.2.1 
Institutional Review Board/Independent Ethics Committee ................ 50 
9.2.2 
Informed consent .................................................................................. 50 
9.2.3 
Declaration of Helsinki ......................................................................... 50 
Appendix 
 
A: Modified RECIST criteria 
 
B: Drug Diary 
 
C: Questionnaires 
 
D: DF/HCC Multi-Center Data and Safety Monitoring Plan 
 
E: Correlative Studies Shipping Guidelines and Submission Form 
 
 
 
 
 
 
List of abbreviations  
4E-BP1 
4E-binding protein 
ADR 
Adverse Drug Reaction 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/glutamic pyruvic transaminase/Serum glutamic-
pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/glutamic oxaloacetic transaminase/Serum 
glutamic-oxaloacetic transaminase 
ATC 
Anatomical Therapeutic Chemical classification system 
AUC 
Area under the plasma-concentration time curve 
BAC 
Bronchoalveolar carcinoma 


 
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Cmax 
Maximum plasma concentration 
CR 
Clinical research 
CRF 
Case report/Record form 
CRO 
Contract Research Organization 
CT 
Computer tomography 
CTC 
Common toxicity criteria 
CV 
Coefficient of Variation 
CYP3A4 
CytochromeP450 3A4 isoenzyme 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
eIF-4E 
Eucariotic Initiation Factor 4E 
EPR 
Early progression rate 
FDG-PET 
Fluorine-18-2-fluoro-Deoxy-D-Glucose Positron Emission Tomography 
FKBP-12 
FK506-binding protein 12 
GF 
Growth factor 
HBV  
Hepatitis B virus  
HBcAb  
Hepatitis B core antibodies  
HBs Ab  
Hepatitis B surface antibodies  
HBsAg  
Hepatitis B surface antigen  
HCV  
Hepatitis C virus  
HDL 
High-density lypoproteins  
HER 
Human Epidermal Receptor 
HUVECS 
human umbilical endothelial cells 
IC50 
Inhibitory concentration at 50% 
IEC 
Independent Ethics Committee 
IGF1-R 
Insulin-like Growth Factor 1 Receptor 
IHC 
Immunohistochemistry 
INN 
International Non-proprietary Name 
INR 
International Normal Ratio 
IRB 
Institutional Review Board 
LC-MS 
liquid chromatography method with mass spectrometry 
LDL 
Low-density lypoproteins 
LLOQ 
Lower limit of quantification 
MAPK 
Mitogen Activated Protein Kinase 


 
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mRNA 
messenger Ribonucleic acid 
mTOR 
mammalian Target of Rapamycin 
NIH/NCI 
National Institutes of Health/National Cancer Institute 
nM 
nano-molar 
NSCLC 
Non-small cell lung cancer 
OS 
overall survival 
P-AKT 
phosphor-AKT 
PD 
Pharmacodynamics 
PET 
Proton emission tomography 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetics 
PK/PD model 
Pharmacokinetic/pharmacodynamic model 
PT/PTT 
prothrombin time 
PTEN 
Phosphatase and Tensin homolog deleted on chromosome 10 
RBC 
red blood cell count 
REB 
Research Ethics Board 
RR 
response rate 
S6K1 
S6 kinase 1 
SAE 
serious adverse event 
SCLC 
Small cell lung cancer 
STAT3 
Signal Transducer and Activator of Transcription 3 
TK 
Tyrosine kinase 
TSC2 
Tuberous Sclerosis Complex 2 
TUNNEL 
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin 
Nick End Labeling 
ULN 
upper limit of normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
total white blood cell count 
WHO 
World Health Organization 


 
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1 
Introduction 
1.1 
RAD001 (everolimus) 
RAD001 (everolimus) is a novel oral derivative of rapamycin.  
RAD001 has been in clinical development since 1996 as an immunosuppressant in solid organ 
transplantation and has obtained marketing authorization (Certican®) for prophylaxis of 
rejection in renal and cardiac transplantation in a number of countries, including the majority 
of the European Union. RAD001 has been in development for patients with various 
malignancies since 2002. RAD001 is being investigated as an anticancer agent based on its 
potential to act: 
i. Directly on the tumor cells by inhibiting tumor cell growth and proliferation 
ii. Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via 
potent inhibition of tumor cell HIF-1 activity, VEGF production and 
VEGF-induced proliferation of endothelial cells). The role of angiogenesis 
in the maintenance of solid tumor growth is well established, and the 
mTOR pathway has been implicated in the regulation of tumor production 
of proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
1.1.1 
mTOR pathway and mechanism of action 
At cellular and molecular level RAD001 acts as a signal transduction inhibitor. RAD001 
selectively inhibits mTOR (mammalian target of rapamycin), a key and a highly conservative 
serine-threonine kinase, which is present in all cells and is a central regulator of protein 
synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR 
is the only currently known target of RAD0011. 
mTOR is downstream of PI3K/AKT pathway, a pathway known to be dysregulated in a wide 
spectrum of human cancers (e.g. through loss/mutation of the PTEN negative regulator; 
through PI3K mutation/amplification; through AKT/PKB overexpression/overactivation; 
through modulation of TSC1/TSC2 tumor suppressors). In addition, activation of the 
PI3K/AKT/mTOR pathway is frequently a characteristic of worsening prognosis through 
increased aggressiveness, resistance to treatment and progression.  
The main known functions of mTOR include the following 1, 2: 
mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels, 
facilitating cell-cycle progression from G1 to S phase in appropriate growth conditions. 
The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors.  
Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and activating 
the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates translation of important 


 
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massages, including those encoding the HIF-1 proteins, c-myc, ornithine decarboxylase, 
and cyclin D1, as well as ribosomal proteins themselves.  
The activation of mTOR pathway leads to the increased production of pro-angiogenic factors 
(i.e., VEGF) in tumors and to tumor, endothelial and smooth muscle cell growth and 
proliferation. 
The regulation of mTOR signaling is complex and involves positive regulators, such as AKT 
that phosphorylate and inactivate negative regulators such as the Tuberous Sclerosis 
Complex (TSC1/TSC2). 
mTOR is represented by two structurally and functionally distinct multiprotein signaling 
complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR 
complex 2, rapamycin insensitive) 3.  
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also known as PKB, 
protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2) 2. Activated AKT 
phosphorylates TSC2, which lead to the dissociation of TSC1/TSC2 complex, thus inhibiting 
the ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small G-protein, 
to remain in a GTP bound state and to activate mTORC1. AKT can also activate mTORC1 by 
PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of mTORC1 4, 5.  
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly 
by receptor tyrosine kinase (RTK) signaling4. It has been suggested that mTORC2 
phosphorylates and activates a different pool of AKT, that is not upstream of mTORC1. 
PHLPP phospatase plays a role of a negative regulator. mTORC2 is rapamycin insensitive and 
is required for the organization of the actin cytoskeleton 3. 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone rapamycin 
and its derivatives, such as RAD001. Once these agents bind to the 12 kDa cytosolic FK506-
binding protein immunophilin FKBP12, the resulting rapamycin-FKBP12 complexes bind to a 
specific site near the catalytic domain of mTORC1 and inhibit phosphorylation of mTOR 
substrates. As a consequence, downstream signaling events involved in regulation of the G1 to 
S-phase transition are inhibited. This mechanism is thought to be responsible for the 
immunosuppressive effects of rapamycin as well as its putative antineoplastic activity 6. As 
many cancers are characterized by dysregulation of G1 transit (for example, overexpression of 
cyclin or cyclin-dependent kinases), inhibition of mTOR becomes an intriguing target for 
inducing cytostasis 2.  
1.1.2 
Preclinical studies 
Pre-clinical investigations have demonstrated that RAD001 is a potent inhibitor of the 
proliferation of a range of human tumor cell lines in-vitro with IC50s ranging from sub/low 
nM to μM concentrations, concentrations capable of being reached in patients at the doses 
used in clinical trials.  
RAD001 was shown to have activity in many human tumor cell lines originating from lung, 
breast, prostate, colon, kidney, melanoma and glioblastoma and neuroendocrine tumor cells. 
Recent data suggests anti-tumor activity also in thyroid cancer7. This study suggests that the 


 
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antiproliferative effects of mTOR inhibition may be due to the inhibition PI3 kinase activation 
and the down-regulation of cyclin D1 and D3.  
RAD001 has shown activity in human pancreatic neuroendocrine cells, where induction of 
apoptosis was reported 8. Other tumor types in which activity was observed include acute 
myeloid leukemia cells 9, adult T-cell leukemia cells 10, diffuse large B cell lymphoma cells 
(DLBCL; 11, pancreatic tumor cells 12, ovarian cancer cells 13 and hepatocellular carcinoma 
cells 14.  
In a clonogenic assay using cells derived from 81 patient-derived tumor xenografts never 
cultured in vitro (11 human tumor types with 3 to 24 tumors each: bladder, colon, gastric, 
NSCLC [adeno, squamous epithelium and large cell], SCLC, breast, ovary, pancreatic, renal, 
melanoma, and pleuramesothelioma), RAD001 inhibited colony formation in a concentration-
dependent manner. In addition, normal hematopoetic stem cells were insensitive to RAD001, 
with an IC50 about 15 fold higher than the tumor lines.  
RAD001 also inhibits the proliferation of human umbilical vein endothelial cells (HUVECS), 
with particular potency against VEGF-induced proliferation. This is particularly important in 
the context of thyroid cancer since thyroid cancer appear to rely to a high degree on 
angiogenesis and high expression of VEGF has been linked to aggressive tumor growth and 
poor prognosis15. Furthermore, tyrosine kinase inhibitors such as Sorafenib, AMG706 and 
axitinib which predominantly block VEGF-receptor activation have been successfully used in 
this disease16-18. The inhibition of endothelial proliferation and antiangiogenic activity of 
RAD001 was confirmed in vivo , as RAD001 selectively inhibited VEGF-dependent 
angiogenic response. Mice with primary and metastatic tumors treated with RAD001 showed 
a significant reduction in blood vessel density when compared to controls at well tolerated 
doses. Additionally, activity in a VEGF-impregnated s.c. implant model of angiogenesis and 
reduced vascularity (vessel density) of RAD001-treated tumors (murine melanoma) provided 
evidence of in vivo effects of angiogenesis. 
RAD001 also inhibits tumor growth in-vivo in xenografted, syngeneic and orthotopic animal 
models, residing longer in tumor tissue than in plasma and demonstrating high tumor 
penetration in a rat pancreatic tumor model. These effects occurred within the dose range of 
2.5 to 10 mg/kg p.o. daily. Typically, the antitumor activity of RAD001 monotherapy was that 
of reduction of tumor growth rates rather than producing regressions or stable disease. 
RAD001, administered p.o., was a potent inhibitor of tumor growth and well tolerated in: 
x s.c. mouse xenograft model, established from a variety of tumor cell lines of diverse 
histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), including a Pgp170 
overexpressing multi-drug resistant tumor line  
x in a series of low-passage tumor xenografts established directly from human tumor 
material, maintained only in vivo and considered highly predictive of therapeutic 
outcome in patients. These included breast (5 lines), colorectal (9 lines), gastric (3 
lines), lung (22 lines including adenocarcinomas, epidermoid cell, large cell and small 
cell histotypes), melanoma (6 lines), ovarian (4 lines), pancreatic (3 lines) and renal (6 
lines) 


 
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x in two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic 
melanoma) 
Taken together, these data indicate the broad antiproliferative potential of RAD001 which 
includes thyroid cancer. 
It is not clear which molecular determinants predict responsiveness of tumor cells to RAD001. 
Molecular analysis has revealed that relative sensitivity to RAD001 in vitro correlates with the 
degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal 
protein. PTEN status alone may not be predictive of RAD001 relative in vitro sensitivity, 
however in some cases (i.e., GBM) there is also a correlation with PTEN status. 
In preclinical models, the administration of RAD001 is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (pS6) 
and p4E-BP1, and occasionally with an increase in phosphorylation AKT (pAKT).  
Pre-clinical safety 
In safety pharmacology studies, RAD001 was devoid of relevant effects on vital functions 
including the cardiovascular, respiratory and nervous systems. RAD001 had no influence on 
QT interval prolongation. Furthermore, RAD001 showed no antigenic potential. Although 
RAD001 passes the blood-brain barrier, there was no indication of relevant changes in the 
behavior of rodents, even after single oral doses up to 2000mg/kg or after repeated 
administration at up to 40 mg/kg/day. Based on these findings, the potential of RAD001 to 
affect vital functions in patients is considered to be low.
RAD001 is considered to have no genotoxicity or carcinogenicity potential. All significant 
adverse events observed in preclinical toxicology studies with RAD001 in mice, rats, 
monkeys and minipigs were consistent with its anticipated pharmacologic action as an 
antiproliferative and immunosuppressant and at least in part reversible after a 2- or 4-week 
recovery period with the exception of the changes in male reproductive organs, most notably 
testes. Ocular effects (lenticular disorders) observed in rats were not observed in any other 
species and are considered to be a species-specific disorder. 
More pre-clinical information is provided in the Investigator’s Brochure. 
1.1.3 
Clinical experience 
1.1.3.1 
RAD001 Pharmacokinetics 
RAD001 is rapidly absorbed with a median tmax of 1-2 hours. The bioavailability of the drug is 
believed to be 11% or greater. The AUC0-Ĳ is dose-proportional over the dose range between 5 
to 70 mg in the weekly regimen and 5 and 10 mg in the daily regimen. Cmax is dose-
proportional between 5 and 10 mg for both the weekly and daily regimens. At doses of 20 
mg/week and higher, the increase in Cmax is less than dose-proportional. The coefficient of 
variation between patients is approximately 50%.  
Trough levels (24 hour post-dose) correlate well with AUC0-Ĳ at steady-state during daily 
administration. 


 
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In whole blood, at a daily dose of 10 mg, about 20% of RAD001 is confined in plasma with 
26% being unbound. The remaining 80% is sequestered in blood cells.  
RAD001 is extensively metabolized in the liver and eliminated in the bile. Major metabolites 
are inactive. Elimination half-life is approximately 30 hours. The clearance of RAD001 is 
approximately halved in patients with mild-moderate hepatic impairment (Child-Pugh Class A 
or B), while renal impairment has little or no impact on the pharmacokinetics of RAD001. 
Age, weight and gender in the adult population do not affect the pharmacokinetics of RAD001 
to a clinically relevant extent. The clearance of RAD001 is reduced in children. 
Pharmacokinetic characteristics are not notably different between Caucasian and Japanese 
subjects, whereas in Black patients pharmacokinetic studies have shown an average 20% 
higher clearance. 
A high-fat meal altered the absorption of RAD001 with 1.3 hour delay in tmax, a 60% 
reduction in Cmax and a 16% reduction in AUC. 
RAD001 is a substrate of CYP3A4 and a substrate and a moderate inhibitor of the multi-drug 
efflux pump P-glycoprotein (P-gP, MDR1, ABCB1). Hence, its metabolism is sensitive to 
drugs which modify these enzymes (substrates, inducers, or inhibitors of these enzymes). 
Competitive inhibition could occur when RAD001 is combined with drugs which are also 
CYP3A4 or P-glycoprotein substrates 
Table 3-3a (Section 3.3.3) lists examples of clinically relevant CYP3A inhibitors and 
inducers. 
Please refer to Section 3.3.3 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications. 
More information on RAD001 pharmacokinetics is provided in the Investigator’s Brochure.
1.1.3.2 
RAD001 Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the biomarker p70S6 
kinase 1 [S6K1] in peripheral blood mononuclear cells [PBMC]) suggests that 5-10 mg daily 
should be an adequate dose to produce a high-degree of sustained target inhibition. 
Furthermore, molecular pharmacodynamic (MPD) studies, using immunocytochemistry (IHC) 
in biopsied tumor tissue, assessed the degree of inhibition and its duration for pS6, p4E-BP1 
and pAKT expression with the daily and weekly dosing. There was high inhibition of the 
downstream markers S6K1 and 4E-BP1 at 5mg/day, which was complete at 10 mg/day, while 
preliminary results suggest increase in pAKT expression with maximal effect at 10 mg daily 
19 
More information is provided in the Investigator’s Brochure. 
1.1.3.3 
Clinical experience with RAD001 
RAD001 has been investigated as a component of multi-drug immunosuppression in solid 
organ transplantation since 1996 and was approved for the indication of prophylaxis of organ 
rejection in adult patients receiving an allogeneic renal or cardiac transplant on 8 Jul 2003 by 


 
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the European Union under the trade name of Certican®. The most frequent adverse drug 
reactions in this context are highly specific to the transplant context. However, certain events 
are generalizable, most notably myelosuppression, skin disorders and increases in blood lipid 
levels. 
RAD001 has been in development for patients with cancer since 2002. Approximately 2586 
patients with various malignancies have been treated in either Novartis sponsored or non-
Novartis sponsored clinical studies as of 31 Aug 2007. Overall, Novartis sponsored a total of 
22 studies of RAD001 administered either as single-agent (n=848), or in combination with 
other anti-tumor agents (n=663). Ongoing or completed Investigator sponsored studies also 
enrolled over 1000 patients globally. 
Eight single-agent Novartis sponsored trials have or are being conducted in various advanced 
malignancies. Five Phase I studies evaluated several escalating doses with either weekly or 
daily administration (Studies C2101/02, C2106, C2107, C1101) of RAD001 with the  
objective to identify an optimal regimen and dosage, based on safety, pharmacokinetics and 
knowledge of the drug’s molecular effects on various tumors. The 10 mg/day and 50-70 
mg/week dosages were proposed for further studies, when using RAD001 as a single agent, 
and as a target maximum dose in combination studies. In addition the Phase I studies, 
conducted in prostate cancer (Study C2106) and in Japanese patients with advanced cancers 
(Study C1101), evaluated the safety and the molecular changes in tumor, associated with the 
administration of RAD001.  
Two Phase II monotherapy studies were designed to evaluate the safety and efficacy of a 
single dose of 10 mg administered daily including Study C2235 in advanced NSCLC (n=81) 
and Study C2239 in advanced pancreatic neuroendocrine tumors (n=160). 
A Phase III study (Study C2240) is ongoing and designed to demonstrate the safety and 
efficacy of RAD001 at an oral dose of 10 mg versus matching placebo in patients with 
metastatic carcinoma of the kidney, whose disease has progressed despite prior VEGF-R 
tyrosine kinase inhibitor therapy. Over 400 patients have been enrolled in this prospective, 
randomized, multicenter study which remains blinded as of the cut-off date.  
This will be the first study to investigate the effects of RAD001 in thyroid cancer.  
Overall, the most frequent mild-moderate Grade 1/2 adverse effects have been rash, 
stomatitis, fatigue, neutropenia and to a lesser extent gastrointestinal disorders (nausea, 
anorexia, diarrhea, vomiting), and headache. The primary DLT has been severe (Grade 3) 
stomatitis, and occasionally fatigue, hyperglycemia, and neutropenia. Reduced blood counts, 
hyperlipidemia (mainly hypercholesterolemia) and hyperglycemia are relatively frequent 
laboratory findings. Infections have not been notably frequent or severe. Non-infectious low-
Grade (Grade 1/2) pneumonitis has led to development of treatment guidelines for the 
disorder (Table 3-2a). Preliminary indications of anti-tumor activity are encouraging. 
For more information on known undesirable effects of RAD001 refer to Section 3.2.5.  
Further detailed information regarding RAD001 clinical development, safety and efficacy is 
provided in the Investigator’s Brochure. 


 
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Rationale for this study:  
 
Thyroid cancer is the most common endocrine cancer and affects approximately 7 per 100,000 
people in the western hemisphere. Over 33000 new thyroid cancer cases are diagnosed 
annually in the US alone and it appears that the incidence is rising 20, 21. Approximately 90% 
of these are well differentiated cancers, 5% to 9% medullary tumors, and 1% anaplastic 
tumors. The well-differentiated tumors include papillary, follicular and Hurthle cell types with 
the papillary subtype predominating. The primary treatment modality for most patients with 
thyroid cancer is surgery followed by thyroid-stimulating hormone (TSH) suppression and 
possibly Iodine 131. In cases in which the tumor has spread to distant sites and has become 
refractory to radioiodine or is not amenable to curative surgery, expected survival declines 
rapidly. In this setting, no standard therapy exists. In the past, chemotherapy was and 
sometimes still is attempted but overall traditional chemotherapy is considered ineffective and 
too toxic. Among classical chemotherapy agents, doxorubicin has been studied most 
extensively, both as a single agent and in combination. Ahuja et al reviewed 17 trials and 
almost 250 patients with thyroid cancer who were treated with single agent doxorubicin and 
showed a composite response rate of 38%22. The response rate to doxorubicin monotherapy 
was further broken down to differentiated 38%, undifferentiated 22%, medullary 42% and 
Hurthle cell 33%. Based on this data, the doxorubicin received FDA approval in this disease. 
Because of the short progression-free survival of 2 months, a median survival of 8 months and 
the toxicity of this drug, it is rarely used23. Doxorubicin has also been used as the backbone of 
combination therapy with many different agents including bleomycin, cisplatin, vincristine, 
melphalan and paclitaxel. Despite reasonable response rates, the median survival in these 
mostly small trials appeared not to be increased compared to doxorubicin alone and therefore 
none of these combinations are used routinely in this disease24, 25.  
 
Recently, progress has been made using small molecule tyrosine kinase inhibitors that inhibit 
VEGF, raf, c-kit and RET such as Sorafenib, Axitinib or Motesanib (AMG706) 17, 26, 27 . 
Sorafenib was used in 30 patients with differentiated, medullary and anaplastic disease with 
documented disease progression. A partial response (PR) by RECIST criteria was achieved in 
23%, 53 % had stable disease. Progression free survival was 79 weeks for all patients and 84 
weeks for patients with differentiated thyroid cancer with no differences between papillary 
and follicular cancer. Axitinib was tested in a similar group of 60 patients although in this trial 
documented disease progression was not an entry criteria. The objective response rate was the 
primary endpoint. A partial response by RECIST criteria was achieved in 30% and stable 
disease was found in 38% in an intent to treat analysis and 4% had disease progression. PFS 
was 18 months and thus remarkably similar to that seen in the Sorafenib trial. Among the nine 
patients in this trial who had received chemotherapy prior to treatment with Axitinib, a PR 
was achieved in five subjects. Motesanib (AMG706) was tested in 93 patients and the results 
were recently published. Among 93 patients with documented disease progression within the 
last 6 months prior to study entry, 14% had an objective response and stable disease was 
achieved in 67%. PFS was 40 weeks. In some patients comorbidities such as uncontrolled 
hypertension and gastrointestinal side effects make the use of these drugs difficult and  


 
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ultimately, the vast majority of these patients becomes refractory to these drugs and their 
disease will progress. Furthermore, side effects which include fatigue, GI symptoms ranging 
from abdominal pain to stomach perforations and co-morbidities such as uncontrolled 
hypertension make this class of drugs a poor choice for some patients. In these cases, no 
established treatment alternatives exist and new therapies are urgently needed.  
Currently there are no major drug trials other than with tyrosine kinase inhibitors under way in 
this disease. It is therefore important to expand treatment options and provide patients with 
alternative treatment options that go beyond tyrosine kinase inhibitors either as first or second 
line treatment.   
  
The activity or RAD001 in thyroid cancer has not been tested in clinical trials. However, data 
form the RADIANT-1 trial in neuroendocrine tumors (NET) of the pancreas, are very similar 
to differentiated and medullary thyroid cancer on a molecular level were recently presented28. 
In the trial, 115 patients with metastatic pancreatic NET and documented disease progression 
on chemotherapy were given either daily RAD001 combined with monthly Sandostatin LAR 
Depot or daily RAD001 alone. Progression-free survival was 9.3 and 12.9 months and the 
fifteen month survival was 52.6 and 90.3%. Treatment was generally well-tolerated and most 
adverse events were mild to moderate in severity. The most frequent adverse events were 
diarrhea (48%) stomatitis (47%) rash (44%) fatigue (42%) nausea (41%) pyrexia (32%) 
vomiting (30%) headache (27%) asthenia (27%) peripheral edema (28%) and abdominal pain 
(27%). 4% of subjects had a grade 4 adverse event possibly related to trial therapy. Grade 1/2 
pneumonitis were reported in 4% of subjects and no Grade 3/4 were reported. 
 
Preclinical studies in thyroid cancer cells suggest that RAD001 may have activity in thyroid 
cancer. Several targets of mTOR have been found to be dysregulated in thyroid cancer, such 
as the cell cycle stimulators c-Myc and cyclin-D129 and the cell cycle inhibitor p27kip1 (p27), 
suggesting a potential role for mTOR in thyroid cancer progression30. mTOR is under control 
by another important kinase, Akt, which is elevated in several types of cancer, including 
anaplastic, papillary, and follicular thyroid cancer31, and may contribute to the dysregulation 
of mTOR activity. Taken together, these data suggest that mTOR is an appropriate target for 
thyroid cancer therapy. 
 
Based on the molecular mechanism outlined above and the response rates with mTOR 
inhibitors in other neuroendocrine cancer types, we propose to study RAD001 as first line 
therapy in patients who are diagnosed with radioiodine non-avid thyroid cancer or who have 
failed treatment with a small molecule tyrosine kinase inhibitor (TKI) such as sorafenib, 
axitinib or AMG70616, 18, 32.  
 
The primary endpoint in this study is progression-free survival (PFS). A minimum PFS of 6 
months in this population with documented disease progression within the last 6 months prior 
to treatment start in at least 2 patients in the first cohort of patients is needed to assess 
antitumor activity in this disease. 6 months is considerably shorter than the median PFS 
reported in the trials with Sorafenib, Axitinib and Motesanib. However, given the palliative 
nature of treatment with any of these substances, close follow-up to detect disease progression 


 
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early and the lack of treatment alternatives to these tyrosine kinase inhibitors makes the use as 
second- but also as first line agent justifiable. Patients who progress will receive further 
therapy at the discretion of the investigator and can include off label use of multi-tyrosine 
kinase inhibitors, traditional chemotherapy or participation in a phase I trial.  


 
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2 
Study objectives 
Rationale 
To date, there is no established therapy option for patients with Radioactive Iodine (RAI) 
refractory thyroid cancer who have progressed on oral tyrosine kinase inhibitors or who are 
not candidates for treatment with these drugs. This study seeks to obtain first information 
about the effectiveness of RAD001 in thyroid cancer that has shown evidence for disease 
progression as first or second line therapy.  If promising activity is detected, this will be the 
basis for larger subsequent studies.  
 
Primary end point: 
x Progression free survival  
 
Secondary 
Secondary endpoints are: 
x Objective response rate (complete and partial responses by modified RECIST criteria) 
x Survival 
x Symptom improvement (medullary thyroid cancer only) 
 
3 
Investigational plan 
3.1 
Overall study design 
This is a non-randomized phase II study with RAD001 as first or second line treatment in 
patients who are either newly diagnosed with radioiodine refractory thyroid cancer or have 
progressed after chemotherapy with doxorubicine or a small molecule tyrosine kinase 
inhibitor such as Sorafenib and who have documented disease progression within  6 months. 
 
Similar to prior studies in patients with thyroid cancer, all histologic thyroid cancer types will 
be included in this trial. While there may be differences in response to treatment between 
tumor types, this trial will provide an overview about responsiveness to therapy in this rare 
disease.  
 
Our trial will follow a 2 step design according to Fleming´s procedure33. In the first step, 18 
patients with differentiated thyroid cancer (excluding medullary or anaplastic thyroid cancer) 
and documented disease progression within 6 months will be enrolled. Then a PFS of 6 
months or more will be required in at least two patients in order to proceed with the 
enrollment of 15 more patients for the study to complete its accrual of 33 patients. The time 
interval of 6 months is chosen because documented disease progression within  6 months  is a 


 
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requirement for enrollment in this trial. Imaging studies will be obtained every 2 months and 
if no progression can be demonstrated at the 6 month time point while on therapy, anti-tumor 
activity is likely. If there is only one or no case of PFS of at least 6 months in the first cohort, 
the drug combination will be considered ineffective and the trial will be terminated.  
 
In addition, two separate exploratory cohorts will be included in the trial but will not be part 
of the statistical analysis of the 2 step study. These cohorts include up to 10 patients with 
medullary thyroid cancer and up to 7 patients with anaplastic thyroid cancer, respectively. 
These cohorts will be evaluated by descriptive statistics and will provide an initial measure of 
efficacy in this disease in which no approved and effective treatment options exist. This brings 
the total number of subjects in this trial to 50. 
 
 
The patients will be followed for a maximum duration of 24 months. Please see Section 
3.4.1.3 for an outline of data that will be collected post 24 months for patient continuing on 
treatment without progression of disease.  
 
 
3.2 
Study population 
3.2.1 
Patient population 
This is a non-randomized phase II study with RAD001 as first or second line treatment in 
patients who are either newly diagnosed with radioiodine refractory thyroid cancer or have 
progressed after chemotherapy with doxorubicine or a small molecule tyrosine kinase 
inhibitor such as Sorafenib and who have documented disease progression within  6 months 
during the year prior to protocol treatment with RAD001. The patient must not have had any 
treatment between the date of progression and the start date of RAD001 treatment, unless 
discussed with the PI.  In selected cases therapy with RAD001 as third or fourth line therapy 
will be allowed for example if the patient had received sequential therapy with tyrosine kinase 
inhibitors and chemotherapy that does not contain mTOR inhibitors as part of the regimen.   
3.2.2 
Inclusion and exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and 
must meet all inclusion and exclusion criteria. Results of all baseline evaluations, which 
assure that all inclusion and exclusion criteria have been satisfied, must be reviewed by the 
Principal Investigator or his/her designee prior to enrollment of that patient. In addition, the 
patient must be thoroughly informed about all aspects of the study, including the study visit 
schedule and required evaluations and all regulatory requirements for informed consent. The 
written informed consent must be obtained from the patient prior to enrollment. The following 
criteria apply to all patients enrolled onto the study unless otherwise specified. 


 
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Inclusion criteria  
x Histologically confirmed locally advanced or metastatic thyroid cancer, excluding 
thyroid lymphomas not amenable to or refractory to surgical resection, external beam 
radiotherapy, radioiodine or other local therapies. 
x Medullary thyroid cancer with documented evidence of disease progression by 
modified RECIST34 within 6 months during the year prior to  study day 1 (see 
Appendix A) or symptomatic disease (ie, medullary thyroid cancer-related diarrhea 
and /or flushing episodes) at the time of screening in the absence of documented 
disease progressionThe patient must not have had any treatment between the date of 
progression and the start date of RAD001 treatment, unless discussed with the PI.   
x Differentiated thyroid cancer (papillary, follicular with subvariants such as Hurthle 
cell thyroid cancer) with documented evidence of disease progression by modified 
RECIST within 6 months during the year prior to  study day 1 (details see Appendix 
A). The patient must not have had any treatment between the date of progression and 
the start date of RAD001 treatment, unless discussed with the PI.   
x Anaplastic thyroid cancer with disease progression with documented disease 
progression by modified RECIST within 6 months during the year prior to  study day 
1.The patient must not have had any treatment between the date of progression and the 
start date of RAD001 treatment, unless discussed with the PI.   
x Patients must have at least one measurable site of disease according to RECIST 
criteria that has not been previously irradiated. If the patient has had previous radiation 
to the marker lesion(s), there must be evidence of progression since the radiation 
x Age  18 years 
x ECOG performance status d 2 
x Adequate bone marrow function as shown by: ANC  1.5 x 109/L, Platelets  100 x 
109/L, Hb >9 g/dL 
x Adequate liver function as shown by: 
x serum bilirubin  1.5 x ULN 
x INR < 1.3 (or < 3 on anticoagulants) 
x ALT and AST  2.5x ULN ( 5x ULN in patients with liver metastases) 
x Adequate renal function: serum creatinine  1.5 x ULN 
x Fasting serum cholesterol 300 mg/dL OR 7.75 mmol/L AND fasting triglycerides  
2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient 
can only be included after initiation of appropriate lipid lowering medication. 
x Signed informed consent 
Exclusion criteria 
x Patients receiving anticancer therapies within last 2 weeks or who have received 
radiation therapy within 3 weeks of study day 1 
x Patients, who have had a major surgery or significant traumatic injury within 4 weeks 
of start of study drug, patients who have not recovered from the side effects of any 


 
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major surgery (defined as requiring general anesthesia) or patients that may require 
major surgery during the course of the study 
x Prior treatment with any investigational drug within the preceding 3 weeks 
x Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent. Topical or inhaled corticosteroids are allowed. 
x Patients should not receive immunization with attenuated live vaccines within 2 weeks 
of study entry or during study period 
x Patients who have brain or leptomeningeal metastases that can not be controlled with 
radiotherapy or radioiodine treatment including patients who require glucocorticoids 
for brain or leptomeningeal metastases. 
x Other malignancies within the past 3 years except for adequately treated carcinoma of 
the cervix or basal or squamous cell carcinomas of the skin. Exceptions may be made 
by the PI for other low risk cancer diagnosis within the last 3 years.  
x Patients who have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as: 
x Symptomatic congestive heart failure of New York heart Association Class III 
or IV  
x unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction within 6 months of start of study drug, serious uncontrolled cardiac 
arrhythmia or any other clinically significant cardiac disease 
x severely impaired lung function  
x uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
x active (acute or chronic) or uncontrolled severe infections 
x liver disease such as cirrhosis, chronic active hepatitis,  chronic persistent 
hepatitis 
x positive screening hepatitis C test or history of HCV infection including those 
with a negative viral load test at baseline 
x A known history of HIV seropositivity 
x Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled 
nausea, vomiting,  malabsorption syndrome or small bowel resection) 
x Patients with an active, bleeding diathesis 
x Female patients who are pregnant or breast feeding, or adults of reproductive potential 
who are not using effective birth control methods. If barrier contraceptives are being 
used, these must be continued throughout the trial by both sexes. Hormonal 
contraceptives are not acceptable as a sole method of contraception.  (Women of 
childbearing potential must have a negative urine or serum pregnancy test within 14 
days prior to administration of RAD001) 
x Patients who have received prior treatment with an mTOR inhibitor (sirolimus, 
temsirolimus, everolimus). 


 
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x Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins 
(sirolimus, temsirolimus) or to its excipients 
x History of noncompliance to medical regimens 
x Patients unwilling to or unable to comply with the protocol 
3.2.3 
Interruption or discontinuation of treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. Patients may be re-
escalated back to the previous dose if he/she is stable, his/her symptoms are related to disease 
and not treatment, and you receive the PI’s permission. If administration of RAD001 must be 
interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified 
according to rules described in Table 3-1. Toxicity will be assessed using the NIH-NCI 
Common 
Terminology 
Criteria 
for 
Adverse 
Events, 
version 
3.0 
(CTCAEv3.0, 
(http://ctep.cancer.gov/forms/CTCAEv3.pdf)). 
 
Table 3.0   RAD001 dose level modification guidelines 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg po daily 
-1 
5 mg po daily 
-2 
5 mg po every other day 
 
If patients are unable to tolerate dose level -2, the patient will come off study.  


 
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Table 3-1 
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 3-2a) 
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 d1. Then 
reintroduce RAD001 at same dose. 
If event returns to grade 2, then interrupt RAD001 
until recovery to grade d1. Then reintroduce RAD001 
at the lower dose level. 
Grade 3 
(except hyperlipidemia*) 
(except pneumonitis – refer to Table 3-2a) 
Interrupt RAD001 until recovery to grade d1. Then 
reintroduce RAD001 at the lower dose level. For 
pneumonitis consider the use of a short course of 
corticosteroids. 
Grade 4 
(except hyperlipidemia*) 
 
Discontinue RAD001. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75,  50x10
9/L)  
Interrupt RAD001 until recovery to grade d1 (>75 
x10
9/L). Then reintroduce RAD001 at initial dose. 
If thrombocytopenia again returns to grade 2, 
interrupt RAD001 until recovery to grade d1. Then 
reintroduce RAD001 at the lower dose level.  
Grade 3 Thrombocytopenia (platelets <50,  25 x10
9/L) 
Interrupt RAD001 until recovery to grade 1 
(platelets  75 x10
9/L).  Then resume RAD001 at one 
dose level lower.  If grade 3 thrombocytopenia 
recurs, discontinue RAD001. 
Grade 4 Thrombocytopenia (platelets < 25 x10
9/L)  
Discontinue RAD001. 
Grade 3 Neutropenia (neutrophils <1, 0.5 x10
9/L) 
Interrupt RAD001 until recovery to grade d1 ( 
neutrophils  1.5 x 10
9/L). Then resume RAD001 at 
the initial dose.  If ANC again returns to Grade 3, 
hold RAD001 until the ANC  1.5 x 10
9/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 < 0.5 x10
9/L) 
Interrupt RAD001 until recovery to grade d 1  
(neutrophils  1.5 x 10
9/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/mm
3 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 
*Grade 3 or higher hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should 
be managed using medical therapies (see Sec. 3.2.6.2). 


 
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3.2.4 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 until the adverse event or abnormal laboratory 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. 
 
 
3.2.5 
Known Side Effects of RAD001 
Adverse events most frequently observed with RAD001 are rash, stomatitis/oral mucositis, 
fatigue, headache, anorexia, nausea, vomiting, diarrhea. Infections have not been notably 
frequent or severe. Non-infectious pneumonitis has also been observed. The majority of these 
AEs have been of mild to moderate severity (CTC grade 1-2). Overall, the most frequently 
observed laboratory abnormalities include reduced blood counts, hyperlipidemia mostly 
reported as hypercholesterolemia and/or hypertriglyceridemia.  
3.2.5a The principal DLT in Phase 1 trials has been Grade 3 stomatitis. For guidance on 
management of stomatitis refer to Section 3.2.6.1 
3.2.5b Hyperlipidemia was reported as a serious adverse reaction. It is a recognized side-
effect of rapamycins. Use of lipid-lowering drugs should be associated with dietary 
recommendations. Monitoring of blood lipid levels requires patients to be fasting so that this 
aspect must be verified when interpreting results. For guidance on management of 
hyperlipidemia refer to Section 3.2.6.2. 
3.2.5c Hyperglycemia was reported as a serious adverse reaction. Similarly, the fasting state 
of patients should be verified when interpreting results. For guidance on management of 
hyperglycemia refer to Section 3.2.6.2. 
3.2.5d Pneumonitis is a recognized adverse effect of rapamycins (sirolimus, temsirolimus, and 
everolimus). Numerous case reports in the literature suggest that rapamycin-associated 
pneumonitis is relatively unaggressive, limited in extent, and reversible upon drug 
discontinuation. The term ‘pneumonitis’ is used here to describe non-infectious, non-
malignant infiltration in the lungs which is evident radiologically. More precise diagnosis 
should follow histocytological examination following lung biopsy, generally during 
bronchoscopy which may or may not be symptomatic. Advice on the management of 
pneumonitis has been provided in Table 3-2a.  
In oncology studies with RAD001, severe pneumonitis suspected as drug-related has been 
reported as a serious adverse event on 13 occasions and additionally in the following 
associated preferred terms including acute respiratory distress syndrome (n=2), alveolitis 
(n=1) and allergic alveolitis (n=1), interstitial lung disease (n=10), lung infiltration (n=23), 
cryptogenic organizing pneumonia, lung consolidation, pulmonary alvealoar haemorrhage, 
pulmonary toxicity and pulmonary fibrosis (n=1, each). One fatal case of drug-related 


 
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pneumonitis was reported for a patient with metastatic infiltrating ductal carcinoma of the 
breast treated with 10 mg/day, which developed approximately two months after starting 
RAD001. Cytology for both the pleural and pericardial fluids were positive for malignancy.  
The death was considered possibly related to the underlying late stage tumor and study drug. 
Additionally, one patient treated with 10 mg/day died due to severe acute respiratory distress 
syndrome and septic shock. Thoracic CT scan demonstrated condensation in the majority of 
the left lower lobe and frosted glass appearance in the left upper lobe, lingula, and right lung. 
Along with the cases of non-infectious pneumonitis, serious opportunistic infections have also 
been reported in cancer patients treated with RAD001: mycobactrium, aspergillus, and fatal 
candidal sepsis, and fatal pneumocystis carnii in particular. Because RAD001, as other 
rapamycins, inhibits proliferation of activated lymphocytes and reduces neutrophil counts, 
treatment with RAD001 must be considered as predisposing patients to the risk of infection. 
This risk will be higher in patients severely immunocompromised because of their underlying 
disease and/or co-medications. Outcome may be fatal in case of serious infections.  
 
3.2.5e Pericardial effusions, pleural effusions, and weight loss have been reported as serious 
adverse events with suspected causality. Due to the imprecision of causality assessments it 
should not be assumed that all of these events are indeed the result of therapy with everolimus 
since confounding factors are present relating mainly to complications of the underlying 
disease and to the use of concomitant medications.  
3.2.5f A reduction in blood cell counts is frequent when RAD001 therapy is initiated. Without 
clinical significance and infrequently, anemia and thrombocytopenia have been reported. In 
heavily pretreated patients with aggressive lymphoma, the incidence of grade 3 anemia, 
neutropenia, and thrombocytopenia was reported to be 11%, 16%, and 30%, respectively. 
Serious, suspected drug-related hemorrhages have been exceptional. Nevertheless, RAD001 
should be considered as predisposing patients to hemorrhage, potentially fatal, should they 
develop severe drug-related thrombocytopenia. 
3.2.5g Discrete, reversible changes in liver enzymes have been found to occur in numerous 
patients during treatment with RAD001 in oncology clinical studies, and in a study in 
rheumatoid arthritis. In oncology studies, these changes may be evident only in patients 
without severe underlying morbidity. The increase in transaminase’s (AST and ALT) 
generally appears after 4 weeks of treatment. In all but a few cases it does not exceed Grade 1 
( 2.5 x ULN). Similarly, mild increases in alkaline phosphatases can coexist. Spontaneous 
corrections or intermittent correction with continued treatment can occur. Serum bilirubin is 
not increased.  In studies of patients with advanced cancers, clinically relevant changes in 
liver enzymes have been invariably associated with the presence of liver metastases and/or 
progression of the underlying cancer.  
3.2.5h Renal failure has been reported in five suspected cases to date. One patient with no 
alternative explanation made a complete recovery following study drug adjustment and no 
treatment/therapy for the event. The rest or the patients had concurrent morbidities, which 
might have contributed to the reported events. 


 
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3.2.5i Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been 
reported as serious adverse reactions. Electrolytes should be monitored in patients treated with 
RAD001. 
Table 3-1 provides general recommendations for the management of patients, with suspected 
drug toxicities while on treatment with RAD001 as single-agent therapy. 
More detailed information regarding RAD001 reported suspected toxicities and individual 
cases is provided in the [Investigator’s Brochure]. 
 
3.2.5j Reactivation of Hepatitis B (HBV) has been observed in sporadic cases with patients in 
this setting with everolimus. Use of antivirals during anti-cancer therapy has been shown to 
reduce the risk of Hepatitis B virus reactivation and associated morbidity and mortality. A 
detailed assessment of Hepatitis B/C medical history and risk factors must be done for all 
patients at screening, with testing performed prior to the first dose of everolimus. 
 
Patients who test positive for a past or active Hepatitis B infection should be given 
prophylactic administration. If the patient has a positive Hepatitis B test result, they should be 
treated with Hepatitis B anti-viral lamivudine 100 mg prior to start of RAD001 therapy and 
throughout the treatment period with RAD001. Some associated toxicities to the lamivudine 
may include headache, diarrhea, and rash. If the patient needs to be treated with lamivudine, 
the cost of the treatment will be charged to the patient’s insurance. For guidance on 
management of Hepatitis B and C reactivation, refer to Section 3.2.6.4. 
 
3.2.6 Management of Side Effects of RAD001    
3.2.6.1   Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to RAD001 should be treated using local 
supportive care.  
When described, the disorder has been identified as inflammation or ulcers in the mouth. If 
exam reveals mouth ulcers, rather than a more general inflammation of the mouth, please 
classify the adverse event as ‘mouth ulcers’. If inflammation is limited to the mouth without 
ulcers please use the term ‘stomatitis’ rather than the less specific term ‘mucositis’. 
If the disorder is elsewhere than the mouth please describe the location as well as any specific 
procedures carried out for exploration (e.g. endoscopy).   
Please use the Grading according to the NIH-NCI Common Terminology Criteria for Adverse 
Events, Version 3.0 (CTCAEv3.0; http://ctep.cancer.gov/forms/CTCAEv3.pdf). 
Grade 1: 
minimal symptoms; normal diet 
Grade 2: 
symptomatic but can eat -and swallow modified diet 
Grade 3: 
symptomatic and unable to adequately aliment or hydrate orally 
Grade 4: 
symptoms associated with life-threatening consequences  


 
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Recommendations 
For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth wash, 
decadron mouthrinse, or salt water (0.9%) mouth wash several times a day until 
resolution. For more severe toxicity (Grade 2 or 3), the suggested treatments are topical 
analgesic mouth treatments (i.e., local anesthetics such as benzocaine, butyl 
aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical 
corticosteroids, such as triamcinolone oral paste 0.1% (e.g. Kenalog in Orabase®). 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. 
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, therefore 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. 
3.2.6.2   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 (>300 mg/dL or 7.75 mmol/L) or grade 2 or higher 
hypertriglyceridemia (>2.5 x upper normal limit) 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 in [Study RAD001C2222] 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. 
3.2.6.3   Management of non-infectious pneumonitis 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious 
pneumonitis (grade 2 = not interfering with activities of daily living or grade 3 = interfering 
with activities of daily living and oxygen indicated) have been noted in patients receiving 
RAD001 therapy. Non-infectious pneumonitis has been associated with RAD001 and other 
mTOR inhibitors (Atkins 2004). In order to monitor for asymptomatic (grade 1) pulmonary 


 
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infiltrates, a chest X-ray is required if a CT scan of chest is not used for bi-monthly disease 
evaluations. Additional chest CT scans may be performed, when clinically necessary. If non-
infectious pneumonitis develops, a consultation with a pulmonologist should be considered. If 
the patient develops grade 3 pneumonitis, treatment with RAD001 should be interrupted and 
the patient should be treated as medically indicated (short course corticosteroids, oxygen, etc). 
Management of non-infectious pneumonitis suspected to be associated with RAD001 and 
dose modifications instructions are provided in Table 3-2a and Table 3-0, respectively. 


 
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Table 3-2a 
Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
RAD001 Dose Adjustment 
Grade 1 
CT scans with lung windows 
and pulmonary function 
testing including: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat chest x-ray/CT scan 
every 2 Cycles until return to 
baseline. 
No specific 
therapy is 
required 
Administer 100% of RAD001 dose. 
Grade 2 
CT scan with lung windows 
and pulmonary function 
testing including: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat each subsequent 
Cycle until return to 
baseline**. Consider 
bronchoscopy *  
Symptomatic 
only. Prescribe 
corticosteroids if 
cough is 
troublesome. 
Reduce RAD001 dose until 
recovery to  Grade 1. RAD001 may 
also be interrupted if symptoms 
are troublesome. Patients will be 
withdrawn from the study if they 
fail to recover to  Grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing including: 
spirometry, DLCO, and room 
air O2 saturation at rest.; 
Repeat each subsequent 
Cycle until return to 
baseline**. Bronchoscopy is 
recommended * 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Hold treatment until recovery to  
Grade 1. May restart protocol 
treatment within 3 weeks at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Patients will be withdrawn from the 
study if they fail to recover to  
Grade 1 within 3 weeks. 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat each subsequent 
Cycle until return to 
baseline**. Bronchoscopy is 
recommended *. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
** Pulmonary function tests are dependent on a variety of parameter such as patient's age, 
gender, height etc. Normal references are provided when a patient undergoes PFT testing 
based on his or her individual characteristics. These are usually based on normal values 
published by John L. Hankinson, Robert O. Crapo and Robert L. Jensen et al CHEST 
November 2003 vol. 124 no. 5 1805-1811.   
 
3.2.6.4 Management of Hepatitis B or C Reactivation  
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 3-2 provides details of monitoring and prophylactic therapy according to the baseline 
results of viral load and serologic markers testing.
 


 
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Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study 
drug. For patients who have already received study drug prior to the approval of the 
amendment, the same process should be followed at the patient's next visit. The first HBV-
DNA result would be regarded as baseline. For hepatitis B reactivation, definition and 
management guidelines, see Table 3-3 Guidelines for management of hepatitis B. 

 


 
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Screening for Hepatitis C  
Patients with a positive Hepatitis C test or known to have a history of HCV infection 
including those with a negative viral load test at baseline are excluded from the study.  
 
All interruptions or changes to study drug administration must be recorded. 
 
It will be documented whether or not each patient completed the clinical study. If for any 
patient either study treatment or observations were 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: 
adverse event(s) 
abnormal laboratory value(s) 
abnormal test procedure result(s) 
disease progression 
protocol violation 
subject withdrew consent 
lost to follow-up 
administrative problems 
death 
3.3 
Treatments 
3.3.1 
RAD001 Administration 
The study drug RAD001 will be self-administered (by the patients themselves). The 
investigator will instruct the patient to take the study drug exactly as specified in the protocol. 
RAD001 will be administered orally as once daily dose of 10 mg (one 10mg tablet or two 5mg 
tablets) continuously from study day 1 until progression of disease or unacceptable toxicity. 
Patients will be instructed to take RAD001 in the morning, at the same time each day.   
RAD001 should be taken by the patient in a fasting state or with no more than a light fat-free 
meal. Dietary habits around the time of RAD001 intake should be as consistent as possible 


 
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throughout the study. Tablets should be swallowed whole with a glass of water. The tablets 
must not be chewed or crushed and grapefruit or citrus juices should be avoided. For patients 
unable to swallow tablets, everolimus tablet (s) should be dispersed completely in a glass of 
water (containing approximately 30mL) by gently stirring, immediately prior to drinking. The 
glass should be rinsed with the same volume of water and the rinse should be completely 
swallowed to ensure that the entire dose is administered.  
A dose of RAD001 is considered missed if the patient did not take RAD001 within 6 hours of 
the scheduled time. If vomiting occurs, no attempt should be made to replace the vomited 
dose. All dosages prescribed and dispensed to the patient and all dose changes during the 
study must be recorded. 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient. The storage conditions for study drug will be 
described on the medication label.  RAD001 will be provided by Novartis. RAD001 is 
formulated as tablets for oral administration of 5mg and 10 mg strength. Tablets are blister-
packed under aluminum foil, which should be opened only at the time of administration as 
drug is both hygroscopic and light-sensitive. Patients will be given a two-months supply.  
 
3.3.2 
Treatment assignment 
This is a non-randomized trial. In the first step of the trial, 18 patients with differentiated 
thyroid cancer will be enrolled and if responses are seen, the study will proceed to the full 
enrollment of 50 patients.  
3.3.3 
Concomitant therapy 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At 
each visit, the investigator will ask the patient about any new medications he/she is or has 
taken after the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken  30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be 
recorded. 
The following restrictions apply during the entire duration of the study: 
x No other investigational therapy should be given to patients. 
x No anticancer agents other than the study medication should be given to patients. If such 
agents are required for a patient then the patient must first be withdrawn from the study. 
x Growth factors (e.g.G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are not 
to be administered prophylactically but may be prescribed by the investigator for rescue 
from severe hematologic events, if this is thought to be appropriate. 
Concurrent administration of RAD001 and strong CYP3A4 inhibitors (such as ketoconazole, 
itraconazole, ritonavir) and inducers (such as rifampin, rifabutin) should be avoided. 


 
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Provided there is no alternative treatment available, patients should be closely monitored 
for potential toxicities. 
Concurrent administration of RAD001 and moderate CYP3A4 inhibitors (such as 
erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and moderate 
CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) should also be avoided 
if possible, or used subject to caution (e.g. increased frequency of safety monitoring, 
temporary interruption of RAD001). 
Competitive inhibition could occur when RAD001 is combined with drugs which are also 
CYP3A4 substrates. Therefore caution should be exercised in such cases. 
Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be avoided, 
if possible, or used subject to caution (e.g. increased frequency of safety monitoring, 
temporary interruption of RAD001).  
Grapefruit,grapefruit juice and pomegranate juice affect cytochrome P450 and P-glycoprotein 
activity and should therefore be avoided.  
x In addition, patients should avoid Seville oranges and star fruit, as well as the juice of 
these fruits, which are potent CYP3A4-inhibitors.  
x No chronic treatment with systemic steroids or other immunosuppressive agents while 
taking RAD001. Topical or inhaled corticosteroids are allowed. 
x In case of severe mucositis, systemic treatment with oral steroids for up to one week is 
allowed. RAD001 is held while on oral steroids.  
x RAD001 may affect the response to vaccinations making the response to the vaccination 
less effective. Live vaccines should be avoided while a patient is treated with RAD001. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
RAD001 is expected. However, drug-drug interaction studies between macrolide antibiotics 
and warfarin have produced mixed outcomes and the disparity in these findings has led to the 
conclusion that multiple factors may alter the clearance of warfarin. The coadministration of 
RAD001 and oral anticoagulants is possible but should be subject to verification of 
coagulation (INR) once steady state is reached (after one week’s treatment). 
Examples are provided in Table 3-3a. A comprehensive list of cytochrome P450 isoenzymes 
and 
CYP3A4 
inhibitors, 
inducers, 
and 
substrates 
can 
be 
found 
at 
http://medicine.iupui.edu/flockhart.  This website is continually revised and should be 
checked frequently for updates. 
 


 
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Table 3-3a Examples of clinically relevant drug interaction: substrates, inducers and 
inhibitors of isoenzyme CYP3A.  
Substrates (competitive inhibition) 
 
Antibiotics1: 
 
clarithromycin* 
 
erythromycin  
 
telithromycin* 
Anti-arrhythmics: 
 
quinidine 
Benzodiazepines: 
 
alprazolam 
 
diazepam 
 
midazolam 
 
triazolam 
Immune Modulators: 
 
cyclosporine 
 
tacrolimus (FK506) 
HIV Protease Inhibitors: 
 
indinavir* 
 
ritonavir* 
 
saquinavir* 
Prokinetic: 
 
cisapride 
Antihistamines: 
 
astemizole 
 
chlorpheniramine32 
Calcium Channel Blockers: 
 
amlodipine 
 
diltiazem 
 
felodipine 
 
nifedipine 
 
nisoldipine 
 
nitrendipine 
 
verapamil 
HMG CoA Reductase Inhibitors2:  
 
atorvastatin 
 
cerivastatin 
 
lovastatin 
 
simvastatin 
Miscellaneous: 
 
aprepitant 
 
buspirone 
 
haloperidol 
 
methadone 
 
pimozide  
 
quinine 
 
sildenafil 
 
tamoxifen 
 
trazodone 
 
vincristine 
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin* 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Cimetidine 
Clarithromycin 
Delaviridine 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Sevilla orange 
 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and 
polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104.  and 
[http://www.medicine.iupui.edu/flockhart/clinlist.htm as of July 13, 2006] 
* asterisk denotes strong inhibition/ induction  
Please note: 
strong inhibitor implies that it can cause 5-fold increase in AUC or 80% decrease in clearance of sensitive 
CYP substrates 
moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values or 50-80% decrease in 
clearance  of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions). 


 
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Macrolide antibiotics: 
Azithromycin is not a CYP3A substrate. It may therefore be employed where 
antibiotherapy with a macrolide is desirable in a patient being treated with RAD001 
Statins: Atorvastatin and pravastatin may be associated with RAD001, since a PK interaction study has shown 
that there is no relevant PK interaction.  
 
3.3.4 
Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to 
return all unused study medication. 
3.4 
Visit schedule and assessments 
3.4.1 
Visit schedule 
The visit schedule is outlined in Table 3.4a below.  


 
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General/safety assessments 
Study entry 
(within 14 days of day 
1 unless otherwise 
noted)) 
Day1
2 
 
At office visit every  4 
weeks
1 
Every 8 weeks for 
max. 24 months
1 
Informed consent 
X 
(within 28 days of 
day1) 
 
 
 
Medical history, height and vital signs 
X 
 
X 
 
Inclusion/exclusion criteria 
X 
 
 
 
ECOG Performance status 
X 
X 
X 
 
QOL questionnaire (EQ-5D) 
 
X 
X 
 
MTC-related symptoms  
questionnaire (MTC subjects only) 
 
X 
X 
 
Physical examination and weight 
X 
X 
X 
 
ECG 
X 
 
 
 
AE’s and con-medications/treatments 
X 
X 
X 
 
Laboratory assessments 
 
 
 
 
Pregnancy test for WOCBP (female 
subjects <50) 
X 
 
 
 
Coagulation tests 
X 
 
 
 
Hepatitis B tests (Hep B Core, Hep B 
Surf AB, Hep B Surf AG, HBV DNA)
3 
X 
(within 30 days of 
Day 1) 
 
X 
(only HBV DNA if 
positive at baseline) 
 
Hepatitis C test (HCV RNA PCR)
3 
X 
(within 30 days of 
Day 1) 
 
 
 
Hematology and blood chemistry 
X 
 
X 
 
Urinalysis 
X 
 
 
 
 
Calcitonin and CEA if elevated at 
baseline (only MTC subjects) 
X 
 
X 
(if elevated at 
baseline) 
 
Thyroglobulin and anti-thyroglobulin 
antibodies (only DTC subjects) 
X 
 
X 
(if elevated at 
baseline)
4 
 
Free T4 and TSH 
X 
 
X 
 
Radiological assessments 
 
 
 
 
CT/MRI neck, chest, abdomen
5 
X 
(within 30 days of day 
1) 
 
 
X 
 
Whole body bone scan (only MTC, 
FTC, HCTC subjects) 
X 
(within 30 days of day 
1) 
 
 
 
First dose of Rad001 
 
X
2 
 
 
Rad001 dispensed/returned 
 
 
 
X 
 
x 
1+/- one week depending on appointment availability due to holidays or unforeseen events 
x 
2First dose of RAD001 may start the morning of Study Day 2. 


 
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x 
3All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C infection. It is 
highly recommended that patients positive HBV-DNA or HBsAg are treated prophylactically with an antiviral (i.e. 
Lamivudine) for 1-2 weeks prior to receiving study drug (see Section 3.2.6.4). The antiviral treatment should continue 
throughout the entire study period and for at least 4 weeks after the last dose of everolimus. Patients on antiviral 
prohpylaxis treatment or positive HBV antibodies should be tested for HBV-DNA on Cycle 1 Day 1 and Day 1 of all 
subsequent cycles (every 28 days) to monitor for re-activation. If re-activation is confirmed, everolimus must be interrupted 
or discontinued according to the guidance in Table 3-3. Patients with viral hepatitis C risk factors should be screened for 
HCV RNA-PCR. Patients with positive HCV RNA-PCR results at screening and/or a history of past infection (even if test at 
baseline is negative) will be ineligible for the study.  
x 
4Thyroglobulin and thyroA are both drawn at monthly visits only if AT BASELINE thyroA lab value is negative AND 
thyroglobulin value is elevated. 
x 
5 CT/MRI scans are to be perfomed every 2 months until first progression or death through 24 months from study entry. Post 
24 months, if a patient has already stopped study treatment, but still alive without first progression, follow for first 
progression (CT/MRI scans every 3 months) and survival through 5 years from study entry. Post 24 months, If patient is 
scheduled to continue treatment, follow for first progression (CT/MRI scans every 3 months)  and survival  through 5 years 
from study entry; If treatment is stopped post 24 months but prior to 5 years from study entry  for reasons other than 
progression, follow for first progression and survival  through 5 years from study entry; if treatment  is stopped post 24 
months but prior to 5 years from study entry  due to first progression, follow until death or 5 years from study entry, 
whichever is first.; 
 
3.4.1.1 
Screening 
All subjects or their legally acceptable representative and the person who conducted the 
informed consent discussion must personally sign and date the consent form before any study-
specific screening procedures are performed. Procedures that have been performed before 
consent was obtained as part of routine care are not considered study-specific procedures.  
Medical history information to be collected during screening must date back to the original 
diagnosis of thyroid cancer. If a subject is referred to the study center, a copy of all applicable 
reports and histological or cytological evidence, confirming the diagnosis must be provided to 
the study center before enrollment. Copies of   radiographic images confirming disease 
progression (ie, within 6 months during the year prior to study day 1) by modified RECIST 
should be provided to the study center. To document disease progression by modified 
RECIST, radiographic evidence must consist of 2 radiographic imaging studies that were both 
obtained within 6 months during the year prior to study day 1. The two radiographic imaging 
studies cannot be more than 6 months apart. Also, the patient must not have had any treatment 
between the date of progression and the start date of RAD001 treatment, unless discussed with 
the PI.   
All subjects who have signed the IRB approved consent form must be registered as a screened 
subject. At the time of registration, the subject will receive a unique 5 digit subject 
identification number. This number will be used to identify the subject throughout the study 
and must be used on all study documentation related to that subject. The subject identification 
number must remain constant throughout the entire study.  
All screening tests and procedures must be performed and the results available within a 
maximum of 14 days before study day 1 unless otherwise noted.  
Subjects who do not meet eligibility criteria within the 14 day screening period will not be 
eligible for enrollment. However, subjects may be re-screened up to 2 additional times at the 
discretion of the investigator. The subject must be re-consented if more than 28 days have 
elapsed since the date of last informed consent.  


 
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The following screening assessments must be performed: 
Review of inclusion and exclusion criteria 
Medical history review, documentation of diagnosis and previous treatment. 
Physical examination, ECOG performance status, blood pressure, respiratory rate, resting 
pulse, temperature, height and weight. 
A 12 lead ECG 
CT scans (contrast-enhanced or MRI scan (contrast-enhanced or PET CT scans of areas with 
known disease and that are of acceptable quality as baseline study within 30 days prior to 
study day 1.  
Whole body bone scan for subjects with medullary, follicular or Hurthle cell thyroid cancer.  
Laboratory assessment consisting of  
x Hematology 
x Chemistry 
x Urinalysis 
x Coagulation tests  
x beta HCG pregnancy test for WOCBP  
x Hepatitis B and C Screening tests 
3.4.1.1.1  
Registering 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must occur 
prior to the initiation of therapy. Any participant not registered to the protocol before 
treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the protocol-
specific eligibility checklist.  
Following registration, participants may begin protocol treatment. Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a participant 
does not receive protocol therapy following registration, the participant’s protocol status must 
be changed. Notify the QACT Registrar of participant status changes as soon as possible. 
For institutions outside of DF/HCC: While in the pre-screening stage, contact the DFCI 
clinical research coordinator/team to inform them of the potential screening patient. This 
will allow the DFCI team to monitor and maintain the patient accrual limits for each of the 


 
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cancer diagnosis categories. For more information, please refer to Appendix D for 
registration guidelines. 
 
3.4.1.2 
Treatment period procedures 
The first does of RAD001 may be administered on the same day as enrollment but no more 
than 10 business days after enrollment. The treatment period begins on the first day of 
treatment with RAD001. The time points of study visits are outlined in table 3.4a.  
If a subject is unable to come into the clinic for a required study visit or if unforeseen events 
occur, the visit procedures may be performed within a one week time frame.  
The following assessments will be performed at each clinic visit according to table 3.4a 
throughout the treatment period:  
Physical examination, 
ECOG performance status,  
blood pressure, respiratory rate, resting pulse, temperature, and weight. 
Patient reported outcomes questionnaire (EQ-5D), see appendix 
Medullary thyroid cancer-related symptoms questionnaire, see appendix 
Laboratory evaluations are done at screening and monthly and need not be repeated on day 1. 
CT scans (contrast-enhanced or MRI scan (contrast-enhanced or PET CT scans of areas with 
known disease and that are of acceptable quality every 8 weeks with a 5 business-day time 
window in case unforeseen events occur. Evaluation according to RECIST criteria compared 
to previous scan.  
Documentation of all adverse events will occur at each clinic visit and at any other time point 
when necessary.  
Survival status will be recorded for all patients until death or 5 years from study entry 
Subjects who complete 24 months of therapy without progression may continue treatment 
with RAD001 and will have the following assessed: 
x Physical exam and labs at the discretion of the physician approximately every 
4-6 weeks. Deviation from this schedule must first be approved by the 
Principal Investigator. 
x Disease Status per RECIST approximately every 3 months 
x Serious Adverse Events (SAEs) per section 3.4.3.2 
x Drug accountability  


 
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3.4.1.3 
End of treatment period procedures 
Patients removed from study treatment for reasons other than progression of disease should 
continue to be followed for first disease progression per RECIST. See footnote #5 in 3.4.1 for 
details. 
 
All patients who terminate treatment with RAD001 should be evaluated in the outpatient 
clinic within 5 business days after the last dose of RAD001 and again 4 weeks after their last 
dose of RAD001 (plus or minus one week depending on appointment availability due to 
holidays or unforeseen events). In certain instances, if a patient is unable to return to clinic 
every effort should be made to follow-up with a phone call to the patient or their provider.  
This evaluation will include: 
Physical examination, 
ECOG performance status,  
blood pressure, respiratory rate, resting pulse, temperature, and weight. 
Patient reported outcomes questionnaire (EQ-5D), see appendix 
Medullary thyroid cancer-related symptoms questionnaire, see appendix 
Laboratory evaluations are also performed according to table 3.4a. The necessary components 
of the laboratory tests are outlined below. Documentation of all adverse events 
3.4.1.4 
Study procedures 
3.4.1.4.1 Laboratory evaluations 
Hematology 
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential. PT (INR) evaluation will be included for baseline evaluations. 
ANC will be determined by this equation:  
(%Neutrophils + %Bands) (WBC Count x 101) = ANC1 
 
Blood chemistry 
Blood chemistry must include sodium, potassium, chloride, bicarbonate, calcium, glucose, 
creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total 
bilirubin, alkaline phosphatase, uric acid, phosphorus, serum lipid profile (triglycerides, total 
cholesterol, HDL and LDL). 
                                                 
1 WBC Count is in K/UL units.  
 


 
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Because accurate serum glucose and lipid m
easurements are required, patients should be 
fasting at the time of the blood sampling. 
Tumor markers which were elevated prior to treatment start with RAD001 will be assessed 
every month or whenever clinically indicated. Patients with differentiated thyroid cancer will 
have thyroglobulin and thyroglobulin antibody measured every month and patients with 
medullary thyroid cancer will have CEA and calcitonin levels evaluated every month (see 
table 3.4a) 
The Hepatitis B and C screening tests (Hep B Core, Hep B Surface antibody, Hep B Surface 
antigen, HCV RNA-PCR) need to be performed at baseline. HBV DNA follow-up testing 
should be done according to table 3.4a and section 3.2.6 “Management of Hepatitis B or C 
Reactivation,” depending on results from baseline.  
Urinalysis 
Standard urinalysis assessment (pH, protein, glucose, blood, ketones, and leukocytes) should 
be performed at baseline. This must be supplemented with laboratory quantification of any 
potentially relevant abnormalities.  
Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position. 
Physical examination 
Physical examination will be performed monthly and must comprise a total body examination. 
Significant findings made after the start of study drug which meet the definition of an Adverse 
Event must be recorded. 
ECG 
A standard 12 lead ECG is to be performed during screening and significant findings must be 
recorded. 
Performance status 
Performance status will be assessed according to the ECOG performance status scale at the 
screening visit and monthly thereafter (see schedule of assessment, appendix B). 
Special tests 
Special tests may be added in a future amendment. 
Drug levels and pharmacokinetic assessments 
No drug levels will be assessed. 
 


 
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3.4.2 
Efficacy assessments 
Progression-free survival will be measured based on the appearance of disease progression on 
imaging based on RECIST criteria (see Appendix A). This can be on imaging studies that are 
part of the regular study schedule or based on studies which were obtained based on the 
appearance of symptoms.  
3.4.3 
Safety assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, 
regular measurement of vital signs and the performance of physical examinations. 
These assessments should be performed within 1 week of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study. Safety and 
tolerability 
will 
be 
assessed 
according 
to 
the 
NIH/NCI 
CTC 
http://ctep.cancer.gov/forms/CTCAEv3.pdf. 
3.4.3.1 
Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug. Medical conditions/diseases present before starting study drug are 
only considered adverse events if they worsen after starting study drug. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or symptoms, 
are considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine: 
 the severity grade (mild, moderate, severe) or (grade 1-4) 
 its relationship to the study drug(s) (suspected/not suspected) 
 its duration (start and end dates or if continuing at final exam) 
 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) 
 whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 


 
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if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigators’ Brochure. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
3.4.3.2 
Serious adverse events 
Information about all serious adverse events will be collected and recorded. To ensure patient 
safety each serious adverse event must also be reported to Novartis within 24 hours of 
learning of its occurrence. A serious adverse event is an undesirable sign, symptom or medical 
condition which: 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 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 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
x routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (specify what this includes) 
x 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 
x treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
x social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
3.4.4 
Novartis and FDA instructions for rapid notification of serious adverse 
events 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
Novartis Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E), and IRB. 
Reporting to the FDA 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA. The DF/HCC Overall Principal Investigator will report to the 
FDA, regardless of the site of occurrence, any adverse event that is serious, unexpected and 
reasonably related (i.e., possible, probable, definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later than 7 calendar 
days after initial receipt of the information. 


 
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All other serious unexpected experiences associated with the use of the study treatment will 
be reported to FDA as soon as possible but in no event later than 15 calendar days after 
initial receipt of the information. 
 
 
 
All events meeting the criteria of an INDSR will be submitted to the appropriate division 
center via mail using Form FDA 3500A (Mandatory Reporting Form for investigational 
agents) in compliance with FDA reporting timelines. Forms are available at 
http://www.fda.gov/medwatch/getforms.htm. 
Reporting to Novartis 
All events must be reported, by FAX (888-299-4565), to Novartis Pharmaceuticals CS&E 
Department within 24 hours of learning of its occurrence.  This includes serious, labeled 
(expected) and unlabeled (unexpected) adverse experiences. All deaths during treatment or 
within 30 days following completion of active protocol therapy must be reported within 5 
working days. 
Any serious adverse event occurring after the patient has provided informed consent and until 
4 weeks after the patient has stopped study participation must be reported. This includes the 
period in which the study protocol interferes with the standard medical treatment given to a 
patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed dose 
of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
3.4.5 
IRB Instructions for notification of serious adverse events 
 
For DF/HCC Sites:  
The DFCI IRB SAE Reporting Form must be used to report SAEs experienced by DF/HCC 
participants enrolled in a DF/HCC study including any serious adverse events on 
DF/HCC led Multi-Center trials where the event occurs at a non-DF/HCC site. Full written 
SAE report must be submitted to OHRS as soon as possible, but no later than 10 working 
days from notification of event. For DF/HCC participant centers, reports must be submitted 
via OHRS Submit, and the lead site must be notified prior to submission to OHRS.  
  
The DFCI IRB requires the following events be reported: 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
Unexpected and Possibly, Probably or Definitely Related/Associated with the 
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 ALL Grade 4 (life threatening or disabling) Events  
 ALL Grade 5 (fatal) Events – When subject is enrolled and actively 
participating in the trial OR when event occurs within 30 days of the last study 
intervention. 
 
Follow Up SAE Reports (DF/HCC participating centers only): 
When submitting follow up reports to previously reported SAEs, attach a copy of the 
original report and any prior IRB determinations to the follow up report. This gives the 
reviewer all the information required to conduct a thorough review and eliminates questions 
that might otherwise be raised.
For Non-DF/HCC Sites:  
For institutions outside of DF/HCC, please report grade 2 or higher AEs considered 
unexpected and possibly, probably, or definitely related/associated with the intervention to 
DFCI Study Team (Dr. Lorch: Principal Investigator) for reporting to the DFCI IRB. All 
outside institutions are also required to report events to their IRB per individual 
institutional guidelines.  
 
3.4.5.1 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects, congenital abnormalities or maternal and newborn complications. 
 
4 
Protocol amendments, or changes in study conduct 
This protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) and any other necessary 
documents must be submitted, reviewed, and approved by a properly constituted IRB 
governing each study location.  
 
Any changes made to the protocol must be submitted as amendments and must be approved 
by the IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The Principal Investigator (or Protocol Chair) will disseminate protocol amendment 
information to all participating investigators.  
 


 
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All decisions of the IRB concerning the conduct of the study must be made in writing.  
For Non-DF/HCC Sites:  
For institutions outside of DF/HCC, any protocol or amendment changes need to be first 
approved by Dr. Lorch.  
 
5 
Correlative Studies 
For correlative studies, patients will be asked for the permission to obtain and store either a 
tumor tissue block from a previous biopsy and/or undergo sequential biopsies.  
 If tumor tissue blocks are unavailable, then up to forty unstained slides should be obtained. 
These will be kept in the clinical research lab in a secure location.  
They will be used for immune histochemistry (IHC) studies and possible analysis of genetic 
mutations in the future. IHC staining for the expression of AKT, PTEN, PI3K and others will 
be performed when funding becomes available. Analysis of mutations such as B-raf may also 
be performed depending on funding in the future. Patients may decide against participating 
but will be encouraged to give permission for using their tumor tissue.   
Patients with easily accessible tumors such as skin metastases, will be asked to undergo 
sequential biopsies before and during treatment with RAD001. This will be performed in 
collaboration with Dr Daniel Ruan from the Department of Surgery at BWH at his outpatient 
office. Obtaining biopsies will be optional for patients and will only be pursued if they can be 
obtained with a minimal risk to the patient. Biopsies will be evaluated in the lab of Dr Ruan 
for the presence of markers of autophagy. It will also be analyzed for tyrosine kinase 
phosphorylation status in collaboration with Dr. Jinyan Du at the Broad Institute, Harvard 
University.  
For Non-DF/HCC Sites:  
 Institutions outside of DF/HCC will also be participating in the correlative studies. They 
will send their participants’ archival tissue with the submission form to Dr. Jochen Lorch 
and his study team. Before any tissue is sent, the external sites need to contact the DFCI 
Study Team to coordinate the shipment. For specimen preparation, submission and shipping 
guidelines, please see Appendix E.  


 
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6 
Data management 
6.1 
Data collection 
Investigators must record the information required by the protocol.  
 
6.1.1 
Data Safety 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer protocols, 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
7 
Statistical methods 
7.1 
Statistical methods 
This study is intended to provide initial efficacy data on RAD001 in patients with RAI 
refractory differentiated thyroid cancer and evidence for progressive disease. The design 
follows the two step method by Fleming et al33. In the first step, 18  patients with differentiated 
thyroid cancer (excluding medullary and anaplastic thyroid cancer) and documented disease 
progression within  6 months will be enrolled. Then a PFS of 6 months or more will be 
required in at least two patients in order to proceed with the enrollment of 15 more patients for 
the study to complete its full accrual of the differentiated thyroid cancer part of the trial of 33 
patients. The time interval of 6 months is chosen because documented disease progression 
within 6 months is a requirement for enrollment in this trial. Imaging studies will obtained 
every 2 months and if no progression can be demonstrated at the 6 month time point while on 
therapy, anti-tumor activity is likely. If there is only one or no case alive and progression-free 
at 6 months in the first cohort, the drug combination will be considered ineffective and the 
trial will be terminated. If at least 2 subjects meet the criteria, the study will proceed to its full 
accrual of patients with differentiated thyroid cancer of 33 patients. Patients who drop out 
before the 6 month binary evaluation will be counted as failures. We will declare the trial a 


 
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success after observing 7 or more patients alive and progression-free at 6 months. The study 
will have alpha = 0.092 and power =0.970, assuming a 6 month PFS of 0.12 for the null and a 
PFS of 0.35 as the alternative hypothesis. 
 
This trial will also include 2 separate exploratory cohorts for patients with medullary and 
anaplastic thyroid cancer to detect a possible signal in these rare diseases in which no 
established treatment alternatives exist. They are not included in the main analysis since there 
are  important differences compared to differentiated thyroid cancer. Medullary thyroid cancer 
originates from parafollicular C-cells which are embryologically and molecularly distinct 
from the rest of the thyroid gland. Anaplastic thyroid cancer is also distinct from differentiated 
thyroid cancer with a high rate of distant metastasis and a poor prognosis. Ten patients with 
medullary thyroid cancer and seven patients with anaplastic thyroid cancer will be treated on 
this protocol and descriptive statistics will be used for analysis of these patient groups. If no 
signal is detected, no conclusions can be drawn. However, if there are a few responses (i.e. 
one or more), a case for a larger, multi-institutional effort to analyze this fully could be made.  
 
Since we expect accrual of a relatively large number of medullary thyroid cancer cases based 
on the patient population that we see at DFCI, we wanted to make sure that the main group for 
which this trial is designed - papillary and follicular thyroid cancer- are sufficiently 
represented in the group of 33 patients of the primary analysis.  
 
 
Thus the grand total of subjects on this trial will be 50.  
 
We will use the Kaplan-Meier survival method and the Cox model to analyze PFS and the 
confidence intervals will be estimated.  
 
For the categorical outcomes, logistic regression or chi-square test will be used. For the 
survival outcomes, the Kaplan-Meier method and the Cox regression model will be used.  
 
8 
References 
 
1. 
Boulay A, Lane HA. The mammalian target of rapamycin kinase and tumor growth 
inhibition. Recent Results Cancer Res 2007;172:99-124. 
2. 
Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev 
Cancer 2004;4:335-48. 
3. 
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 
2006;124:471-84. 
4. 
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 
2007;129:1261-74. 


 
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5. 
Wang L, Harris TE, Roth RA, Lawrence JC, Jr. PRAS40 regulates mTORC1 kinase 
activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 
2007;282:20036-44. 
6. 
Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus 
(CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347-56. 
7. 
Yeager N, Brewer C, Cai KQ, Xu XX, Di Cristofano A. Mammalian target of 
rapamycin is the key effector of phosphatidylinositol-3-OH-initiated proliferative signals in 
the thyroid follicular epithelium. Cancer Res 2008;68:444-9. 
8. 
Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 
(everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. 
Neuroendocrinology 2007;85:54-60. 
9. 
Zeng Z, Sarbassov dos D, Samudio IJ, et al. Rapamycin derivatives reduce mTORC2 
signaling and inhibit AKT activation in AML. Blood 2007;109:3509-12. 
10. 
Ikezoe T, Nishioka C, Bandobashi K, et al. Longitudinal inhibition of 
PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell 
leukemia cells. Leuk Res 2007;31:673-82. 
11. 
Wanner K, Hipp S, Oelsner M, et al. Mammalian target of rapamycin inhibition 
induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises 
DLBCL cells to rituximab. Br J Haematol 2006;134:475-84. 
12. 
Tuncyurek P, Mayer JM, Klug F, et al. Everolimus and mycophenolate mofetil 
sensitize human pancreatic cancer cells to gemcitabine in vitro: a novel adjunct to standard 
chemotherapy? Eur Surg Res 2007;39:380-7. 
13. 
Treeck O, Wackwitz B, Haus U, Ortmann O. Effects of a combined treatment with 
mTOR inhibitor RAD001 and tamoxifen in vitro on growth and apoptosis of human cancer 
cells. Gynecol Oncol 2006;102:292-9. 
14. 
Sieghart W, Fuereder T, Schmid K, et al. Mammalian target of rapamycin pathway 
activity in hepatocellular carcinomas of patients undergoing liver transplantation. 
Transplantation 2007;83:425-32. 
15. 
Kilicarslan AB, Ogus M, Arici C, Pestereli HE, Cakir M, Karpuzoglu G. Clinical 
importance of vascular endothelial growth factor (VEGF) for papillary thyroid carcinomas. 
APMIS 2003;111:439-43. 
16. 
Gupta V, Puttaswamy K, Lassoued W, et al. Sorafenib targets BRAF and VEGFR in 
metastatic thyroid carcinoma. J Clin Oncol (Meeting Abstracts) 2007;25:6019-. 
17. 
Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic 
subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 
2008;26:4708-13. 
18. 
Cohen EE, Vokes EE, Rosen LS, et al. A phase II study of axitinib (AG-013736 [AG]) 
in patients (pts) with advanced thyroid cancers. J Clin Oncol (Meeting Abstracts) 
2007;25:6008-. 


 
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19. 
Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the 
mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic 
study in patients with advanced solid tumors. J Clin Oncol 2008;26:1603-10. 
20. 
Hodgson NC, Button J, Solorzano CC. Thyroid Cancer: Is the Incidence Still 
Increasing? Ann Surg Oncol 2004;11:1093-7. 
21. 
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA 
Cancer J Clin 2007;57:43-66. 
22. 
Ahuja S, Ernst H. Chemotherapy of thyroid carcinoma. J Endocrinol Invest 
1987;10:303-10. 
23. 
Shimaoka K, Schoenfeld DA, DeWys WD, Creech RH, DeConti R. A randomized 
trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid 
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Harada T, Nishikawa Y, Suzuki T, Ito K, Baba S. Bleomycin beneficial for thyroid 
cancer. Aerosp Med 1972;43:330. 
25. 
Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with 
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26. 
Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in 
advanced thyroid cancer. J Clin Oncol 2008;26:4714-9. 
27. 
Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive 
differentiated thyroid cancer. N Engl J Med 2008;359:31-42. 
28. 
Moreno A, Akcakanat A, Munsell MF, Soni A, Yao JC, Meric-Bernstam F. Antitumor 
activity of rapamycin and octreotide as single agents or in combination in neuroendocrine 
tumors. Endocr Relat Cancer 2008;15:257-66. 
29. 
Wang S, Lloyd RV, Hutzler MJ, Safran MS, Patwardhan NA, Khan A. The Role of 
Cell Cycle Regulatory Protein, Cyclin D1, in the Progression of Thyroid Cancer. Mod 
Pathol;13:882-7. 
30. 
Erickson LA, Jin L, Wollan PC, Thompson GB, van Heerden J, RV L. Expression of 
p27kip1 and Ki-67 in benign and malignant thyroid tumors. Mod Pathol 1998;Feb;11(2)::169-
74. 
31. 
Ringel MD, Hayre N, Saito J, et al. Overexpression and Overactivation of Akt in 
Thyroid Carcinoma. Cancer Res 2001;61:6105-11. 
32. 
Sherman SI, Schlumberger MJ, Droz J, et al. Initial results from a phase II trial of 
motesanib diphosphate (AMG 706) in patients with differentiated thyroid cancer (DTC). J 
Clin Oncol (Meeting Abstracts) 2007;25:6017-. 
33. 
Fleming TR. One-sample multiple testing procedure for phase II clinical trials. 
Biometrics 1982;38:143-51. 


 
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34. 
Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response 
to treatment in solid tumors. European Organization for Research and Treatment of Cancer, 
National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl 
Cancer Inst 2000;92:205-16. 
 
 


 
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9 
Procedures and instructions 
9.1.1 
Publication of results 
The results should be made public within 24 months of the end of data collection. If a report is 
planned to be published in a peer-reviewed journal, then that initial release may be an abstract 
that meets the requirements of the International Committee of Medical Journal Editors. A full 
report of the outcomes should be made public no later than three (3) years after the end of data 
collection. Outside institutions planning publications must send copies of any intended 
communication in advance of publication (at least fifteen working days for presentational 
materials 
and 
abstracts 
and 
thirty 
working 
days 
for 
manuscripts). 
Principal 
Investigation/Institution shall have the final authority to determine the scope and content of 
the publications. 
9.1.2 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and 
to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately 
to ensure their confidentiality. The information provided by Novartis to the investigator may 
not be disclosed to others without direct written authorization from Novartis, except to the 
extent necessary to obtain informed consent from patients who wish to participate in the trial. 
9.1.3 
Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the 
clinical trial agreement. 
9.2 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Novartis standard operating procedures and: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to. 


 
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9.2.1 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis before study initiation. Any amendments to the 
protocol, other than administrative ones, must be reviewed by Novartis approved by this 
committee. 
9.2.2 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval. 
9.2.3 
Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon 
request or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
 
Summary of Major Changes, Protocol Amendment Dated January 28th, 2014 
Protocol Section 
Change 
Study Objectives 
The secondary endpoint of overall survival 
will now be collected for 5 years from study 
entry, updated from 1 year. 
 
Visit Schedule and Assessments 
Footnote #5 describes the imaging schedule. 
The schedule is unchanged; this update is to 
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changes after subjects have been on trial for 
>24 months. 
 
Treatment Period Procedures 
This section now describes all study 
procedures rather than just those occurring 
throughout the first 24 months on trial. 
 
Procedures for subjects on trial for >24 
months were previously located in the “End 
of Treatment Period Procedures” section 
 
Adverse Events 
Protocol now reflects that all serious events 
are reported to the sponsor, regardless of 
whether their relatedness to study drug.  
 
Throughout the Protocol 
Minor administrative changes 
 


 
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Appendix A
Modified RECIST criteria (adapted from Therasse et al 34.  
 
RECIST: Response Evaluation Criteria in Solid Tumors 
 
Eligibility: To be eligible, subjects must have at least one uni-dimensionally measurable 
lesion. 
 
Measurable lesion: To be considered measurable, lesions must be equal or greater than 20mm 
in at least one dimension using conventional techniques (CT or MRI scan) or 10 – 16mm with 
spiral CT scan.  
 
Lesions identified on physical exam and clinically measured by the investigator will 
automatically be considered non-target lesions. Lesion in a radiation therapy port will not be 
considered target lesions. 
 
Non-measurable lesions 
Non-measurable lesions are all other lesions including small lesions9 longest diameter less 
that 20mm with conventional techniques or equal or more that 10-16mm with spiral CT scan. 
Other examples of non-measurable lesions include bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusion, lymphangitis cutis/pulmonis, cystic lesions and also 
abdominal masses that are not confirmed and followed by imaging techniques. Additionally, 
the following will be considered non-measurable for this study: Non-measurable skin lesions, 
peritoneal carcinomatosis, military lesions, irradiated lesions and groups of lesions that are 
small and numerous.  
 
Method 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. The same 
method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up evaluations. 
Conventional CT and MRI will be performed with contiguous cuts of 10mm or less in slice 
thickness and spiral CT will be performed by use of up to an 8mm contiguous reconstruction 
algorithm. Standard whole body bone scans will be utilized to follow the non-measurable 
bony lesions for progression.  


 
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Measurement of lesions on chest x-ray will not be performed. CT of the chest is required for 
lesion measurement.  
When the primary endpoint of the study is objective response evaluation, ultrasound should 
not be used to measure tumor lesions that are not clinically easily accessible. It may be used 
as a possible alternative to clinical measurements for superficial palpable lymph nodes, 
subcutaneous lesions and thyroid nodules. Ultrasound might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination.  
Tumor markers will not be used to assess objective response for the primary study endpoint.  
 
Baseline documentation of target and non-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 (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline for sum LD will be used as reference by which to characterize 
the objective tumor.  
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurement of these lesions is not required but the presence or 
absence of each should be noted through follow-up evaluations.  
Response criteria 
Evaluation of target lesions 
Complete response 
Disappearance of all target lesions 
Partial response 
At least a 30% decrease in the sum of the LD 
of target lesions, taking as reference the 
baseline  sum LD  
Progressive disease (PD)  
At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the 
smallest sum LD recorded since the treatment 
started or the appearance of one or more new 
lesions.  
Stable disease (SD) 
Neither sufficient shrinkage to qualify for a 
partial response nor sufficient increase to 
qualify for progressive disease, taking as 
reference the smallest sum LD since the 
treatment started 


 
Confidential 
Page 55 
Clinical study protocol 
 
DFCI Study No 09-049.  
 
Version 12 
Updated: 1/28/2014 
 
Evaluation of non-target lesions 
Complete response 
Disappearance of all non-target lesions 
Incomplete response/stable disease 
Persistence of one or more non-target 
lesion(s) 
Progressive disease 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesions. A clear progression of 
non-target lesions only is exceptional. In such 
circumstances, the opinion of the investigator 
will prevail for the purpose of deciding 
whether to continue treatment. Bone scans 
will be utilized to follow subjects at risk for 
bony disease progression. Because of the 
difficulties in interpreting changes in the 
intensity or size of bone lesions on bone 
scans, progressive disease in bone is defined 
as the appearance of one or more new lesions 
determined 
by 
the 
investigator 
to 
be 
compatible with metastases. In questionable 
cases, plain radiographic films or other 
imaging may be performed to confirm or 
refute the clinical suspicion.  
 
Evaluation of Response 
Response is recorded each time a CT is performed. The smallest measurements since 
treatment started are taken as reference for progressive disease. In general, the subject’s 
response assignment will depend on the achievement of both target lesions and non-target 
lesions. 
 
Target lesions 
Non-target lesions 
New lesions 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 


 
Confidential 
Page 56 
Clinical study protocol 
 
DFCI Study No 09-049.  
 
Version 12 
Updated: 1/28/2014 
Any 
Any 
Yes 
PD 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at the time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective 
progression even after discontinuation of treatment in the long term follow-up portion of the 
study. 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
 
Response confirmation 
To be assigned a status of PR or complete response, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after the 
criteria for response are first met.  
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for 
complete response or PR (whichever status is recorded first) until the first date that recurrence 
or progressive disease is objectively documented, taking as reference for progressive disease 
the smallest measurements recorded since the treatment started.  
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for disease progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
 


Created on: 5/6/2014 
Appendix B 
Drug Diary 
 
Appendix C 
Questionnaire 
 
 
Appendix D 
DF/HCC Multi-center Data and Safety Monitoring Plan 
 
Appendix E 
Correlative Studies Shipping Guidelines and Submission Form 
 
 


Participant Name:_________________________ Record #:__________________Cycle #:_______________
RAD001
1.) RAD001 should be taken:
               Participant Signature:____________________________Date:____/____/____
· 1 time every other day in the morning, at approximately the same time every day when taken
· On an empty stomach or with no more than a light fat-free meal.
2.) Please record each dose in the calendar below, indicating what time the dose was taken.
3.) List any noticeable side effect, reason for missed dose, or other pertinent information in the “Notes” column.
4.) If you vomit after taking RAD001 or miss a RAD001 dose, do not repeat or make up that dose. Take your next 
     scheduled dose on the following day.  If you do not take RAD001 within 6 hours of the scheduled time this is 
    considered a missed dose.  Please record the missed dose in your diary below. 
5.) Please do not drink or eat grapefruit juice, pomegranate juice, star fruit, and Seville oranges while taking this medication.
6.) Please return this diary, all empty bottles and unused pills at the end of each cycle.
Day #
Date
Time
Dose of Drug Notes  (Side effects, reason for missed dose, etc.)
1
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3
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Participant Name:_________________________ Record #:__________________Cycle #:_______________
RAD001
1.) RAD001 should be taken:
               Participant Signature:____________________________Date:____/____/____
· 1 time per day in the morning, at approximately the same time every day
· On an empty stomach or with no more than a light fat-free meal.
2.) Please record each dose in the calendar below, indicating what time the dose was taken.
3.) List any noticeable side effect, reason for missed dose, or other pertinent information in the “Notes” column.
4.) If you vomit after taking RAD001 or miss a RAD001 dose, do not repeat or make up that dose. Take your next 
     scheduled dose on the following day.  If you do not take RAD001 within 6 hours of the scheduled time this is 
    considered a missed dose.  Please record the missed dose in your diary below. 
5.) Please do not drink or eat grapefruit juice, pomegranate juice, star fruit, and Seville oranges while taking this medication.
6.) Please return this diary, all empty bottles and unused pills at the end of each cycle.
Day #
Date
Time
Dose of Drug Notes  (Side effects, reason for missed dose, etc.)
1
2
3
4
5
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1 1 
DFCI IRB Protocol #: 09-049 
APPENDIX D
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 


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Version Date: October 2009 
Table of Contents 
1.0  Introduction ………………………………………………………………......... 4   
1.1  Purpose 
1.2  Data and Safety Monitoring Plan Components 
 
2.0     General Roles and Responsibilities …………………………………………...5
2.1  Protocol Chair 
 
 
2.2  Coordinating Center 
 
 
2.3  Participating Institution 
 
 
3.0     DF/HCC Quality Assurance Office for Clinical Trials ……………………… 6 
3.1  Organizational Structure 
 
 
 
4.0 Protocol Development ………………………………………………………….. 7 
 
  4.1   Activation of a Protocol 
 
 
 
  4.2   Coordinating Center Support Function 
 
5.0   Protocol Management ……………………………………………………………8 
 
5.1 Protocol Distribution 
 
 
5.2 Protocol Revisions and Closures 


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Version Date: October 2009 
5.3 Informed Consent Requirements 
5.4 IRB Documentation 
 
 
5.5 IRB Re – Approvals  
 
5.6 Participant Confidentiality and Authorization 
5.7 Participant Registration 
 
 
5.8 DF/HCC Multi-center Protocol Case Number 
5.9 DF/HCC Multi-center Protocol Registration Policy 
 
5.10 Schedule of Data Submission 
 
 
5.11 Data Form Review 
 
 
5.12 Missing and Deficient Memorandum 
 
6.0  Requisitioning Investigational Drug ………………………………………………..…. 16
 7.0   Safety Assessments and Toxicity Monitoring ………………………………………….
 18
 
      
7.1 Serious Adverse Events 
 
 
7.2 Guidelines for Reporting Serious Adverse Events 
7.3 Guidelines for Processing IND Safety Reports 
8.0  Protocol Violations and Deviations ……………………………………………………  19
 
8.1 Definitions   
 
 
             8.2 Reporting Procedures 
 
 
9.0  Quality Assurance ……………………………………………………………………….  20 


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Version Date: October 2009 
        9.1 Ongoing Monitoring of Protocol Compliance 
 
            9.2 Evaluation of Participating Institution Performance 
 
            9.3 On-Site Auditing 
 
 
            9.4 Substandard Performance 
 
1.0
INTRODUCTION 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol.  
1.1
Purpose 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) Multi-
center protocol will comply with Federal regulations (21 CFR Part 11); Good Clinical Practice (GCP) 
Guidelines; and  Health Insurance Portability and Accountability Act (HIPAA) requirements in 
accordance with the CTEP Multi-center Guidelines.        
1.2
Multi-Center Data and Safety Monitoring Plan Components 
 
The Multi-Center Data and Safety Monitoring Plan includes the following components: 
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with Dana-
Farber/Harvard Cancer Center on a research  protocol where DF/HCC is the Lead Institution. 
Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates are not viewed as outside sites in 
this definition.
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, BIDMC, 
CH, BWH) will be the Lead Institution and will be responsible for the coordination, development, 


Page 5
Version Date: October 2009 
submission, and approval of a protocol as well as its subsequent amendments per the DFCI IRB 
and applicable regulatory guidelines (FDA, etc.).  
DF/HCC Contract Principal Investigator:  Investigator located at the Lead Institution who will 
be charged with the responsibility of the administration of the DF/HCC Project. This most often 
will be the Protocol Chair, but occasionally this may be the overall grant or contract holder, as 
applicable. 
Protocol Chair:  The Protocol Chair is the Principal Investigator for the DF/HCC protocol 
submitted as the Lead Institution.  For applicable protocols, the Protocol Chair will be the single 
liaison with any regulatory agencies (i.e. FDA, etc.).  
Participating Institution:  A participating institution is an institution that desires to collaborate 
with DF/HCC and commits to accruing participants to a DF/HCC protocol.  The participating 
institution acknowledges the Protocol Chair as having the ultimate authority and responsibility for 
the overall conduct of the study.    
Coordinating Center: The Lead Institution is the Coordinating Center for the DF/HCC Multi-
center Protocol. The Coordinating Center will provide the administrative support to the Protocol 
Chair in order that he/she may fulfill the responsibilities outlined in the DSMP and as specified in 
applicable regulatory guidelines. In addition to the Lead Institution, the Quality Assurance Office 
for Clinical Trials (QACT) provides support services to assist the Protocol Chair.  
2.0
GENERAL ROLES AND RESPONSIBILITIES 
In accordance with the CTEP Multi-center Guidelines, the Protocol Chair (DF/HCC Principal 
Investigator), Coordinating Center (Lead Institution or designee), and the Participating Institutions 
will all agree to the general responsibilities as follows (specific procedures for these general 
responsibilities are detailed in the DSMP): 
2.1.1
Protocol Chair (DF/HCC Principal Investigator) 
The Protocol Chair, Jochen Lorch MD, MSc, will accept responsibility for all aspects of the 
Multi-Center Data and Safety Monitoring Plan to: 
x
Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.    
x
Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the protocol. 
x
Assure all participating institutions are using the correct version of the protocol. 


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Version Date: October 2009 
x
Monitor progress and overall conduct of the study at all participating institutions.  
x
Ensure all DFCI IRB, DF/HCC and other applicable (i.e. FDA) reporting requirements are 
met.  
x
Review data and maintain timely submission of data for study analysis.  
x
Act as the single liaison with FDA (sponsor-investigator IND trials), as applicable. 
x
Identify participating institutions and obtain accrual commitments . The title page must 
include the names and contact information for all participating institutions that perform the 
function of recruiting, enrolling, and treating participants for the protocol. The Coordinating 
Center (Lead Institution or designee) must be designated on the title page.  
    2.2   Coordinating Center (Lead Institution) 
The Coordinating Center is the DF/HCC Lead Institution’s study team or designee (i.e Medical 
Monitor, Clinical Research Organization). The DF/HCC Lead Institution Dana-Farber Cancer 
Institute will ensure that all participating sites within the Multi-Center Protocol demonstrate their 
intent and capability of complying with Federal Regulations, GCPs and Health Insurance 
Portability and Accountability Act (HIPAA) requirements.   To assist the Protocol Chair in 
meeting his/her responsibilities as required by the DSMP, the DF/HCC Lead Institution’s study 
team or designee will assume the following general responsibilities: 
x
Assist in protocol review. 
x
Maintain copies of Institutional Review Board (IRB) approvals from all participating 
institutions. 
x
Maintain FDA correspondence, as applicable. 
x
Maintain updated roster of participants.  
x
Verify eligibility. 
x
Verify response. 
x
Collect data on protocol specific CRFs. 
x
Prepare all submitted data for review by the Protocol Chair. 
x
Maintain documentation of Serious Adverse Event (SAE) reports submitted by Participating 
Institutions and submit to Protocol Chair for timely review.   
x
Distribute external Serious Adverse Event safety reports.  
x
Monitor and audit Participating Institutions either by on-site inspection of selected participant 
records and/or with source documents and research records submitted to the Lead Institution.  
In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical Trials 
provides the following support services to assist the Protocol Chair: 
x
Develop protocol specific case report forms (CRF/eCRFs). 
x
QA/QC data of protocol specific CRFs.  


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Version Date: October 2009 
x
Provide Central Participant Registration. 
x
Confirm eligibility and consent.  
x
Provide auditing services (funding and QACT approval required). 
    2.3   Participating Institution 
The Participating Institution(s) will be identified on the title page for each protocol.   In addition,
each participating institution will provide to the Lead Institution or designee a list of the key 
personnel assigned to the role for oversight of data management at their site. All sites must have 
office space, office equipment, and internet access that meet HIPAA standards. 
The general responsibilities for each participating institution are as follows: 
x
Commit to accrual to the Lead Institution’s (DF/HCC) protocol. 
x
Submit protocol and/or amendments to their local IRB. 
x
Update Coordinating Center (Lead Institution or designee) with research staff changes on     
a timely basis. 
x
Register participants through the QACT.  
x
Submit source documents, research records, and CRFs per protocol specific                           
submission guidelines to the Coordinating Center (Lead Institution or designee).  
x
Submit Serious Adverse Event reports to local IRB and directly to the Coordinating  
 
Center (Lead Institution or designee). Submit deviations and violations to local IRB and the 
Coordinating Center (Lead Institution or designee). 
x
For protocols using investigational agents, the participating institution will                
         order their own investigational agents regardless of the supplier (i.e. pharmaceutical 
company). 
3.0
DF/HCC QUALITY AS SURANCE OFFICE FOR CLINICAL TRIALS 
The DF/HCC QACT is a unit that has been developed to computerize, manage, and monitor data for 
DF/HCC trials.  The DF/HCC QACT is located administratively in the office of the Senior Vice 
President for Clinical Research, at Dana-Farber Cancer Institute.  The QACT uses DF/HCC 
computerized institutional databases for participant registrations and for the management of trial data 
as well as a set of quality assurance programs designed to monitor DF/HCC trials.  
3.1
Organizational Structure 
The DF/HCC Quality Assurance Office for Clinical Trials administrative structure consists of: 


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Version Date: October 2009 
DF/HCC Quality Assurance Officer for Clinical Trials: Oversees the functions of the 
DF/HCC QACT. 
QACT Assistant Director for Data: Provides direct oversight to the QACT Data Analysts 
assigned to CRF design, data collection and computerization for DF/HCC trials.  
The DF/HCC QACT Data Analysts will be assigned on a protocol by protocol basis. Each 
protocol’s data analyst is responsible for database management, data entry, data quality 
assurance, and protocol specific correspondence related to the collection and quality assurance of 
data. 
QACT Assistant Director for Monitoring: Provides direct oversight to the QACT Protocol 
Registrars and Clinical Research Auditors. 
The DF/HCC Protocol Registrars are responsible for the confirmation of each participant’s 
eligibility and consent prior to protocol registration.
If funded and QACT approved, the DF/HCC Clinical Research Auditors may assist the Lead 
Institution in their auditing responsibilities for multi-center trials. The QACT auditor is 
responsible for systematically evaluating participant safety, protocol compliance, institutional 
SOPs, ICH GCP and Federal regulation compliance, data accuracy and investigational drug 
handling to assure a high standard of quality for DF/HCC trials. 
4.0 PROTOCOL DEVELOPMENT 
4.1 Activation of a Protocol 
The Protocol Chair is responsible for the coordination, development, and approval of the protocol 
as well as its subsequent amendments, and reporting SAEs, violations and deviations per DFCI 
IRB guidelines and if applicable FDA Guidelines.  Further, the Protocol Chair will be the single 
liaison with the FDA as applicable. 
To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards: 
x
Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the 
protocol as an appendix. 
x
Identify participating institutions and obtain accrual commitments. The title page must 
include the names and contact information for all participating institutions that 


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Version Date: October 2009 
perform the function of recruiting, enrolling, and treating participants for the protocol. 
The Coordinating Center (Lead Institution or designee) must be designated on the title 
page.  
x
Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the Protocol Chair. 
x
Ensure that there is only one version of the Protocol and that all Participating 
Institutions use the correct version.  
x
Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the Participating Institutions.  
4.2
Coordinating Center Support Function 
The DF/HCC Lead Institution’s study staff or designee will provide administrative and clerical 
support to the Protocol Chair for the development and distribution of the protocol.  
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee include: 
x
Review of the protocol and consent to check for logistics, spelling, and consistency.  
Provide the Protocol Chair a list of queries related to any inconsistencies. 
x
Provide necessary administrative sections, including paragraphs related to 
registration logistics, data management schedules, and multi-center guidelines.  
x
Maintenance of contact list of all participating institutions in the DF/HCC Multi-
center Protocol and the distribution of updates to the sites as needed.  
x
Derivation of the study calendar, if applicable. 
x
 Assistance in preparation and maintenance of case report forms. Conduct regular 
communications with all participating sites (conference call, emails, etc) Maintain 
documentation of all communications.  
5.0 PROTOCOL MANAGEMENT 
The Coordinating Center (DFCI) is responsible for assuring that each Participating Institution in the 
DF/HCC Multi-center Protocol has the appropriate assurance on file with the Office of Human 
Research Protection (OHRP).  Additionally, the Lead Institution or designee must maintain copies of 
all IRB approvals, for each participating institution.
5.1
Protocol Distribution 
The Coordinating Center (DFCI) will distribute the final approved protocol and any subsequent 


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Version Date: October 2009 
amended protocols to all Participating Institutions.    
5.2
Protocol Revisions and Closures 
The participating institutions will receive phone, fax, mail or e-mail notification of protocol 
revisions from the Lead Institution or designee.  It is the individual participating institution’s 
responsibility to notify its IRB of these revisions. 
Non life-threatening revisions: Participating institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Lead Institution or designee. 
Non-life-threatening protocol revisions should be IRB approved and implemented within 90 days 
from receipt of the notification.
Revisions for life-threatening Causes: Participating institutions will receive telephone 
notification from the Lead Institution or designee concerning protocol revisions required to protect 
lives with follow-up by fax, mail or e-mail.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval 
Protocol Closures and Temporary Holds: Participating institutions will receive fax, e-mail, or 
phone notification of protocol closures and temporary holds, with follow-up by mail from the 
Lead Institution or designee. Closures and holds will be effective immediately.  In addition, the 
Lead Institution or designee will update the Participating institutions on an ongoing basis about 
protocol accrual data so that they will be aware of imminent protocol closures. 
5.3 Informed Consent Requirements 
The Principal Investigator (PI) at each participating site will identify the physician members of 
the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. It is DF/HCC policy that Nurses and Fellows cannot obtain consent to greater than 
minimal risk trials.   
5.4 IRB Documentation 
The following must be on file with the DF/HCC Lead Institution or designee prior to participant 
registration: 
x
Approval Letter of the institution's IRB (An Expedited IRB first approval is NOT 
acceptable)
x
IRB approval for all amendments 


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Version Date: October 2009 
It is the individual institution's responsibility to notify its IRB of protocol revisions.  
Participating institutions will have 90 days from receipt to provide the DF/HCC Lead Institution 
or designee their IRB approval for Major Amendments to a protocol.    
DF/HCC defines a Major Amendment as: A substantive change in the study which may 
increase or decrease the risk to study participants.  Major revisions require full IRB approval.  
The following criteria are examples of revisions to a protocol that are considered to be major 
amendments:  
x
Change of eligibility (inclusion/exclusion) criteria 
x
Change in design of protocol 
x
Change in statistical section 
x
Change in sample size/accrual (e.g., doubling the sample size) 
x
Change in informed consent 
x
Change of estimated dropout rate 
x
Change of treatment or intervention 
x
Change of device 
x
Change in primary objective evaluation process 
5.5 IRB Re-Approval 
Annual IRB re-approval from the Participating institution is required in order to register 
participants onto a protocol.  There is no grace period for annual re-approvals.
Protocol registrations will not be completed if a re-approval letter is not received by the DF/HCC 
Lead Institution or designee from the Participating Institutions on or before the anniversary of the 
previous approval date.   
5.6 Participant Confidentiality and Authorization Statement 
The Health Insurance Portability and Accountability Act of 1996 contains,  as one of its six major 
components, the requirement to create privacy standards for health care information that is used 
or disclosed in the course of treatment, payment or health care operations.  The original Privacy 
Rule, as it has come to be known, was published in December 2000.  The Final Rule was 
published on August 14, 2002, which has modified the privacy rule in significant ways vis-à-vis 
research. 
In order for covered entities to use or disclose protected health information during the course of a 
DF/HCC Multi-Center Protocol the study participant must sign an Authorization.  This 
Authorization may or may not be separate from the Informed Consent.  The DF/HCC Multi-


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Version Date: October 2009 
Center Protocol, with the approval from the DFCI IRB, will provide an Informed Consent 
template, which covered entities (DF/HCC Multi-Center Protocol participating institutions) must 
use.  
The DF/HCC Multi-Center Protocol will use all efforts to limit its use of protected health 
information in its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per National Cancer Institute requirements. These are the primary 
reasons why DF/HCC has chosen to use Authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements.   
5.7 Participant Registration and Randomization  
To register a participant, the following documents should be completed by the DF/HCC Multi-
Center Protocol participating site and faxed to or e-mailed to the research manager at the Lead 
Institution: 
x
Copy of required laboratory tests (coagulation test, hematology and blood chemistry, 
urinalysis, free T4, TSH, calcitonin/CEA (only MTC subjects), thyroglobulin/anti-
thyroglobulin antibodies (only DTC subjects), and pregnancy test)
x
Signed informed consent form 
x
HIPAA authorization form (if separate from the informed consent document)
x
Other appropriate forms (e.g., Eligibility Screening Worksheet/Registration form, 
source documents confirming eligibility (pathology reports, radiology reports showing 
progression within6 months per RECIST criteria, treatment summary forms)) 
The research DF/HCC Multi-center Protocol participating site will then callor e-mail the Lead 
Institution or designee to verify eligibility. To complete the registration process, the Lead 
Institution or designee will: 
x
Verify the patient meets all eligibility criteria through source documentation provided 
by external site.  
x
Register the participant on the study with the DF/HCC Quality Assurance Office        
      for Clinical Trials (QACT).
x
Fax or e-mail the participant case number, and if applicable the dose treatment level, to 
the participating site 
x
Call the research nurse or data manager at the participating site and verbally confirm
registration.
Please fax all registrations to the research manager, Brian Davis, at the Lead Institution. The 
fax number is 617-582-7876. If you have any questions, please call 617-632-2503.
5.8 DF/HCC Multi-center Protocol Case Number 


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Version Date: October 2009 
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five digit protocol case number.  This number is unique to the participant on this trial 
and must be used for QACT CRF/eCRF completion and written on all data and QACT 
correspondence for the participant.
5.9 D
F/HCC Multi-center Protocol Registration Policy 
5.9.1 Initiation of Therapy: Participants must be registered with the DF/HCC QACT before 
receiving treatment.  Treatment may not be initiated until the site receives a faxed or e-
mailed copy of the participant’s Registration Confirmation memo from the DF/HCC 
QACT. Therapy must be initiated per protocol guidelines.  The Protocol Chair and 
DFCI IRB must be notified of any exceptions to this policy.
5.9.2 Eligibility Exceptions: The DF/HCC QACT will make no exceptions to the eligibility 
requirements for a protocol without DFCI IRB approval. The DF/HCC QACT 
requires each institution to fully comply with this requirement. 
5.9.3 Verification of Registration, Dose Levels, and Arm Designation: A registration 
confirmation memo for participants registered to DF/HCC Multi-Center Protocol will 
be faxed or emailed to the registering institution within one working day of the 
registration. Treatment may not be initiated until the site receives a faxed or e-mailed
copy of the registration confirmation memo.  
5.9.4 Confidentiality: All documents, investigative reports, or information relating to the 
participant are strictly confidential. Any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Lead Institution or 
designee must have the participant’s full name & social security number “blacked out” 
and the assigned DF/HCC QACT case number and protocol number written in (with 
the exception of the signed informed consent document). Participant initials may only 
be included or retained for cross verification of identification. 
5.10  Schedule of Data Submission 
The DF/HCC QACT develops a set of either paper or electronic case report forms, 
(CRF/eCRFs) for use with the DF/HCC Multi-Center Protocol.  QACT provides a web based 
training for eCRF users.  These forms are designed to collect data for each study. The schedule 
for submission of case report forms to the DF/HCC QACT is generally specified in each 
protocol. When not specified in the protocol, the DF/HCC QACT will require the forms to be 
submitted as follows: 
x
For on treatment and follow-up forms: Enter data into eCRF system within 10 days of 


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Version Date: October 2009 
visit date. 
x
For baseline and day 1 required data: Enter data into eCRF system within 2 weeks after 
registration. 
Note: It is necessary to send only ONE copy of all paper Case Report Forms, if applicable. 
5.10.1  Eligibility Checklist 
Purpose - Outlines protocol-specific eligibility criteria and includes the following:
Participant Demographics (address, zip code, sex, race, ethnicity, initials, date of birth)
1) Parameters for eligibility
2) Parameters for exclusion
3) Parameters for stratifications
If a time frame is not specified in the protocol, tests must be completed as follows: 
x
Lab tests required for eligibility must be completed within 14 days prior to study 
enrollment by the QACT.
x
For protocols requiring measurable disease, lab baseline measurements must be 
completed within 14 days prior to study enrollment by the QACT. Examples: flow 
cytometry, HLA typing, fluid cytology, tumor markers and hormones (CEA, CA-
27-29, CA-125).
x
Non-lab tests required for eligibility must be performed within 30 days prior to 
study entry. Example: radiological scans
x
For bone marrow transplant (BMT) protocols and non-protocol treatment plans, 
eligibility tests must be completed within 42 days prior to enrollment by the QACT. 
 The extended period of time is allowed to facilitate insurance approval while 
ensuring participant safety. 
Schedule for Submission - Completed prior to participant registration. The                     
  Informed Consent/ Participant Authorization for the Release of Personal    
 Health Information should be submitted with the Eligibility Checklist at the time               
  
of registration. 
5.10.2 On-study Form 
Purpose - documents the following items:
x
Demographic data
x
Prior therapy
x
Past medical and surgical history
x
Description of participant’s physical status at protocol registration


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Version Date: October 2009 
x
Disease site specific data
Schedule for Submission - Submitted to DF/HCC QACT within 14 days after 
registration.
5.10.3 Baseline Assessment Form
Purpose – Documents objective and subjective disease status as defined by the protocol.
Records all pertinent radiographic and laboratory measurements of disease utilized in 
determining response evaluations.  
Schedule of Submission – Submitted within 14 days after registration. 
5.10.4  Treatment Form 
Purpose - Records the following information related to the time the participant receives 
protocol treatment: 
x Participant, Protocol, Affiliate information
x Protocol treatment and supportive therapy per treatment cycle 
x Protocol specific laboratory values per treatment cycle 
x All medications other than protocol chemotherapy agents used to treat 
concomitant    diagnoses, if applicable 
x Toxicities or adverse events experienced since last visit (based on monthly visit 
cycle) 
Schedule for Submission – Submitted within 10 days after the last day of the cycle.   
5.10.5Adverse Event Report Form  
Purpose – Documents adverse events that occur while the participant is receiving 
treatment and for up to 30 days after the last dose of treatment. All adverse events are 
to be graded by number using the toxicity grading scale required by the protocol. This 
form is not for IRB submission, but for recording the AE in the research database.
Schedule for Submission – Submitted within 10 days after the last day of the cycle. 
5.10.6 Response Assessment Form
Purpose – Documents objective and subjective response as defined by the protocol. 


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Version Date: October 2009 
Records all pertinent radiographic and laboratory measurements of disease utilized in 
determining response evaluations.  
Schedule of Submission – Submitted within 10 days after the completion of  
the cycle required for response evaluation.  
5.10.7    Off Treatment/Off Study Form
Purpose - The Off Treatment/Off Study Form is submitted when the participant is  
removed from the study or has completed all protocol treatment.  Note: If the 
participant dies while on protocol, the Off Study Form is the last form submitted. 
Schedule of Submission – Submitted within 14 days after completing treatment or 
taken off study for any reason. 
5.10.8    Follow up/Survival Form
Purpose - Summarizes participant status at a given point in time after being removed 
from treatment.  
Schedule of Submission – Submitted within 14 days after the protocol defined follow 
up visit date or call.    
 5.11 Data Form Review 
When data forms arrive at the DF/HCC QACT, they are reviewed for:
Timeliness:  
Did the form arrive on time as specified in the protocol?
 
 
 
 
Completeness:  
Is all the information provided as required per protocol?
Participant Eligibility:
Does the participant meet the eligibility requirements for the study based on the demographic 
data, lab values and measurements provided?
Stratification:  
Are the stratification parameters consistent with what was given at the time of registration?


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Version Date: October 2009 
Protocol Treatment Compliance:
Are the body surface area (BSA) and drug dosage calculations correct?  The dose must be within 
10% of the calculated protocol dose.
Adverse Events (Toxicities):  
Did the participant experience adverse events (toxicities or side effects) associated with the 
treatment? Was the treatment delayed due to the adverse event? What was the most severe 
degree of toxicity experienced by the participant?
Notations concerning adverse events will address relationship to protocol treatment for each 
adverse event grade.  All adverse events encountered during the study will be evaluated 
according to the NCI Common Toxicity Criteria assigned to the protocol and all adverse events 
must be noted on the participant's Adverse Event (Toxicity) Forms. 
Response:
Did the participant achieve a response?  What level of response did they achieve?  On what date 
did the participant achieve the response and how was the response determined? 
Response criteria are defined in the protocol.  A tumor assessment must be performed prior to 
the start of treatment and while the participant is on treatment as specified by the protocol.   
Objective responses must have documentation such as physical measurements, x-rays, scans, or 
laboratory tests.   
A subjective response is one that is perceived by the participant, such as reduction in pain, or 
improved appetite. 
5.12 Missing and Deficient Memorandum
Data submissions are monitored for timeliness and completeness of submission. Participating 
institutions are notified of their data submission delinquencies in accordance with the following 
policies and procedures: 
Incomplete or Questionable Data
If study forms are received with missing or questionable data, the submitting institution will 
receive a written query from the DF/HCC QACT Data Analyst.  Responses to the query 
should be completed and returned within 14 days.  Responses may be returned on the written 
query or on an amended case report form. In both instances the query must be attached to the 
specific data being re-submitted in response.   


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Version Date: October 2009 
Missing Forms
If study forms are not submitted on schedule, the participating institution will receive a Missing 
Form Report from the DF/HCC QACT noting the missing forms.  These reports are compiled 
by the DF/HCC QACT and distributed a minimum of three times a year.  
6.0
REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agent is generally specified in the protocol.  
Participating sites should order their own agent regardless of the supplier (Novartis).  
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure that the 
agent can be ordered once the protocol is approved by the local IRB. If the agent is investigational, 
ensure that the pharmacy will be able to receive and store the agent. The local IRB should be kept 
informed of who will supply the agent (Novartis) so that any regulatory responsibilities can be 
met in a timely fashion.  
7.0  
SAFETY ASSESSMENTS AND TOXICITY MONITORING 
All participants receiving investigational agents will be evaluated for safety.   The safety 
parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by participants. 
 All toxicities encountered during the study will be evaluated according to the NCI criteria 
(CTCAE v3.0) assigned to the protocol and recorded prior to each course of therapy.  Life-
threatening toxicities should be reported immediately to the Protocol Chair and Institutional 
Review Board (IRB).  
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
7.1 Serious Adverse Events 
A serious adverse event (SAE) is any adverse drug experience at any dose that results  in any of 
the following outcomes: death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious 


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Version Date: October 2009 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions in a participant who has never 
had seizure activity in the past that do not result in inpatient hospitalization, or the 
development of drug dependency or abuse. 
Novartis guidelines on serious adverse events 
Information about all serious adverse events will be collected and recorded. A serious adverse event is 
an undesirable sign, symptom or medical condition which: 
x
      is fatal or life-threatening 
x
results in persistent or significant disability/incapacity 
x
constitutes a congenital anomaly/birth defect 
x
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
x
routine treatment or monitoring of the studied indication, not associated with any               
deterioration in condition (specify what this includes) 
x
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 
x
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
x
social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
x
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 
7.2 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is delineated 
in Section 3 of the protocol: 
In addition, the Participating Institutions must report the serious adverse events to the Protocol 
Chair and the Coordinating Center (Lead Institution) at the time SAEs are submitted.   
Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within 24 business hours of learning of the occurrence. In the event that the 
participating investigator does not become aware of the serious adverse event immediately (e.g., 


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Version Date: October 2009 
participant sought treatment elsewhere), the participating investigator is to report the event 
within 24 hours after learning of it and document the time of his or her first awareness of the 
adverse event. Report serious adverse events by telephone or email to: 
DF/HCC Overall Principal Investigator: Jochen Lorch, MD, MS 
Telephone: 617-632-3090 
Email: Jochen_Lorch@dfci.harvard.edu 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. The Lead Institution will maintain 
documentation of all Adverse Event Reporting and be responsible for communicating all SAEs to 
all Participating sites.
Novartis and FDA instructions for rapid notification of serious adverse events 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, and 
Novartis Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E). 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form). 3500A forms should be faxed to the FDA at 301-796-9845. For  any questions, 
you can contact the FDA at 301-796-4058.  
All even ts mu st b e r eported, b y FAX (888-299-4565), t o N ovartis P harmaceuticals CS &E 
Department within 24 h ours of l earning of i ts occurrence. This includes serious, related, labeled 
(expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol therapy must be reported within 
5 working days. 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the period in 
which the study protocol interferes with the standard medical treatment given to a patient (e.g. 
treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant 
medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be reported 
if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 


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Version Date: October 2009 
7.3 Guidelines for Processing IND Safety Reports  
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. In compliance with these FDA 
regulations, the Protocol Chair is responsible for reviewing all IND Safety Reports and forwarding 
the IND Safety Reports to the Participating Institutions.  The investigator’s are to file a copy 
with their protocol file and send a copy to their IRB according to their local IRB’s policies and 
procedures. 
8.0 PROTOCOL VIOLATIONS AND DEVIATIONS 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or “protocol 
deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the DFCI IRB, the 
definitions for protocol violation and deviation as described by the DFCI IRB will be applied for 
reporting purposes for all institutions participating in the DF/HCC Multi-center Protocol.  
8.1 Definitions 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol. 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g., 
enrollment of a subject who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
8.2 Reporting Procedures 
The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record to describe all protocol exceptions, deviations and violations.  
The Protocol Chair will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines.  
Participating Institutions: Protocol deviations require prospective approval from DFCI IRB. 
The Participating institution must submit the deviation request to the Protocol Chair or 
designee, who will submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the 
deviation should be submitted to the participating site’s own IRB, per its institutional policy. 


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Version Date: October 2009 
A copy of the participating institution’s IRB report and determination will be forwarded to the 
DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail within 10 business days 
after the original submission.  
All protocol violations must be sent to the DF/HCC Lead Institution Protocol Chair or designee 
in a timely manner.  
Coordinating Center:  Upon receipt of the violation/deviation report from the participating 
institution, the DF/HCC Lead Institution or designee will submit the report to the Protocol 
Chair for review. Subsequently, the participating institution’s IRB violation/deviation report 
will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
9.0 QUALITY ASSURANCE 
The quality assurance process for a clinical trial research study requires verification of protocol 
compliance and data accuracy. As the Coordinating Center, the DF/HCC Lead Institution or 
designee with the aid of the QACT provides quality assurance oversight for the DF/HCC Multi-
center Protocol.
9.1
Ongoing Monitoring of Protocol Compliance
All data submitted to the DF/HCC QACT will be monitored for timeliness of submission,
completeness, and adherence to protocol requirements.  Monitoring will begin at the time of 
participant registration and will continue during protocol performance and completion.  The Lead 
Institution or designee and if applicable QACT Data Analysts assigned to the Protocol will 
perform the ongoing protocol compliance monitoring with the support of the participating 
institution’s Coordinators, the Principal Investigators, and the Protocol Chair.  
9.2 Evaluation of Participating Institution Performance 
9.2.1  Eligibility Checklist: Eligibility criteria are checked on a protocol-specific eligibility 
checklist and faxed to the DF/HCC QACT prior to registration on protocol.  The checklist and 
informed consent document are reviewed by a DF/HCC QACT Protocol Registrar before the 
participant can be registered on a protocol.  The DF/HCC QACT cannot make exceptions to the 
eligibility requirements. 
9.2.5  Accrual of Eligible Participants: Annual accrual rates for eligible participants enrolled 
onto therapeutic clinical trials is calculated for each institution. Institutions are expected to 
maintain the minimum annual average accrual as defined by the protocol grant or contract. 


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Version Date: October 2009 
9.3 On-Site Auditing
9.3.1.2 DF/HCC Sponsored Trials
 Sites are expected to notify DFCI of all deviations and violations from the required data set based 
on the DFCI OHRS guidelines. The site is expected to comply with DF/HCC Lead Institution 
regulatory submission guidelines and should include IRB documents, CV’s, case report forms, and 
all institutional licenses and documents.  We will virtually monitor the external site monthly for 
source verification of case report forms and all regulatory documents. Some of these documents 
will include eligibility source documents (radiology reports proving progression, lab values, 
performance status, pathology reports, etc), prior treatment reports, bimonthly adverse event 
(toxicity) reports, laboratory hematology and chemistry reports (baseline, bimonthly, and end of 
treatment), serious adverse events supplementary documents, tumor measurement reports 
(baseline and bimonthly), and documentation of progression (if applicable).  
The participating institution may be subject to on-site monitoring conducted by the DF/HCC 
Lead Institution or designee. Sites will be monitored for compliance to the data collection 
guidelines found in the protocol under the section titled, “3.4 Visit Schedule and Assessments.” 
Participating sites should have source documentation for all data collected. 
9.3.2 Participating Institution: It is the participating institution’s responsibility to notify the 
DF/HCC Lead Institution or designee of all scheduled audit dates (internal or NCI) and re-audit 
dates (if applicable), which involve the DF/HCC Multi-Center Protocol. All institutions will
forward a copy of final audit and/or re-audit reports and corrective action plans (if applicable) to the 
DF/HCC Lead Institution or designee within 12 weeks after the audit date.  
9.3.3 Coordinating Center (Lead Institution or designee): The Protocol Chair will review all 
DF/HCC Multi-Center Protocol Final Audit reports and corrective action plans if applicable. The 
Lead Institution or designee must forward these reports to the DF/HCC QACT per DF/HCC 
policy for review by the DF/HCC Audit Committee. Based upon the audit assessments the 
DF/HCC Audit Committee could accept or conditionally accept the audit rating and final report. 
Conditional approval could require the Protocol Chair to implement recommendations or require 
further follow-up.  For unacceptable audits, the Audit Committee would forward the final audit 
report and corrective action plan to the DFCI IRB as applicable.
9.4 Sub-Standard Performance
 
 
The Protocol Chair and DFCI IRB are charged with considering the totality of an institution’s 
performance in considering institutional participation in the DF/HCC Multi-Center Protocol. 


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Version Date: October 2009 
9.4.1 Corrective Actions: Institutions that fail to meet the performance goals of accrual, 
submission of timely accurate data, and adherence to protocol requirements will be recommended 
for a six- month probation period. Such institutions must respond with a corrective action plan and 
must demonstrate during the probation period that deficiencies have been corrected, as evidenced by 
the improved performance measures. Institutions that fail to demonstrate significant improvement 
will be considered by the Protocol Chair for revocation of participation.


Appendix E: Correlative Studies Shipping Guidelines and 
Submission Form 
Submission of specimens 
1. Paraffin-embedded tissue blocks: In general, this is the preferred specimen and 
is especially important to submit in cases where tissues have been in formalin for 
a significant time.  Prolonged fixation (>2 weeks) may interfere with some 
immunohistochemical and molecular diagnostic assays.
2. Wet tissue:  If available, we also highly recommend that unprocessed tissues in 
10% neutral buffered formalin be submitted in addition to paraffin blocks.   
3. Unstained slides: Although not optimal, it may be possible to utilize unstained 
sections cut at 3-5 microns (40 slides per block) if paraffin blocks are unavailable.  
4. Fresh-frozen tissue: (sent separately on dry ice)
Obtaining Biopisies 
For formalin fixed biopsy: Immediately place biopsy into biopsy bag and then into the 
histocassette. Place histocassette into formalin (completely submerged). 24 hours+ 2 hours later, 
transfer histocassette containing the biopsy fixed in formalin and ship in vial with 30ml 70% 
ethanol. Formalin-fixed tissues should be thin (~1/4 inch) and fixed in 9 parts 10% buffered 
formalin to 1 part tissue. 
For fresh frozen tumor biopsy: Only in cases where a reasonable size biopsy (e.g. excisional 
biopsy, 5 mm punch, or 14G) could be collected for formalin fixation, a fresh frozen biopsy can be 
collected. Place tissue in cyrotube and let slide to bottom. Transfer tube into liquid nitrogen, 
Remove tube from liquid nitrogen with pair of tweezers and transport to freezer in liquid nitrogen 
or dry ice, and place in tube in a freezer of -70°C or below.  
General Guidelines for Shipping Pathology Specimens 
Packaging and Shipping Guidelines 
Room Temperature 
Frozen (dry-ice ) 
Formalin-fixed wet tissues. 
Formalin-fixed paraffin-embedded blocks.* 
Glass slides with sections from paraffin-embedded blocks. 
Fresh frozen tissue. 
Formalin Fixed Tissues:
• To avoid shipping large quantities of formalin, you may fix an appropriately sized sample 
for 24 hours, then ship with a smaller quantity of formalin; please indicate that the sample 
has been fully fixed prior to shipping. 
• Avoid putting large samples in narrow-mouthed containers; once these tissues fix, they can 
be difficult to retrieve.
• DO NOT ship formalin-fixed tissues and cytology or hematology slides in the same 
container. Formalin fumes can compromise these results.  


• Formalin is a noxious volatile and toxic chemical and should be shipped with appropriate 
precautions.
• Submit specimens in leak-proof containers.  
• Surround this container with enough absorbent material to absorb any possible leakage.  
• Containers and absorbent material should then be enclosed in a second leak proof container 
(e.g., sealed plastic bag).  
• Samples can then be enclosed in a sturdy and sealed container (cardboard box, styrofoam, 
plastic) for shipping.  
• Enclose the completed submission form in a separate sealed plastic bag, and place them 
between the inner sample container and the outer shipping container.  
• A completed submission form must accompany the sample. 
• Please clearly label each container with the tissue, number of sample (i.e. slides, 
blocks, etc), and patient initials and ID number.  
Unfixed Fresh Tissue (Only large specimens that are impractical for formalin fixation 
should be submitted fresh.):
• Arrange for a delivery time to our facility, Monday through Friday only by emailing Dr. 
Lorch or calling the study manager at 617-632-2503. 
• Call our study team at (617) 582-8039 when the specimen is on its way to our facility.  
• Double-bag the specimen in leak proof Bio-Hazard bags.
• Pack the specimen with sufficient, sealed ice packs in another, leak proof bag.  
• Samples can then be enclosed in a sturdy and sealed container (cardboard box, styrofoam, 
plastic) for shipping.  
• Enclose the completed submission form in a separate sealed plastic bag, and place them 
between the inner sample container and the outer shipping container.  
• A completed submission form must accompany the sample. 
• Please clearly label each container with the tissue, number of sample (i.e. slides, 
blocks, etc), and patient initials and ID number.
Shipping Considerations: 
x U.S. Federal holidays should be taken into consideration before mailing the packages.  
Exceptions can be made on urgent cases with prior approval.  
x Specific regulations for packaging, labeling, and shipping may be found at 
http://www.cdc.gov/ncidod/srp/specimens/shipping-packing.html, and at 
http://www.cdc.gov/od/ohs/biosfty/shipdir.htm
x Please provide us with the shipper’s package tracking number(s) on the submission form. 
During the warmer months (June-Aug), in order to prevent the melting of paraffin-embedded 
tissue blocks during transit, it is advisable to ship the block(s) with a frozen gel ice-pack. 
x When shipping frozen specimens from long distances, it is best to use a combination of 
dry-ice and frozen gel ice-packs.  The gel ice-packs will remain frozen for a day or two after 
the dry-ice has dissipated. 
Required supporting electronic or hard-copy documentation: 
1. Copy of the preliminary or final pathology report


2. Copy of any pertinent laboratory reports (including rapid antigen, culture, and 
PCR test results)  
3. Submission form including the full name, title, complete mailing address, phone 
and fax numbers of the submitter.    
Shipping Address:
C/O Tyler Haddad 
Dr. Jochen Lorch
Dana-Farber Cancer Institute 
450 Brookline Avenue, LG 1B 
Boston, MA 02215 
Contact Information:
Principal Investigator: Dr. Jochen Lorch, Jochen_Lorch@dfci.harvard.edu, 617-632-3090 
Clinical Research Nurses: Pamela Rothe, RN, 617-632-6817 
Clinical Research Manager: Farzana Masood, Farzana_Masood@dfci.harvard.edu,
Phone: 617-632-6725, Fax: 617-582-7876 
Clinical Research Coordinator: Tyler Haddad, Tyler Haddad@dfci.harvard.edu,
Phone: 617-582-7323, Fax: 617-582-7876 
Clinical Scientists: Dr. Daniel Ruan, Department of Surgery, BWH,  
Druan@partners.org, 617-732-6830 
Dr. Jinyan Du, Broad Institute, Harvard University, 
Jinyan_Du@dfci.harvard.edu, 617-632-6688 
 
 
 
 


Correlative Studies Submission Form 
 
 
 
*MAIL SPECIMENS TO ADDRESS BELOW:  
C/O Tyler Haddad 
Dr. Jochen Lorch  
Dana-Farber Cancer Institute 
450 Brookline Avenue, LG 1B 
Boston, MA 02215 
(P) 617-582-8039 
(F) 617-582-7876 
**Please clearly label each container with the tissue, patient ID number, and date of 
birth.
**Please include the preliminary or final pathology report and any other pertinent 
laboratory reports with this submission form.  
 
 
SENDER’S INFORMATION 
DATE :____________________ 
Sender’s Name:_______________________________________________________________ 
Title:_________________________________________________________________________ 
Doctor’s Name:_______________________________________________________________ 
Address:______________________________________________________________________ 
City:_____________________________State______________________Zip______________  
Phone#:___________________________________Fax #:_____________________________  
E-mail Address:______________________________________________________________ 
 
PATIENT INFORMATION 
Initials and ID#:_______________________________________________________  
Type of Sample Sent (formalin fixed, fresh frozen, etc):________________________ 
Number of Sample sent (ie # of slides etc):_______________________________ 
Anatomic Location of lesion:____________________________________________ 
Tissue 
Submitted:______________________________________________________Date of 
Biopsy (if applicable):___________________________________________ 
 
SHIPPING INFORMATION 
Date Sent:_______________________ 
Shipping Company (Fedex, UPS, etc):__________________________________________ 
Mode of Shipping (Next day Air, etc):__________________________________________ 
Tracking Number:____________________________________________________________ 
 
 
If you have any questions, please contact Margaret Suda at 617-582-8039.