Clinical trial NCT00576680
Conditions: Pancreatic Neuroendocrine Tumor
Keywords: RAD001 temozolomide
Sponsor: Dana-Farber Cancer Institute
Start date: 2008-05-01; Completion date: 2019-03-29
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study will test the safety of RAD001 in combination with temozolomide.

Detailed description:
* Participants will take RAD001 by mouth daily. They will also take temozolomide by mouth daily for one week, followed by a one-week break period. This one-week on/one week off schedule for temozolomide will continue for the duration of the treatment.
* After the first month of treatment, there will be a 7-day observation period during which no study medication will be taken to observe for any side effects.
* During all treatment cycles (1 cycle is 28 days in length) participants will have a physical exam and will be asked questions about their general health and specific questions about any problems they may be experiencing. Initially, participants will come in every other week. At each of these visits, blood work will be taken to monitor the participants health.
* After every 2 months of treatment, participants will have a CT scan or MRI done to see how the medication is working.

Arms: arm 1: None
Interventions: intervention 1: RAD001 intervention 2: Temozolomide
Intervention descriptions: intervention 1: Given orally once a day intervention 2: Taken orally once a day for one week followed by a one-week break period

Protocol documents:
Prot_SAP_000.pdf: 
Phase I/II Study of RAD001 in Combination with Temozolomide
in Patients with Advanced Pancreatic Neuroendocrine Tumors
Protocol Version Date: 01/07/2019
Author(s):
Coordinating Center:
Participating Institutions:
Jennifer A. Chan, MD, MPH
Matthew H. Kulke, MD
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute/Brigham & Women’s Hospital
Overall Principal Investigator: Jennifer A. Chan MD, MPH
Massachusetts General Hospital
Site Principal Investigator: David Ryan, MD 


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Table of Contents
Table of Contents................................................................................................................2
List of abbreviations ...........................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Overview of pancreatic neuroendocrine tumors.....................................................7
1.2
Temozolomide........................................................................................................7
1.3
RAD001 (everolimus) ..........................................................................................10
1.3.1
Preclinical studies..................................................................................10
1.3.2
Clinical experience................................................................................11
2
Study objectives.................................................................................................................16
3
Investigational plan ...........................................................................................................16
3.1
Overall study design.............................................................................................16
3.2
Basic Design Characteristics ................................................................................16
3.3
Definition of dose limiting toxicity (DLT) and maximum tolerated dose 
(MTD)...................................................................................................................18
3.4
Study population...................................................................................................18
3.4.1
Patient population..................................................................................18
3.4.2
Inclusion and exclusion criteria ............Error! Bookmark not defined.
4
Treatment Program............................................................................................................21
4.1
Study Treatment ...................................................................................................21
4.2
Interruption or discontinuation of treatment.........................................................22
4.3
Monitoring of suspected toxicities .......................................................................22
4.4
Dose Modification................................................................................................22
4.4.1
RAD001 dose adjustments....................................................................22
4.4.2
Temozolomide dose adjustments..........................................................23
4.4.3
Dose reductions for hematologic toxicity .............................................24
4.4.4
Dose reductions for non-hematologic toxicity......................................24
4.4.5
Management of stomatitis/oral mucositis/mouth ulcers .......................26
4.4.6
Management of hyperlipidemia and hyperglycemia.............................26
4.4.7
Management of non-infectious pneumonitis.........................................27
4.5
Treatment Plan......................................................................................................28
4.5.1
Investigational therapy..........................................................................28
4.5.2
Concomitant therapy.............................................................................31
4.5.3
Prohibited medications..........................................................................32
4.5.4
Treatment compliance...........................................................................35


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5
Visit schedule and assessments .........................................................................................35
5.1
Visit schedule and assessments ............................................................................35
5.1.1
Pretreatment evaluation.........................................................................35
5.1.2
Evaluations during treatment ................................................................35
5.1.3
Post-treatment evaluation......................................................................36
6
Efficacy assessments .........................................................................................................38
6.1
Criteria for response .............................................................................................38
6.2
Guidelines for Evaluation of Measurable Disease ...............................................40
6.3
Confirmation Measurement/Duration of Response..............................................41
7
Safety assessments.............................................................................................................41
7.1
Adverse events......................................................................................................42
7.1.1
Serious adverse events ..........................................................................42
7.1.2
Novartis instructions for rapid notification of serious adverse 
events.....................................................................................................43
7.2
Pregnancies...........................................................................................................44
7.3
Evaluations ...........................................................................................................44
7.3.1
Hematology...........................................................................................44
7.3.2
Blood chemistry ....................................................................................44
7.3.3
Vital signs..............................................................................................44
7.3.4
Physical examination ............................................................................44
7.3.5
Performance status ................................................................................44
7.3.6
Drug levels and pharmacokinetic assessments .....................................45
8
Protocol amendments, or changes in study conduct..........................................................45
9
Data management ..............................................................................................................46
9.1
Data collection......................................................................................................46
10 Statistical methods.............................................................................................................46
10.1
Sample size and power calculation.......................................................................46
10.2
Statistical analysis.................................................................................................47
11 Registration Procedures.....................................................................................................47
11.1
General Guidelines for DF/HCC and DF/PCC Institutions..................................47
11.2
Registration Process for DF/HCC and DF/PCC Institutions ................................47
11.3
Registration Process for Other Participating Sites ...............................................48
12
Data and Safety Monitoring .............................................................................................48
12.1
Data Reporting......................................................................................................48
12.1.1
Method ..................................................................................................48
12.1.2
Data Submission....................................................................................48
12.2
Safety Meetings ....................................................................................................49


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12.3
Monitoring............................................................................................................49
13 References .........................................................................................................................50
14 Procedures and instructions...............................................................................................53
14.1
Publication of results ............................................................................................53
14.2
Disclosure and confidentiality..............................................................................53
14.3
Discontinuation of study.......................................................................................53
14.4
Ethics and Good Clinical Practice........................................................................53
14.4.1
Institutional Review Board/Independent Ethics Committee.................54
14.4.2
Informed consent...................................................................................54
14.4.3
Declaration of Helsinki .........................................................................54
Appendix A: Drug Diary
Appendix B: Dana Farber/Harvard Cancer Center Multi-Center Data Safety Monitoring Plan


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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
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
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


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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
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
Overview of pancreatic neuroendocrine tumors
Pancreatic neuroendocrine tumors comprise about 1-2% of pancreatic tumors (Barakat, 
Meeran, and Bloom, 2004).  The annual incidence of pancreatic neuroendocrine tumors is 
approximately 3.5 to 4 per million population.  At the time of diagnosis, many patients have 
disease that is either unresectable or metastatic.  In a study of 83 patients with pancreatic 
neuroendocrine tumor, median survival from the time of diagnosis was approximately 7.5 
years for all patients; among patients with liver metastases, median survival was 4 years 
(Tomassetti, et al, 2005).  In recent studies of patients receiving chemotherapy for pancreatic 
neuroendocrine tumors, the median survival has been 2 to 3 years. 
Patients with unresectable or metastatic neuroendocrine tumors currently have few treatment 
options. The efficacy of standard cytotoxic chemotherapy in the treatment of patients with 
metastatic neuroendocrine tumors has not been clearly established. In the 1980s and early 
1990s, regimens containing the combination of streptozocin and doxorubicin were considered 
standard based on a response rate of 69% and a survival benefit reported by Moertel et al 
(Moertel et al, 1992).  However, the high reported response rates in this study have been 
questioned and are likely the result of the use of non-standard response criteria. Two 
subsequent retrospective analyses of patients receiving this regimen reported objective 
radiologic response rates using modern response criteria of less than 10% (Cheng et al, 1999, 
McCollum et al, 2004). Furthermore, while various combinations of streptozocin, 5-
fluororuacil, doxorubicin, have been reported to result in tumor responses, these regimens 
have also been associated with significant toxicity. Only a single drug, streptozocin, is 
approved for use in pancreatic neuroendocrine tumors.  However, streptozocin-based therapy 
can be associated with significant hematologic and renal toxicity; its use in pancreatic 
neuroendocrine tumors, particularly in the first-line setting, is not universally accepted. Novel 
treatment strategies are therefore clearly needed for this disease.
1.2
Temozolomide
Dacarbazine (DTIC) has been evaluated as a potential alternative to streptozocin-based 
therapy in pancreatic endocrine tumors. One phase II study of DTIC in 50 patients with 
advanced pancreatic islet cell carcinoma reported an objective response rate of 
34%(Ramanathan, Cnaan et al. 2001). However, toxicity was a concern, with a significant 
proportion of patients developing nausea and/or vomiting.  DTIC is therefore rarely used 
currently as a treatment for neuroendocrine tumors.
Temozolomide, a cytotoxic alkylating agent, was specifically developed as an oral and less 
toxic alternative to DTIC(Stevens, Hickman et al. 1987). Temozolomide and dacarbazine 
appear to have identical mechanisms of action: both agents are metabolized to the active agent 
MTIC, an inhibitor of nucleoside incorporation. The cytotoxicity of MTIC is thought to be 


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primarily due to alkylation at the O6 position of guanine (Stevens, Hickman et al. 1987) with 
additional alkylation also occurring at the N7 and N3 positions.  Temozolomide does not 
require metabolic activation; it undergoes spontaneous chemical degradation to MTIC at 
physiologic pH. Temozolomide has demonstrated clinical antitumor activity and a relatively 
well-tolerated and acceptable safety profile in phase I and II trials in patients with a broad 
range of solid tumors (Hammond, Eckardt et al. 1999; Danson and Middleton 2001).
Temozolomide has been shown to be effective in prolonging progression-free survival in adult 
patients with recurrent high-grade gliomas, and has also demonstrated clinically meaningful 
activity in patients with anaplastic astrocytoma (van den Bent, Taphoorn et al. 2003; Chang, 
Prados et al. 2004).
Based on early evidence that dacarbazine has activity in neuroendocrine tumors, as well as the 
fact that thalidomide may contribute to antitumor activity through antiangiogeneic 
mechanisms, we recently explored a combination of temozolomide in combination with 
thalidomide (Kulke, Stuart et al. 2006). A total of 29 patients with metastatic carcinoid, 
pancreatic or pheochromocytoma neuroendocrine tumors were treated with temozolomide, 
administered at a dose of 150 mg/m2 for 7 days, followed by a 7-day rest, together with 
thalidomide administered at doses of 50–400 mg daily without interruption. Objective 
responses (by RECIST) were seen in 45% of the 11 patients with pancreatic neuroendocrine 
tumor.  The 29 enrolled patients received a median of 7.3 months of therapy (range 1-23 
months).  Neuropathy, a known toxicity of thalidomide, developed in 11 patients (38%). In six 
patients (21%), neuropathy persisted for more than 3 weeks despite withholding thalidomide
treatment, and resulted in treatment discontinuation. The median time to treatment 
discontinuation for neuropathy was 10.8 months (range, 7.7 to 11.5 months). Grade 2 or 3 
thrombocytopenia occurred in four patients (14%), resulting in their treatment discontinuation.
Other toxicities resulting in treatment discontinuation included rash (one patient), neutropenia 
(one patient), and infection (four patients).
A total of eleven patients developed infections while receiving study treatment. The infections 
included three opportunistic infections: one case of Pneumocystis carinii pneumonia, one case 
of disseminated varicella zoster virus, and one case of cutaneous herpes zoster limited to one 
dermatome. These three patients had all received more than 6 months of therapy and all 
developed grade 3 or grade 4 lymphopenia. Grade 3 to 4 lymphopenia developed in 69% of 
the patient population. Lymphopenia generally developed in the absence of significant 
leukopenia or neutropenia: grade 3 or 4 leukopenia developed in only four patients, and grade 
3 or 4 neutropenia occurred in only two patients during study treatment.  Based on the 
development 
of 
these 
opportunistic 
infections, 
prophylaxis 
with 
trimethoprim-
sulfamethoxasole was recommended for future patients receiving prolonged treatment courses 
with temozolomide. 
Results from a subsequent phase II study of temozolomide and bevacizumab in patients with 
metastatic neuroendocrine tumors further confirmed the activity of temozolomide-based 
therapy in pancreatic neuroendocrine tumors (Kulke, Stuart et al. 2006). A partial response to 


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therapy was observed in 24% of patients with pancreatic neuroendocrine tumors; stable 
disease was observed in 71% of the patients.  All patients received prophylaxis with 
trimethoprim-sulfamethoxasole, and no opportunistic infections were observed. 
An analysis of 76 patients with neuroendocrine tumors treated with temozolomide based 
regimens at our institutions revealed that temozolomide-based therapy was associated with an 
overall response rate of 31% in pancreatic neuroendocrine tumors. Expression of the MGMT
(O6-methylguanine-DNA-methyltransferase) gene has been associated with response to 
temozolomide and other alkylating agents.  The MGMT gene encodes a DNA-repair enzyme 
that removes alkyl groups from the O6 position of guanine.  In our study, loss of expression of 
MGMT, as assessed by immunohistochemistry, was associated with response to temozolomide 
(Kulke, Frauenhoffer et al. 2007). Loss of MGMT was observed only in pancreatic 
neuroendocrine tumors and not in carcinoid tumors. 
These findings suggest that temozolomide was primarily responsible for the antitumor activity 
observed in pancreatic neuroendocrine tumors with the temozolomide/thalidomide and 
temozolomide/bevacizumab combination regimens. They further suggest that temozolomide 
is an active and appropriate first-line treatment option for patients with neuroendocrine 
tumors, and that further studies building on temozolomide in this setting are warranted. 
Although we estimate the response rate for temozolomide-based therapy to be approximately 
30%, this is not known for certain.  A retrospective analysis conducted in Europe of 
temozolomide as monotherapy for patients with advanced malignant neuroendocrine tumors 
from various gastrointestinal and thoracic sites demonstrated an objective radiographic 
response rate of 14% (Ekeblad et al, 2007).  As above, two prospective phase II studies of 
temozolomide-based therapy have been conducted at DF/HCC in patients with advanced 
neuroendocrine tumors (carcinoid tumor or pancreatic neuroendocrine tumor).  The first study 
combined temozolomide and thalidomide; among patients with pancreatic neuroendocrine 
tumors, objective responses were seen in 5/11 patients (RR 45%, 95% CI 16%-75%).  The 
second study combined temozolomide and bevacizumab; among patients with pancreatic 
neuroendocrine tumors, objective responses were seen in 4/17 patients (RR 24%, 95% CI 3%-
44%).  Additionally, in a retrospective analysis of patients with neuroendocrine tumors treated 
at DF/HCC with temozolmide-based therapy, some of whom received therapy as participants 
in these two phase II trials, objective responses to therapy were seen in 11/35 patients wtih 
pancreatic neuroendocrine tumors (RR 31%, 95% CI 18-44%).
Given the wide confidence intervals associated with these response rates and the uncertainty 
regarding the true response rate of temozolomide in this patient population, we believe that 
the future regimens including temozolomide would be worthy of further study if a 20% 
response rate is demonstrated.


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1.3
RAD001 (everolimus)
RAD001 (everolimus) is a novel derivative of rapamycin. RAD001 has been in clinical 
development since 1996 as an immunosuppressant in solid organ transplantation. Since 2003, 
RAD001 has been approved in Europe (trade name: Certican ) via the Mutual Recognition 
Procedure (MRP) for the prevention of organ rejection in patients with renal and cardiac 
transplantation. Certican
is also approved in Australia, South Africa, the Middle East, 
Central and South America, the Caribbean and some Asian countries.
At the cellular and molecular level, RAD001 acts as a signal transduction inhibitor. It 
selectively inhibits mTOR (mammalian target of rapamycin), a key protein kinase that 
regulates cell growth, proliferation and survival.  The mTOR is mainly activated via the PI3 
kinase pathway through AKT/PKB and the tuberous sclerosis complex (TSC1/2).  Mutations 
in these components or in PTEN, a negative regulator of PI3 kinase, may result in their 
dysregulation. Abnormal functioning of various components of the signaling pathways 
contributes to the pathophysiology of numerous human cancers.  Various preclinical models 
have confirmed the role of this pathway in tumor development (Cohen, 2005).
1.3.1
Preclinical studies
RAD001 inhibits the proliferation of a range of human tumor cell lines in-vitro including lines 
originating from lung, breast, prostate, colon, melanoma and glioblastoma.  IC50s range from 
sub/low nM to µM. RAD001 also inhibits the proliferation of human umbilical vein 
endothelial cells (HUVECS) in vitro, with particular potency against VEGF-induced 
proliferation suggesting that RAD001 may also act as an anti-angiogenic agent. The anti-
angiogenic activity of RAD001 was confirmed in vivo. RAD001 selectively inhibited VEGF-
dependent angiogenic response at well tolerated doses. Mice with primary and metastatic 
tumors treated with RAD001 showed a significant reduction in blood vessel density when 
compared to controls.
The potential of RAD001 as an anti-cancer agent was shown in rodent models. RAD001 is 
orally bioavailable, residing longer in tumor tissue than in plasma in an s.c mouse xenograft 
model, and demonstrating high tumor penetration in a rat pancreatic tumor model.  The 
pharmacokinetic profile of RAD001 indicates sufficient tumor penetration, above that needed 
to inhibit the proliferation of endothelial cells and tumor cell lines deemed sensitive to 
RAD001 in vitro.
RAD001 administered daily p.o. was a potent inhibitor of tumor growth, at well tolerated 
doses, in 11 different mouse xenograft models (including pancreatic, colon, epidermoid, lung 
and melanoma) and two syngeneic models (rat pancreatic, mouse orthotopic melanoma).  
These models included tumor lines considered sensitive and “relatively resistant” in vitro. In 
general, RAD001 was better tolerated in mouse xenograft models than standard cytotoxic 
agents (i.e., doxorubicin and 5-fluorouracil), while possessing similar anti-tumor activity.  
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.


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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; in some cases (i.e., glioblastoma) there is also a correlation with PTEN 
status. 
In vivo studies investigating the anti-tumor activity of RAD001 in experimental animal tumor 
models showed that RAD001 monotherapy typically reduced tumor cell growth rates rather 
than produced regressions or stable disease. These effects occurred within the dose range of 
2.5 mg to 10 mg/kg, p.o. once a day.
In preclinical models, the administration of RAD001 is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated (p)-S6 (p-
S6) and p-4E-BP1, and occasionally with an increase in phosphorylated AKT, a protein 
upstream of mTOR signaling pathway. Study CRAD001A2107 explored MPD (molecular 
pharmacodynamic) changes in tumor at different doses and schedules of RAD001 (weekly 20 
mg, 50 mg and 70 mg or daily 5 mg and 10 mg).
All significant adverse events observed in toxicology studies with RAD001 in mice, rats, 
monkeys and mini-pigs were consistent with its anticipated pharmacological action as an anti-
proliferative 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.
1.3.2
Clinical experience
1.3.2.1
Phase I and II oncology studies
Data are available from phase I clinical studies of RAD001 given as a single agent to 147 
patients with advanced solid tumors. Such studies included various doses and schedules 
(weekly dosing, range 5-70 mg and daily dosing 5-10 mg). Approximately, 46% of patients 
reported rash or erythema and 40% of the patients presented with stomatitis/mucositis. The 
most frequent adverse events suspected to be drug-related observed in three studies using 
RAD001 as a single agent are listed in Table 1-1.


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Table 1-1
Adverse events suspected to be drug-
advanced cancers reported in Phase I RAD001 monotherapy studies 
(C2101, C2102 and 2107)
Weekly
Daily
Total
n=147
5-30 mg
n=30
50 mg
n=18
70 mg
n=38
5mg
n=16
10 mg
n=45
No. Pts with AEs
Any event
23 (1)
17 (2)
38 (10)
14 (1)
43 (14)
135 (28)
By event
-
Rash 
5
8
18
10
27 (1)
68 (1)
-
Stomatitis/mucositis
6
8 (2)
16 (2)
6 (1)
23 (3)
59 (8)
-
Fatigue
8
7 (1)
14 (1)
1
17 (1)
47 (3)
-
Nausea
5
4
8
2
18 (1)
37 (1)
-
Anorexia
1
6
10
3
15
35
-
Diarrhea
1
7
7
-
9
24
-
Vomiting
4
5
5
-
10
24
-
Headache
7
4
6
6
4
20
-
Pruritus
2
1
6
3
4
16
-
Infections1
1
3
3 (1)
1
6 (2)
14 (3)
-
Constipation
-
1
2
2
9
14
The numbers of pat
1 toxicities is given in 
brackets.
1.
events included in brackets reached no more than grade 3 severity
2
Infections noted as drug-related included:
Herpes simplex: 
5 pts (1 at 50 mg/wk; 1 at 5mg/d; 3 at 10 mg/d)
Oral candidiasis:
5 pts (1 at 50 mg/wk; 3 at 70 mg/wk, 1 at 10 mg/d)
Pneumonia (gr3) 1 pt (10 mg/d)
Pustular rash
1 pt (20 mg/wk)
Rhinitis
2 pts (50 mg/wk)
URT Infection
1 pt (50 mg/wk
Urinary Tract Infect 1 pt (50 mg/wk)
Reduced blood cell counts at the initiation of treatment are frequent but remain mostly within 
the normal range or limited to grade 1 although a grade 3 neutropenia was a DLT in one 
patient as was a grade 3 thrombocytopenia in a patient receiving RAD001 with letrozole 
where pharmacodynamic interaction is unlikely. This suggest that some patients may be 
particularly sensitive to the myelosuppressive effect of RAD001 making it necessary to 
monitor carefully blood cell counts at initiation of treatment.
Metabolic changes (hyperlipidemia and hyperglycemia) may be observed during treatment 
with RAD001. Both events may be medically managed. Hyperlipidemia has been reported as 
an adverse reaction in 10% of patients although review of the laboratory values suggests that 
as many as a quarter of patients develop grade 1-2 hyperlipidemia on treatment, mostly 
hypercholesterolemia. Hyperglycemia has been reported as an adverse event in 7% of 
patients. Grade 3 hyperglycemia has been observed, especially in diabetics receiving RAD001 
treatment. Therefore, patients with diabetes should have their blood glucose monitored 
carefully and their medications adjusted, as needed, to maintain adequate control of their 
blood glucose levels. 


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In Novartis-sponsored clinical trials, symptomatic non-infectious pneumonitis has been 
reported as a serious adverse event in less than 1% of patients out of approximately 1000 
cancer patients treated with RAD001 as of April 30, 2006. This adverse event has been noted 
in the Investigators’ Brochure (IB, Edition 4 dated November 11, 2005). Corticosteroids were 
often administered to the patients with symptomatic pneumonitis. 
Novartis has recently received reports of low-grade non-infectious pneumonitis in cancer 
patients treated with RAD001. Most of these reports involve patients with no respiratory 
symptoms (CTC grade 1 pneumonitis: radiographic findings only) or mild severity (CTC 
grade 2: symptomatic, not interfering activities of daily living), and were from two 
investigator-sponsored (private IND) trials, as follows:
In a study of patients with advanced renal cell carcinoma receiving 10 p.o. mg/day, 15/20 
patients reviewed by an independent radiologist were noted to have lung infiltrates 
consistent with pneumonitis on routine chest CT scans performed to follow the patients’ 
thoracic metastases.
In a study of patients with advanced breast cancer, 7/18 patients treated with RAD001 10 
mg/d and 2/16 patients treated with RAD001 70 mg/week, had findings consistent with 
pneumonitis. In this study, two patients, one on the daily RAD arm and one on the weekly 
RAD001 arm, developed severe (grade 3) pneumonitis that resolved after RAD001 was 
discontinued. 
In both studies, most patients had radiological changes with mild or no symptoms and have 
continued RAD001 treatment without developing symptoms. The reason for an increased rate 
of reported low-grade pneumonitis among oncology patients in these studies is unclear.  Both 
studies included serial chest CT scans allowing prolonged, detailed evaluation of the lung 
parenchyma; the dosage and drug exposure in these phase 2 trials is generally longer than in 
the phase 1 experience. In addition, the dosage of RAD001 used in the treatment of cancer 
patients is substantially higher than that given routinely in the organ transplant setting.  
Everolimus (RAD001) is approved at a daily dose of 0.75 mg twice a day guided by 
therapeutic drug monitoring (3-8 ng/ml) in combination with cyclosporine microemulsion in 
many regions of the world for renal and cardiac transplantation. In phase 3 trials investigating 
everolimus in renal and cardiac transplantation, the overall reported rate of pneumonitis 
ranged from 0.0 to 1.4%. The spontaneous reporting rate for pneumonitis following exposure 
to commercially available everolimus in transplantation is very low (0.08% or 84.4 
events/100,000 patient-years). Refer to the latest version of the RAD001 Investigator’s 
Brochure and safety letters (Investigator Notifications) for the most up to date information 
available.
Two phase I studies combining RAD001 with systemic cytotoxic chemotherapy (paclitaxel, 
gemcitabine) have been performed.  
In the phase I study of gemcitabine and RAD001, RAD001 was administered orally at a dose 
of 20 mg/week, without interruption, in combination with weekly gemcitabine, 600 mg/m2 on 
days 1,8,15 of each 27-day cycle.  Successive cohorts were to be defined by the dosage of 
gemcitabine, beginning with 600 mg/m2, which would have been increased to 800 mg/m2 and 


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1000 mg/m2 if feasible.  5/8 patients in the 600 mg/m2 cohort experienced a dose limiting 
toxicity in the first cycle (
thrombocytopenia, or anemia).  Due to the high rate of DLT at the first dose level, no dose 
escalation was undertaken in this study.  The high frequency of DLT in the lowest-dose cohort 
was attributed to the antiproliferative activity of RAD002, increasing the direct myelotoxic 
effect of gemcitabine and/or delaying post-cytotoxic recovery.
In a separate phase I study combining RAD001 (15 mg and 30 mg /week orally) with 
paclitaxel (80 mg/m2 on days 1,8,15 of each 21 day cycle) among patients with advanced solid 
tumors, the combination was found to be well tolerated.  No dose limiting toxicities among 
the 16 treated patients were observed.  (Dose limiting toxicity was defined as any grade 4 
toxicity, grade 3 non-
treatment is permitted) within two weeks.)  For further details, please refer to Investigator’s 
Brochure, section 5.3.3.
1.3.2.2
Phase II studies of RAD001 in neuroendocrine tumors
A recent phase II clinical trial examined the combination of RAD001 5 mg per day and depot 
octreotide (Sandostatin LAR depot) in patients with advanced neuroendocrine tumors (Yao, 
Phan et al. 2006).  Thirty patients who were treated were classified as follows: 17 patients had 
carcinoid, and 13 had pancreatic neuroendocrine tumor.  All were evaluabe for response.  
Four patients were reported to have partial response (3 verified by independent radiologic 
review), 22 had stable disease, and 4 had progressive disease by RECIST criteria.  Responses 
appeared to be durable; at last analysis, responses were ongoing in 3 patients at 12, 9, and 6 
months on treatment, and the fourth patient progressed at 9 months on treatment.  A partial 
response to therapy was seen in 2 of 11 patients with pancreatic neuroendocrine tumor who 
were evaluable for response.  Of the 17 patients whose tumors had documented radiological 
progression prior to study entry, 13 (76%) were progression-free at 12 weeks and 11 (65%) 
were progression-free at 12 weeks and 11 (65%) were progression free at 24 weeks.  Nineteen 
of the 30 evaluable patients had elevated chromogranin A at baseline.  Eleven (37% of all 
patients or 58% of those with elevated chromogranin A at baseline) had >50% reductions in 
chromogranin A.
The combination of RAD001 5 mg per day and Sandostatin LAR Depot 30 mg every 28 days 
appears to have been well tolerated.  The most common toxicity reported was mild aphthous 
ulceration.  CTC Grade 3/4 toxicities reported included those previously reported for RAD001 
alone (anemia, thrombocyotpenia, aphthous ulcer, diarrhea, edema, fatigue, hypoglycemia, 
nausea, pain, and rash).  Only one patient discontinued treatment because of drug-related 
toxicities.  When grade 3 toxicities occurred, RAD001 was held until toxicity resolved to 
grade 1, and RAD001 was resumed at the initial dose of 5 mg per day. 


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In phase I clinical studies of RAD001 as a monotherapy agent in oncology patients, the side-
effect profile is essentially mild to moderate adverse events with a low frequency of DLT at 
the daily dose of 10 mg/d (see Table 1-1).  Based on the PK/PD model, a daily dose of 10mg 
RAD001 is assumed to provide a persistently high degree of target inhibition in the tumor 
[Investigators’ Brochure-Section 5.3.1.1]. In addition, preliminary data from phase 1 studies, 
in which changes in molecular characteristics of tumor induced by treatment with RAD001 at 
the doses of 5 and 10 mg/d were investigated, confirm the pharmacodynamic activity 
predicted previously by PK/PD modeling [Investigators’ Brochure-Section 5.3.1.1].
Therefore, a dose of 10 mg/d should ensure adequate drug target inhibition for most patients, 
taking into consideration the known inter-patient variability in drug levels (CV of approx 
50%).
The efficacy and safety of RAD001 at a dose of 10 mg per day, alone and in combination with 
Sandostatin LAR, currently is being evaluated in an ongoing multi-institutional phase II 
clinical trial.
1.5
Study Rationale
Given the single-agent activity demonstrated with both temozolomide and RAD001 in 
patients with neuroendocrine tumors, evaluation of a combination of these two agents in 
neuroendocrine tumors is warranted. The activity of temozolomide appears to be limited 
primarily to patients with pancreatic neuroendocrine tumors, based on our recent clinical 
experience. We therefore propose a phase I/II study to evaluate the efficacy and safety of 
RAD001 in combination with temozolomide in patients with metastatic pancreatic 
neuroendocrine tumors.
Although the combination of RAD001 and gemcitabine was associated with toxicity, 
RAD001 has been studied in combination with paclitaxel without evidence of synergistic 
toxicity. This data, as well as the markedly different mechanisms of action of RAD001 and 
temozolomide, suggest that combining these two agents at standard doses, with appropriate 
safety monitoring, may be feasible. However, to ensure that we do not miss unexpected 
toxicities, we will initiate treatment at a dose level below the anticipated phase II dose. Three 
patients will be treated with RAD001 orally at a dose of 5 mg daily, in combination with 
temozolomide at a standard dose (150 mg/m2 daily for 7 days, followed by a 1 week break). 
Patients will be observed for toxicity. If no dose limiting toxicity is observed in this first 
cohort, subsequent patients will receive the full anticipated phase II dose of RAD001 10 mg 
daily, in combination with temozolomide 150 mg/m2 daily for 7 days, every other week. To 
minimize the risk of lymphopenia-related opportunistic infections, temozolomide therapy will 
be limited to a maximum of 6 months, and all patients will receive PCP prophylaxis. 


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2
Study objectives
Primary
To determine the objective response rate of RAD001 in combination with temozolomide 
in patients with advanced (unresectable or metastatic) pancreatic neuroendocrine tumors.
Secondary
To determine the duration of response to the combination of RAD001 and temozolomide 
in patients with advanced pancreatic neuroendocrine tumors.
To determine the safety and tolerability of the combination or RAD001 and 
temozolomide in patients with advanced pancreatic neuroendocrine tumors.
To determine the progression free survival and overall survival of patients receiving the 
combination of RAD001 and temozolomide.
3
Investigational plan
3.1
Overall study design
This is an open-label phase I/II study to evaluate the efficacy and safety of RAD001 in 
combination with temozolomide in patients with advanced pancreatic neuroendocrine tumor.
Patients on study therapy may be at risk for temozolomide-related selective lymphopenia and 
opportunistic infections. To reduce the risk of opportunistic infections, patients will receive 
prophylaxis with Bactrim DS, 1 tablet by mouth every Monday, Wednesday, and Friday 
beginning after the first month of treatment.  Patients allergic to Bactrim should be initiated 
on an alternate, standard PCP prophylaxis regimen.  Previous infections associated with 
temozolomide-induced lymphopenia in neuroendocrine tumor patients have developed after 
more than 6 months of treatment. Treatment with temozolomide in this study will therefore be 
limited to a maximum duration of 6 months. 
3.2
Basic Design Characteristics
Up to 44 patients with locally advanced or metastatic pancreatic neuroendocrine tumors who 
meet eligibility criteria will be enrolled sequentially into three cohorts.  
3.2.1
Cohort 1
The first cohort will consist of a minimum of three patients who will receive an oral dose of 5 
mg of RAD001 administered daily and an oral dose of temozolomide of 150 mg/m2 daily for 


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7 days every other week beginning on Day 1 of RAD001 administration.  The patients will be 
treated for a 28-day Treatment Period and then observed over a 7-day observation period for 
signs of treatment-emergent toxicity.  Patients will not receive treatment with either RAD001 
or temozolomide during the 7-day observation period.  If these patients do not exhibit disease 
progression or a dose limiting toxicity (DLT), as defined in section 3.3, they will receive 
subsequent 28-day cycles of treatment without additional 7-day observation periods.  Patients 
in this cohort may be treated simultaneously without requiring previously enrolled patients to 
complete their first cycle of treatment and observation.
If a dose limiting toxicity (DLT), as defined in section 3.3, is observed in 1 of the first 3 
patients, 3 additional patients will be enrolled at that same dose level.  If no additional DLT is 
observed after all patients have completed the first cycle of treatment and 7-day observation 
period, the trial will continue to enroll the second cohort of patients.
If a DLT is observed in 2 or more of the first 3 patients or of the total 6 patients during Cycle 
1 of treatment, accrual to the trial will be suspended pending review of the events and revision 
of the protocol.
3.2.2
Cohort 2
Once the first cohort of patients completes the initial 35-day cycle without experiencing a 
DLT, the second cohort of patients will begin enrollment.  The second patient cohort will 
consist of at least 3 patients who will receive an oral dose of 10 mg of RAD001 administered 
daily and an oral dose of temozolomide of 150 mg/m2 daily for 7 days every other week 
beginning on Day 1 of RAD001 administration.  The patients will be treated for a 28-day 
Treatment Period and then observed over a 7-day observation period for signs of treatment-
emergent toxicity.  Patients will not receive treatment with either RAD001 or temozolomide 
during the 7-day observation period.  If patients do not exhibit disease progression or a dose 
limiting toxicity (DLT), as defined in section 3.3, they will receive subsequent 28-day cycles 
of treatment without additional 7-day observation periods.  Patients in this cohort may be 
treated simultaneously without requiring previously enrolled patients to complete their first 
cycle of treatment and observation.
If a DLT is observed in 1 of the first 3 patients, 3 additional patients will be enrolled at that 
same dose level.  If no additional DLT is observed after all patients have completed the first 
cycle of treatment and observation period, the trial will continue to enroll the third cohort of 
patients. If additional DLTs are observed, enrollment to the trial will be stopped and the study 
will be re-evaluated.
If a DLT is observed in 2 or more of the first 3 patients or of the total 6 patients during Cycle 
1 of treatment, accrual to the trial will be suspended pending review of the events and revision 
of the protocol.


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3.2.3
Cohort 3
Once the second cohort of patients completes the initial 35-day cycle without experiencing a 
DLT, the third cohort of patients will begin enrollment.  The third patient cohort will consist 
of 32 patients who will receive an oral dose of the maximum tolerated dose of RAD001 
administered daily and an oral dose of temozolomide of 150 mg/m2 daily for 7 days every 
other week beginning on Day 1 of RAD001 administration.  The patients will be treated for a 
28-day Treatment Period.  Patients who complete the initial cycle of therapy without evidence 
of significant treatment-emergent toxicity or progressive disease may receive additional 28-
day cycles of treatment until the appearance of significant treatment-emergent toxicities or 
disease progression.  
3.3
Definition of dose limiting toxicity (DLT) and maximum tolerated 
dose (MTD)
Dose limiting toxicity is defined as drug-related toxicity according to the NCI CTCAE v3.0 
during the first cycle of treatment leading to the following:
Grade 3 or higher non-hematologic toxicity (excluding nausea and/or vomiting). 
Grade 3 or higher nausea/vomiting uncontrolled by aggressive antiemetic support.
Grade 3 or higher neutropenia or thrombocytopenia failing t
at which cytotoxic treatment is permitted) in three weeks
Febrile neutropenia
Inability of the patient to take > 75% of the planned chemotherapy dose during the 
treatment period.
Clinically significant treatment related toxicity
The maximum tolerated dose (MTD) is defined as the highest dose level at which less than 
33% of the patients experience a DLT.
If a DLT is observed in 2 or more of the first 3 patients or of the total 6 patients in a dose level 
during cycle 1 of treatment, that dose level will be considered to be above the maximum 
tolerated dose (MTD).  The dose one level lower will be declared as the MTD, if a DLT is 
observed in 1 or less patient of the total 6 patients in the dose level.  If 2 or more patients have 
experienced a DLT at the first dose level, the investigator, medical monitor, and Sponsor may 
discuss to add a dose level at 50% of the first level.
3.4
Study population
3.4.1
Patient population
The target population is comprised of adult patients with histologically-confirmed, advanced 
pancreatic neuroendocrine tumor.  The study will enroll up to 44 patients. Patients must have 


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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.
Inclusion criteria 
1. Locally unresectable or metastatic pancreatic neuroendocrine tumor.
Radiologic, operative, or pathology reports should document a pancreatic location 
of tumor.
Patients must have confirmed low-grade or intermediate-grade neuroendocrine 
carcinoma.  
Patients with poorly differentiated neuroendocrine carcinoma, high-grade 
neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid, and small cell 
carcinoma are not eligible. 
2. 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, 
chemoembolization, or cryotherapy to the marker lesion(s), there must be evidence of
progression since the radiation.
3.
4. Minimum of two weeks since any major surgery, completion of radiation, or completion 
of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of 
any prior therapy).
5. Prior treatment with chemotherapy is allowed, with the exception of prior treatment with 
temozolomide or dacarbazine.
6. No prior therapy with RAD001 or any other mTOR inhibitor.
7. ECOG performance status 
2.
8. Life expectancy 12 weeks or more.
9.
9/L
9/L, 
Hgb > 9 g/dL.
10.
transaminases (< 5 x ULN) if the patient has liver metastases.
11. Adequate renal function as shown by serum creatinine 
12.
2.5 x ULN.  NOTE: In cases where one or both of these thresholds are exceeded, the 
patient can only be included after initiation of appropriate lipid lowering medication, see 
Section 4.4.6.


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13. Women of childbearing potential must have a negative serum pregnancy test within 14 
days of the administration of the first study treatment.  Women must not be lactating. Both 
men and women of childbearing potential must be advised of the importance of using 
effective birth control measures during the course of the study.
14. Signed informed consent to participate in the study must be obtained from patients after 
they have been fully informed of the nature and potential risks by the investigator (or 
his/her designee) with the aid of written information.
Exclusion criteria
1. Prior treatment with any investigational drug within the preceding 4 weeks.
2. Chronic treatment with systemic steroids or another immunosuppressive agent, with the 
exception of patients receiving physiologic steroid replacement for adrenal insufficiency 
or other similar conditions. 
3. Patients should not receive immunization with attenuated live vaccines during study 
period or within 1 week of study entry.
4. Uncontrolled brain or leptomeningeal metastases, including patients who continue to 
require glucocorticoids for brain or leptomeningeal metastases.
5. Other malignancies within the past 3 years except for adequately treated carcinoma of the 
cervix or basal or squamous cell carcinomas of the skin.
6. Patients who have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as:
Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
Severely impaired lung function
Any active (acute or chronic) or uncontrolled infection/ disorders.  
Nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the treatment with the study therapy
Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
A known history of HIV seropositivity
Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
7. Women who are pregnant or breast feeding, or women/men able to conceive and 
unwilling to practice an effective method of birth control. (Women of childbearing 
potential must have a negative serum pregnancy test within 14 days prior to administration 
of RAD001). Oral, implantable, or injectable contraceptives may be affected by 
cytochrome P450 interactions, and are therefore not considered effective for this study.
8. Patients who have received prior treatment with an mTOR inhibitor or temozolomide.
9. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins 
(sirolimus, temsirolimus) or to its excipients


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10. History of noncompliance to medical regimens
11. Patients unwilling to or unable to comply with the protocol
4
Treatment Program
4.1
Study Treatment
The investigational study drugs used in the course of this trial are RAD001 and 
temozolomide:
Cohort 1: Patients will receive an oral dose of 5 mg of RAD001 administered daily and an 
oral dose of temozolomide of 150 mg/m2 daily for 7 days every other week beginning on 
Day 1 of RAD001 administration.  Temozolomide will be administered for a maximum of 
6 months; RAD001 may be administered until treatment progression, unacceptable or dose 
limiting toxicity, withdrawal of consent, or other reason for treatment discontinuation.
Cohort 2: Patients will receive an oral dose of 10 mg of RAD001 administered daily and 
an oral dose of temozolomide of 150 mg/m2 daily for 7 days every other week beginning 
on Day 1 of RAD001 administration.  Temozolomide will be administered for a maximum 
of 6 months; RAD001 may be administered until treatment progression, unacceptable 
toxicity, withdrawal of consent, or other reason for treatment discontinuation.
Cohort 3: Patients will receive an oral dose of RAD001 administered daily at the MTD as 
established in the phase I component of the study (Cohorts 1 and 2) and an oral dose of 
temozolomide of 150 mg/m2 daily for 7 days every other week beginning on Day 1 of 
RAD001 administration.  Temozolomide will be administered for a maximum of 6 
months; RAD001 may be administered until treatment progression, unacceptable toxicity, 
withdrawal of consent, or other reason for treatment discontinuation.
Patients on study therapy may be at risk for temozolomide-related selective lymphopenia and 
opportunistic infections. To reduce the risk of opportunistic infections, patients will receive 
prophylaxis with Bactrim DS, 1 tablet by mouth every Monday, Wednesday, and Friday 
beginning after the first month of treatment.  Patients allergic to Bactrim should be initiated 
on an alternate, standard PCP prophylaxis regimen.  Previous infections associated with 
temozolomide-induced lymphopenia in neuroendocrine tumor patients have developed after 
more than 6 months of treatment. Treatment with temozolomide in this study will therefore be 
limited to a maximum duration of 6 months.
Novartis will supply RAD001, and Schering-Plough will provide temozolomide free of charge 
for study participants.


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4.2
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. If administration of 
RAD001 or temozolomide must be interrupted because of unacceptable toxicity, drug dosing 
will be interrupted or modified according to rules described in Section 4.4. 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)).
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:
1. adverse event(s)
2. abnormal laboratory value(s)
3. abnormal test procedure result(s)
4. disease progression
5. protocol violation
6. subject withdrew consent
7. lost to follow-up
8. administrative problems
9. death
4.3
Monitoring of 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 or temozolomide 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.
4.4
Dose Modification
4.4.1
RAD001 dose adjustments
Three RAD001 dose levels are defined for dose adjustment: 10 mg daily, 5 mg daily, and 5 
mg every other day.


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Table 4.1.1 : Dose Reduction Schedule for RAD001 – Cohort 1
Dose Level
Dose and schedule
Days per cycle
(cycle length = 28 days)
0
5 mg daily
Continuous
Decrease 1 dose level
5 mg every other day
Continuous
Decrease 2 dose levels
Discontinue therapy
Table 4.1.2 : Dose Reduction Schedule for RAD001 – Cohort 2
Dose Level
Dose and schedule
Days per cycle
(cycle length = 28 days)
0
10 mg daily
Continuous
Decrease 1 dose level
5 mg daily
Continuous
Decrease 2 dose levels
5 mg every other day 
Continuous
Decrease 3 dose levels
Discontinue therapy
4.4.2
Temozolomide dose adjustments
Three temozolomide dose levels are defined for dose adjustment: 150 mg/m2 daily, 100 
mg/m2 daily, and 50 mg/m2 daily, administered on days 1-7 and days 15-21 of each cycle.
Table 4.2 : Dose Reduction Schedule for Temozolomide
Dose Level
Dose and schedule
Days per cycle
(cycle length = 28 days)
0
150 mg/m2 daily
Days 1-7; 15-21
Decrease 1 dose level
100 mg/m2 daily
Days 1-7; 15-21
Decrease 2 dose levels
50 mg/m2 daily
Days 1-7; 15-21
Decrease 3 dose levels
Discontinue therapy


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4.4.3
Dose reductions for hematologic toxicity
Cohort 1: If the ANC is <1,000 or the platelet count is <50,000 during study therapy, 
RAD001 and temozolomide will be delayed. If RAD001 or temozolomide cannot be 
administered on the scheduled day of dosing, the CBC will be repeated weekly for up to and 
including 3 weeks until the ANC is 
1000/mm3 and the platelet count 
50,000mm3. At that 
time, temozolomide will be reinitiated at one reduced dose level (100 mg/m2 daily, see Tables 
4.1-4.2).  The dose of RAD001 will remain at 5 mg daily.  For subsequent dose reductions, 
both temozolomide and RAD001 will be reduced by one dose level.  If treatment is held more 
than 3 weeks, the patient should be taken off protocol therapy.
Cohort 2: If the ANC is <1,000 or the platelet count is <50,000 during study therapy, 
RAD001 and temozolomide will be delayed. If RAD001 or temozolomide cannot be 
administered on the scheduled day of dosing, the CBC will be repeated weekly for up to and 
including 3 weeks until the ANC is 
1000/mm3 and the platelet count 
50,000mm3. At that 
time, RAD001 and temozolomide will be reinitiated at one reduced dose level (see Tables 4.1-
4.2).  If treatment is held more than 3 weeks, the patient should be taken off protocol therapy.
Growth factors cannot be used to induce elevations in neutrophil count for the purposes of 
administration of RAD001 and temozolomide on the scheduled dosing OR to allow treatment.
Administration of erythropoietin is allowed.
4.4.4
Dose reductions for non-hematologic toxicity
Both RAD001 and temozolomide should be held for all clinically significant drug related 
toxicities that are grade 3 or higher and not specified in the drug-specific toxicities below. All 
drug related CTCAE Grade 3 and 4 toxicities must have resolved to at least CTCAE Grade 1 
prior to repeat dosing.   For patients with baseline grade 2 elevations in transaminases or 
bilirubin or alkaline phosphatase, transaminase, bilirubin, or alkaline phosphatase levels must 
have resolved to the level defined by the Inclusion Criteria prior to repeat dosing. 
Once toxicities have resolved to at least grade 1, RAD001 and temozolomide will be 
reinitiated at one reduced dose level per Table 4.3.  If treatment is held more than 3 weeks, the 
patient should be taken off protocol therapy.
If multiple toxicities are seen, the dose administered should be based on the dose reduction 
required for the most severe grade of any single toxicity observed. If unacceptable toxicity 
occurs, therapy should be discontinued.


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Table 4.3
Criteria for dose-modification of RAD001 and temozolomide for non-
hematologic toxicity
Toxicity
Actions
Grade 2
(except pneumonitis  [refer to Table 4.4] and mucositis)
If the toxicity is tolerable to the patient, 
maintain the same dose. If the toxicity is 
intolerable to patient, interrupt RAD001 and 
temozolomide until recovery to grade 1. Then 
reintroduce RAD001 and temozolomide at one 
lower dose level.
Grade 2 mucositis
If the toxicity is tolerable to the patient, 
maintain the same dose. If the toxicity is 
intolerable to patient, interrupt RAD001 and 
temozolomide until recovery to grade 1. Then 
reintroduce RAD001 at one lower dose level 
and continue same dose of temozolomide.  
See section 4.4.5 for further details.
Grade 3
(except hyperlipidemia and hyperglycemia and 
mucositis and pneumonitis)
Interrupt RAD001 and temozolomide until 
recovery to grade 1. Then reintroduce both 
RAD001 and temozolomide at one lower dose 
level.  
Grade 3 hyperlipidemia
Grade 3 hyperlipidemia (hypercholesterolemia 
and/or hypertriglyceridemia) should be 
managed using medical therapies, per section 
4.4.6.  Dose reduction of RAD001 or 
temozolomide can be considered but is not 
required.
Grade 3 hyperglycemia
Grade 3 hyperglycemia should be managed 
using medical therapies, per section 4.4.6.  .  
Dose reduction of RAD001 or temozolomide 
can be considered but is not required.
Grade 3 mucositis
For Grade 3 mucositis, interrupt RAD001 and 
temozolomide until recovery to grade 1. Then 
reintroduce RAD001 at one lower dose level 
and continue temozolomide at same dose.  
See section 4.4.5 for further details.
Grade 3 pneumonitis
Please refer to Table 4.4.
Grade 4
Discontinue protocol therapy
Any non-hematological toxicity requiring interruption for 
> 3 weeks
Discontinue protocol therapy


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4.4.5
Management of stomatitis/oral mucositis/mouth ulcers
Stomatitis/oral mucositis/mouth ulcers are common toxicities associated with RAD001 and 
should be treated using local supportive care. Please note that investigators in earlier trials 
have described the oral toxicities associated with RAD001 as mouth ulcers, rather than 
mucositis or stomatitis. If your examination reveals mouth ulcers rather than a more general 
inflammation of the mouth, please classify the adverse event as such. Dose modification of 
RAD001 for stomatitis/oral mucositis/mouth ulcers is described in Section 4.4.4.  
Additionally, please follow the paradigm below for treatment of stomatitis/oral 
mucositis/mouth ulcers:
1. For 
mild 
toxicity 
(grade 
1), 
use 
conservative 
measures 
such 
as 
non-alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution.
2. For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate 
oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e.,
local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®).
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents.
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.
4.4.6
Management of hyperlipidemia and hyperglycemia
Treatment of hyperlipidemia is recommended but not required as part of study therapy, and 
should take into account the patient’s underlying condition and the relative risk/benefit ratio 
of treatment. Treatment of hyperlipidemia should take into account the pre-treatment status 
and dietary habits. For patients with grade 2 hypercholesterolemia (>300 mg/dL or 7.75 
mmol/L) or grade 2 hypertriglyceridemia (>2.5 x upper normal limit) consideration should be 
given to treatment 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 


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Study No. 
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 almost 
all cases the affected patients had an abnormal fasting glucose at baseline. Based on this 
finding, we suggest that optimal glucose control should be achieved before starting a patient 
on RAD001 and should be monitored during RAD001 therapy.  For patients who develop 
clinically significant hyperglycemia while on therapy, initiation of oral hypoglycemic or 
insulin therapy should be considered.
4.4.7
Management of non-infectious pneumonitis
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious 
pneumonitis (grade 2 = not interfering with activities of daily living or grade 3 = interfering 
with activities of daily living and oxygen indicated) have been noted in patients receiving 
RAD001 therapy.  Non-infectious pneumonitis has been associated with RAD001 and other 
mTOR inhibitors (Atkins, 2004). In order to monitor for asymptomatic (grade 1) pulmonary 
infiltrates, a chest X-ray is required if a CT scan of chest is not used for bi-monthly disease 
evaluations. Additional chest X-rays/CT scans may be done, when clinically necessary. If 
non-infectious pneumonitis develops, consultation with a pulmonologist should be 
considered. Management of non-infectious pneumonitis suspected to be associated with 
RAD001 and dose modifications instructions are provided in Table 4.4.  
Table 4.4
Management of non-infectious pneumonitis
Worst Grade 
Pneumonitis
Required Investigations
Management of 
Pneumonitis 
Actions
Grade 1
CT scans with lung 
windows.
No specific 
therapy is 
required
Administer 100% of RAD001 and 
temozolomide doses.
Grade 2
CT scan with lung windows.  
Consider pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat each subsequent 
Cycle until return to within 
normal limits. Consider a 
bronchoscopy. 
Symptomatic 
only. Prescribe 
corticosteroids if 
cough is 
troublesome.
Discontinue study therapy until 
recovery to < grade 1. Study 
therapy may also be interrupted if 
symptoms are troublesome. If 
recovered, resume treatment with 
RAD001 and temozolomide at one 
lower dose level. 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 includes: spirometry, 
DLCO, and room air O2
saturation at rest.; Repeat 
each subsequent Cycle until 
return to within normal 
limits. Bronchoscopy is 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Hold RAD001 and temozolomide  
until recovery to < grade 1. May 
restart RAD001 and temozolomide 
within 2 weeks at a reduced dose 
(by one level) if evidence of clinical 
benefit.


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Worst Grade 
Pneumonitis
Required Investigations
Management of 
Pneumonitis 
Actions
recommended.
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 within 
normal limits. Bronchoscopy 
is recommended.
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Discontinue RAD001 and 
temozolomide.  
*  Patients will be removed from study if there is a repeat episode of pneumonitis or if pneumonitis 
does not resolve within 2 weeks.
4.5
Treatment Plan
4.5.1
Investigational therapy
The investigational therapy used in the course of this study is RAD001 in combination with 
temozolomide. Study medication will be administered by the patients themselves. Patients are 
provided with a diary to document date, time, dose and any symptoms they experience while 
taking study medications. During the study, RAD001 will be administered orally as a once 
daily dose continuously from study day 1 until progression of disease or unacceptable 
toxicity.  Patients in cohort 1 will receive RAD001 at a dose of 5 mg per day in combination 
with temozolomide 150 mg/m2/day on days 1-7 and 15-21 of each 28-day treatment cycle.  
Patients will be monitored for 7 days after their first cycle of therapy.  They will not receive 
therapy during this observation period.  Patients in cohort 2 will receive RAD001 at a dose of 
10 mg per day in combination with temozolomide 150 mg/m2/day on days 1-7 and 15-21 of 
each 28-day treatment cycle.  Patients will be monitored for 7 days after their first cycle of 
therapy.  They will not receive therapy during this observation period.  Patients in cohort 3 
will receive RAD001 at the maximum tolerated dose in combination with temozolomide 150 
mg/m2/day on days 1-7 and 15-21 of each 28-day treatment cycle. 
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.
4.5.1.1
RAD001
RAD001 will be provided by Novartis. RAD001 is formulated as tablets for oral 
administration of 5mg strength. Tablets are blister-packed under aluminum foil in units of 10 
tablets, which should be opened only at the time of administration as drug is both hygroscopic 
and light-sensitive.
RAD001 should be taken by the patient in a fasting state or with no more than a light fat-free 
meal. Vomited doses and missed doses should not be repeated.  Dietary habits around the time 
of RAD001 intake should be as consistent as possible throughout the study.


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4.5.1.2
RAD001 pharmacokinetics
The pharmacokinetic characteristics of RAD001 have been extensively investigated in the 
context of the drug’s development as an immunosuppressant in solid organ transplantation 
where RAD001 was administered twice daily as a part of an immunosuppressant, multi-drug 
regimen consistently including cyclosporin A and glucocorticoids. Recent Phase I studies 
provide steady-state pharmacokinetics for both the weekly and daily schedules at varying dose 
levels in patients with advanced cancers.
RAD001 is rapidly absorbed after oral administration, with a median time to peak blood 
levels (tmax) of 1-2 hours postdose. The extent of absorption is estimated at above 11%.  The 
area under the blood concentration-time curve (AUC) is dose-proportional over the dose range 
tested while maximum blood concentration Cmax appears to plateau at dose levels higher than 
20 mg. The terminal half-life in cancer patients averaged 30 hours, which is similar to that in 
healthy subjects. Inter-patient variability is moderate with the coefficient of variation (CV) of 
approximately 50%.  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. In whole blood, approximately 
80% of RAD001 is contained in red blood cells. Of the fraction of drug contained in plasma, 
74% is protein-bound. The apparent distribution volume (Vz/F) after a single dose was 4.7 
L/kg. RAD001 is eliminated by metabolism, mainly by hydroxylation, then excreted into the 
feces >80%.
RAD001 is mainly metabolized by CYP3A4 in the liver and to some extent in the intestinal 
wall. RAD001 is also a substrate of P-glycoprotein (P-gp). Therefore, absorption and 
subsequent elimination of systematically absorbed RAD001 may be influenced by medicinal 
products that interact with CYP3A4 and/or P-glycoprotein. In vitro studies showed that 
RAD001 is a competitive inhibitor of CYP3A4 and of CYP2D6 substrates, potentially 
increasing the concentrations of medicinal products eliminated by these enzymes. In two 
phase III clinical trials in patients following kidney transplantation, strong inhibitors of 
CYP3A4 (azoles, antifungals, cyclosporine, erythromycin) have been shown to reduce the 
clearance of RAD001 therapy thereby increasing RAD001 blood levels. Similarly, Rifampin, 
a strong inducer of CYP3A4, increases the clearance of RAD001 thereby reducing RAD001 
blood levels. Caution should be exercised when co-administering RAD001 with CYP3A4 
inhibitors or inducers.
Pharmacokinetic drug to drug interactions with cancer agents are being evaluated in ongoing 
phase Ib studies. Based on currently available results, gemcitabine (study 2101 part 2) and 
paclitaxel (study 2104) did not alter RAD001 pharmacokinetics to a clinically relevant extent 
whereas imatinib notably increased RAD001 exposure with a mean increase in AUC by a 
multiple of 3.7 for RAD001 administered weekly and two-fold for RAD001 administered 
daily (study 2206). Exposure to RAD001 in the presence of letrozole did not exceed that in 
monotherapy (study 2108). Co-administration of RAD001 did not influence pharmacokinetics 
of gemcitabine, imatinib or letrozole. Exposure to paclitaxel in the presence of RAD001 was 
slightly decreased (average by 23%).
RAD001 pharmacokinetics in transplant patients was investigated in special populations such 
as subjects with hepatic or renal impairment, various ethnic groups and pediatric renal 
transplant patients. In subjects with mild–moderate hepatic impairment, mean AUC to 
RAD001 is increased by 3-fold whilst renal impairment does not affect the pharmacokinetics 


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Study No. 
of RAD001. Age, weight (both over the adult range) and gender do not affect the 
pharmacokinetics of RAD001 to a clinically relevant extent. Also, pharmacokinetics does not 
alter in Japanese or Asian patients whereas black patients have 21% higher clearance 
compared to non-blacks. In children, the apparent clearance of RAD001 increases linearly 
with body surface. The clearance per square meter of body surface area is 12-fold higher 
compared with adult patients.
The pharmacokinetic parameters derived for RAD001 given weekly are summarized in Table 
4.5.
Table 4-5
Steady-state RAD001 pharmacokinetics (weekly dosing)
Parameter
5 mg
10 mg
20 mg
30 mg
50 mg
70 mg
N
4
4
2
5
5
6
Tmax ()
1 (1-2)
1 (1)
1 (1)
2 (1-2)
1 (1-2)
1 (1)
Cmax (ng/mL)
32 ± 15 
69 ± 8
94 ± 0
88 ± 20
163 ± 63
174 ± 49
Cmax/Dose
6.5 ± 3.1
6.9 ± 0.8
4.7 ± 0.0
2.9 ± 0.7
3.3 ± 1.2
2.5 ± 0.7
Ng/mL/mg
AUC ss (ng-h/mL)
283 ± 48
573 ± 258
1001 ± 301
1798 ± 827
2621 ± 633
3615 ± 1497
AUC ss/Dose
57 ± 10
57 ± 27
50 ± 15
60 ± 28
52 ± 13
52 ± 21
(ng-h/mL/mg)
t1/2 (h)
26 ± 3
38 ± 14
31 ± 12
37 ± 6
27 ± 7
26 ± 2
Values are median (range) for tmax and mean ± standard deviation for all others.
Reference:  RAD001 Investigator’s Brochure 2005
Cmax was achieved by 1 to 2 hours post dose.  While Cmax rose in roughly dose proportional 
manner from 5 to 20 mg/week, it appeared to increase less than proportionally at higher doses.
4.5.1.3
RAD001 Pharmacodynamic studies
Pharmacokinetic/pharmacodynamic modeling based on inhibition in a peripheral biomarker 
(S6 kinase inhibition in peripheral blood mononuclear cells) 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 IHC in biopsied tumor tissue 
assessed the degree of inhibition and its duration (for p-S6, p-4E-BP1 and p-Akt expression) 
with the daily and weekly dosing. The pathologist was blinded for the biopsy sequence. There 
was almost complete inhibition of p-S6 at all doses and schedules studied (p=0.001). 
Preliminary results suggest a dose-related decrease in p-4E-BP1 and increase in p-Akt 
udy results are 
provided in Table 4-6.
Table 4-6
p-S6, p-4E-BP1 and p-Akt expression at various doses of RAD001
Dose of RAD001
p-S6 inhibition 
(mean %)
p-4E-BP1 inhibition 
(mean %)
p-Akt activation  
(mean %)


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Daily 5 mg (n=3)
100.0
48.0
22.2
Daily 10 mg (n=6)
92.5
58.2
45.5
Weekly 20 mg (n=5)
96.7
5.9
32.7
100.0
63.8
63.1
Reference:  RAD001 Investigator’s Brochure 2005
4.5.1.4
Temozolomide
Temozolomide is available in 5mg, 20mg, 100mg, and 250mg capsules which are supplied in 
amber glass bottles with child-resistant polypropylene caps. The capsules should not be
opened or chewed. They should be swallowed whole with a glass of water. Procedures for 
handling and disposal of anticancer drugs should be considered.
The dose of Temozolomide will be based on baseline BSA +/- 5%.  The dose of 
temozolomide should be rounded down to the nearest dose available through combination of 
appropriate capsules. To facilitate patient administration of temozolomide, a simpler 
combination of pills is acceptable if the total dose is within +/- 5% of the calculated dose 
based on BSA. The exact dose administered will be recorded in the case report form (CRF).  
The dose of temozolomide will be recalculated when BSA changes >5% or <5% from 
baseline.
Temozolomide should be given with approximately 8 ounces of water over as short a time as 
possible.  Patients should be instructed to swallow capsules whole and in rapid succession and 
to not chew capsules.  If vomiting occurs during the course of treatment, no re-dosing of the 
patient is allowed before the next scheduled dose.  Missed doses should not be repeated.  It is 
recommended that patients take Temozolomide at bedtime and fast for 2 hours before each 
dose and continue fasting for 1 hour after each dose.  Water is allowed during the fasting 
period.
4.5.2
Concomitant therapy
1. Patients on study therapy may be at risk for temozolomide-related selective lymphopenia 
and opportunistic infections. To reduce the risk of opportunistic infections, patients will 
receive prophylaxis with Bactrim DS, 1 tablet orally every Monday, Wednesday, and 
Friday.  Patients allergic to Bactrim should be initiated on an alternate, standard PCP 
prophylaxis regimen.  Prophylaxis will begin for all patients after completing their first 
cycle of therapy (approximately one month after beginning therapy).
2. Temozolomide may be emetogenic, and it is suggested that patients take compazine 10 mg 
po prior to each dose while beginning their treatment regimen. Other antiemetics may be 
utilized at the discretion of the treating physician.  If patients appear to tolerate 
Temozolomide without nausea, the routine prophylactic use of compazine may be 


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discontinued. If refractory nausea develops, the use of prophylactic odansetron should be 
considered.
3. All patients should be maintained on the same medications throughout the study period, as 
medically feasible.
4. The investigator should instruct the patient to notify the study staff about any new 
medications he/she takes after the start of the study drug. All medications (other than 
study drug/s) and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient starts treatment with study drug/s must be 
recorded.
4.5.3
Prohibited medications
1. Growth factors cannot be used to induce elevations in neutrophil count for the purposes of
administration of Temozolomide on the scheduled dosing interval or to allow treatment 
with Temozolomide at a higher dose.  
2. Use of erythropoietin is allowed.
3. No other investigational drugs will be allowed during the study.
4. Patients must be instructed not to take any additional medications (including over-the-
counter products) during the trial without prior consultation with the investigator. All 
medications taken within 30 days of screening should be recorded. If concomitant therapy 
must be added or changed, the reason and name of the drug/therapy should be recorded.
5. In general, the use of any concomitant medication/therapies deemed necessary for the care 
of the patient are allowed, including drugs given prophylactically (e.g. antiemetics +/-
steroids), with the following exceptions:
no other investigational therapy should be given to patients
no chronic treatment with systemic steroids or another immunosuppressive agent
no anticancer agents other than the study medications administered as part of this 
study protocol should be given to patients. If such agents are required for a patient 
then the patient must first be withdrawn from the study.
leukocyte growth factors (e.g.G-CSF and GM-CSF) are not to be administered 
systematically but may be prescribed by the investigator for severe neutropenia if this 
is thought to be appropriate. 
no live vaccines should be administered to patient due to immunosuppressant potential 
of RAD001.   
drugs or substances known to be inhibitors or inducers of the isoenzyme CYP3A
(Table 4.7) cannot be administered in association with RAD001 as these can alter 


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metabolism. Strong inhibitors or inducers of the isoenzyme CYP3A cannot be 
administered as systemic therapy.


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Table. 4.7    Clinically relevant drug interaction: substrates, inducers and inhibitors of 
isoenzyme CYP3A
Substrates
Antibiotics:
clarithromycin
erythromycin 
NOT azithromycin
telithromycin
Anti-arrhythmics:
quinidine
Benzodiazepines:
alprazolam
diazepam
midazolam
triazolam
Immune Modulators:
cyclosporine
tacrolimus (FK506)
HIV Protease Inhibitors:
indinavir
ritonavir
saquinavir 
Prokinetic:
cisapride
Antihistamines:
astemizole
chlorpheniramine
Calcium Channel Blockers:
amlodipine
diltiazem
felodipine
nifedipine
nisoldipine
nitrendipine
verapamil
HMG CoA Reductase Inhibitors:
atorvastatin
cerivastatin
lovastatin
NOT pravastatin
simvastatin
Miscellaneous:
aripiprazole
buspirone
gleevec
haloperidol (in part)
methadone
pimozide 
quinine
NOT rosuvastatin 
sildenafil
tamoxifen
trazodone
vincristine
Inducers
Carbamazepine
Phenobarbital
Phenytoin
Rifabutin
Rifampin
St John’s wort
Troglitazone
Inhibitors
Amiodarone
Cimetidine
Clarithromycin
Diltiazem
Erythromycin
Fluvoxamine
Grapefruit juice
Seville orange juice or 
product
Indinavir
Itraconazole 
Ketoconazole
Mibefradil
Nefazodone
Nelfinavir
Ritonavir
Troleandomycin
Verapamil
Reference to published literature: http://www.medicine.iupui.edu/flockhart/clinlist.htm as of 
July 13, 2006


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4.5.4
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.
5
Visit schedule and assessments
5.1
Visit schedule and assessments
5.1.1
Pretreatment evaluation
Tests to be performed within 28 days prior to initiation of therapy (if day 28 falls on a 
weekend or holiday the deadline may be extended to the next working day):
Radiologic assessment of tumor burden by CT scan within 28 days prior to
initiation of therapy.
Assessment of secretory proteins within 28 days prior to initiation of therapy. 
All patients will undergo an initial assessment of chromogranin A. 
Measurement of gastrin, VIP, or other secretory proteins will also be 
performed depending on tumor type.
Tests to be performed within 14 days prior to initiation of therapy (if day 14 falls on a 
weekend or holiday, the deadline may be extended to the next working day):
All patients will be assessed by history and physical examination, including 
height, weight, vital signs, and performance status within 14 days prior to 
initiation of therapy.
Baseline hematological and biochemical profiles, including CBC with 
differential, platelets, and serum chemistries: fasting glucose, sodium, 
potassium, chloride, bicarbonate, creatinine, blood urea nitrogen, albumin, total 
protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, 
calcium, magnesium, phosphate.
Serum pregnancy test for women of childbearing potential
5.1.2
Evaluations during treatment
5.1.2.1
Day 1 of every cycle 
Physical examination
Toxicity assessment
Vital signs
Weight
Serum chemistries


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CBC with differential
5.1.2.2
Day 15 of cycles 1 through 6 only 
Physical examination
Toxicity assessment
Vital signs
Weight
CBC with differential
5.1.2.3
Data to be obtained following every 2 cycles of treatment (time of 
restaging):
Radiologic assessment of tumor burden by CT scan
Assessment of serum chromogranin A and other secretory proteins (if 
applicable).
5.1.3
Post-treatment evaluation
Data to be obtained at completion of study:
Physical examination
Toxicity assessment
Vital signs
Weight
Serum chemistries
CBC with differential
Radiologic assessment of tumor burden by CT scan. All sites of tumor 
progression or metastases will be noted
Progression-free and overall survival will be determined
Patients who have an ongoing Grade 4 or serious adverse event at the time of discontinuation 
from study drug treatment will continue to be followed at monthly intervals, until resolution 
of toxicity to < Grade 2.  


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5.1.3.1
Table of required data
Table 5.1.  Evaluation and visit schedule
Examination
Screening
Every 
Cycle
Cycles 
1- 6
Every 2 
cycles
End
-28 days
-14 days
Day 1
Day 15
Screening a
X
History
X
X*
X
X
Physical Exam
X
X*
X
X
Vital Signs
X
X*
X
X
Height
X
Weight
X
X*
X
X
ECOG PS
X
X*
X
Pregnancy Test b
X
Hematology c
X
X*
X
X
Serum Chemistry d
X
X*
X
Serum Lipid Profile e
X
X
X
Radiologic Assessment of 
Tumor Burden f
X
X
X
Secretory proteins, serum 
chromogranin g
X
X
X
Prior/concomitant 
medication
X
continuous -------------------------------------
Adverse events
X
continuous --------------------------------------


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* Screening tests do not need to be repeated for cycle 1.
a Screening includes review of: demography/informed consent, inclusion/exclusion criteria, 
relevant medical history/concomitant medications, diagnosis and extent of cancer
b For women of child-bearing potential: Women of childbearing potential must have a 
negative serum pregnancy test within 14 days of enrollment.  Acceptable contraception should 
be used while on study and for at least 30 days after the last dose of RAD001.
c Hematology must include: hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential
d Serum chemistry should be performed while fasting and include: fasting glucose, sodium, 
potassium, chloride, bicarbonate, creatinine, blood urea nitrogen, albumin, total protein, 
SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, calcium, magnesium, 
phosphate.
e Fasting serum lipid profile (repeated every three months) must include: total cholesterol, 
triglycerides, LDL, and HDL
f Screening radiologic tests include abdominal and pelvic CT or MRI and must be done within 
28 days of first RAD001 and temozolomide dose.  Radiological scans documenting target 
lesions should be repeated every two months.  If an initial observation of a partial or complete 
response is made, a confirmation scan should be done no sooner than 4 weeks and no more 
than 6 weeks after the initial observation.  The same type of scan should be used at each 
evaluation.
g Assessment of secretory proteins will be performed within 28 days prior to initiation of 
therapy.
6
Efficacy assessments
The primary efficacy endpoint is objective response rate as determined by radiology review.  
Important secondary endpoints are response duration and progression-free survival.
6.1
Criteria for response
The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines will be employed in 
this study.  For the purposes of this study, target lesions are defined as metastatic lesions that 
are bidirectionally measurable with one diameter measuring at least 2 cm (or 1 cm with spiral 
CT scan).  All lesions up to a maximum of 10 lesions representative of all involved organs 
should be identified as target lesions and will be 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 repetitive measurements (either by imaging techniques or 


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clinically).  A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD.  The baseline sum LD will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease.
Measurable disease: lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as > 20mm with conventional techniques or as > 10mm with spiral 
CT scan.
Non-measurable disease: all other lesions, including small lesions (longest diameter < 20mm 
with conventional techniques or < 10mm with spiral CT scan).
Complete response (CR): complete disappearance of all target lesions, confirmed by repeat 
assessments at no less than 4 weeks after the criteria for response are first met.
Partial response (PR): at least a 30% decrease in the sum of the longest diameter of target 
lesions, taking as reference the baseline sum longest diameter. This must be confirmed by 
repeat assessment at no less than 4 weeks after the criteria for response are first met.
Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of target 
lesions, taking as reference the smallest sum longest diameter recorded since the treatment 
started or the appearance of one or more new lesions.
Stable Disease (SD): neither sufficient decrease to qualify for partial response nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest sum longest 
diameter since the treatment started.
Non-target Lesions: all other lesions (or sites of disease) not included in the “target disease” 
definition should be identified as non-target lesions and should also be recorded at baseline.  
Measurements are not required and these lesions should be followed as “present” or “absent”.
Complete Response:  Disappearance of all non-target lesions.
Non-complete response/Non-progression:  Persistence of one or more non-target lesions.
Progression:  Appearance of one or more new lesions.  Unequivocal progression of existing 
non-target lesions.
Cytology and Histology: if the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should ideally be confirmed by cytology or histology.  These techniques can
be used to differentiate between PR and CR in rare cases.
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response, stable disease, and progressive disease


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Evaluation of Best Overall Response: the best overall response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  In general, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria.
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Note:
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment.
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status.
6.2
Guidelines for Evaluation of Measurable Disease
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g. skin nodules, palpable lymph nodes).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended.
Chest X-ray.  Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT scan is preferable.


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CT scan.  Conventional CT scan should be performed with cuts of 10mm or less in slice 
thickness contiguously.  Spiral CT scan should be performed using a 5mm contiguous 
reconstruction algorithm.  This applies to the chest, abdomen, and pelvis.  Head & neck and 
extremeties usually require specific protocols.
Ultrasound.  Ultrasound should not be used to measure tumor lesions that are clinically not 
easily accessible when the primary endpoint of the study is objective response evaluation.  It 
is a possible alternative to clinical measurements of superficial palpable nodes, subcutaneous 
lesions, and thyroid nodules.  Ultrasound may also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.
6.3
Confirmation Measurement/Duration of Response
Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed no less than 4 weeks after the criteria 
for response are first met.  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 6 weeks.
Duration of Overall Response:  The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
Duration of Stable Disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started.
Progression Free Survival (PFS): PFS is defined as the time from the date of first study 
treatment to the date of the first documented disease progression or death due to any cause.  If 
a patient has not progressed or died at the date of the analysis cut-off or when he/she receives 
any further anti-cancer therapy, PFS is censored at the time of the last tumor assessment 
before the cut-off or the anti-cancer therapy date.
7
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 ±2 days of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study. Safety and 
tolerability 
will 
be 
assessed 
according 
to 
the 
NIH/NCI 
CTCAE
http://ctep.cancer.gov/forms/CTCAEv3.pdf.


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7.1
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:
1. the severity grade (mild, moderate, severe) or (grade 1-4)
2. its relationship to the study drug(s) (suspected/not suspected)
3. its duration (start and end dates or if continuing at final exam)
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization)
5. whether it constitutes a serious adverse event (SAE)
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the [Investigators’ Brochure] or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
7.1.1
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


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requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission
social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Lymphopenia is an expected toxicity of this regimen and is not life threatening.  Patients are 
prescribed prophylactic Bactrim and do not receive more than 6 months of treatment with 
Temozolomide to minimize the effects of this toxicity.  Grade 3-4 lymphopenia will not be 
considered a Serious Adverse Event. Information regarding this toxicity will be collected 
although reporting of each instance of grade 3-4 lymphopenia will not be required.
7.1.2
Novartis instructions for rapid notification of serious adverse events
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E).
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form). 
All events must be reported, by FAX (888-299-4565), to Novartis Pharmaceuticals CS&E
Department within 24 hours of learning of it’s 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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7.2
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.
7.3
Evaluations
7.3.1
Hematology
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential. 
7.3.2
Blood chemistry
Blood chemistry must be performed in a fasting state and include: fasting glucose, sodium, 
potassium, chloride, bicarbonate, creatinine, blood urea nitrogen, albumin, total protein, 
SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, calcium, magnesium, 
phosphate.  Serum lipid profile (triglycerides, total cholesterol, HDL and LDL) will be 
checked after every two cycles of therapy.
Because accurate serum glucose and lipid measurements are required, patients should be 
fasting at the time of the blood sampling.
Assessment of secretory proteins will be performed at baseline. All patients will undergo an 
initial assessment of chromogranin A. Measurement of gastrin, VIP, or other secretory 
proteins will also be performed depending on tumor type.
7.3.3
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
7.3.4
Physical examination
Physical examination will be performed which must comprise a total body examination 
(general appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities and basic nervous system).
Significant findings made after the start of study drug which meet the definition of an Adverse 
Event must be recorded.
7.3.5
Performance status
Performance status will be assessed using the Eastern Cooperative Oncology Group (ECOG) 
perfomance status scale, as follows:


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Grade Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
* As published in Am. J. Clin. Oncol.:
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
7.3.6
Drug levels and pharmacokinetic assessments
Drug level and pharmacokinetic assessments will not be measured.
8
Protocol amendments, or changes in study conduct
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Novartis and the investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB at each study center.  All 
amendments must be reviewed by the DFCI IRB. A copy of the written approval of the IRB 
must be provided to Novartis. Examples of amendments requiring such approval are:
1. increases in drug dose or duration of exposure of subjects,
2. significant changes in the study design (e.g. addition or deletion of a control group),
3. increases in the number of invasive procedures,
4. addition or deletions of a test procedure required for monitoring of safety.
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients 
included in the trial.  If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons Novartis must be notified and the IRB at 
the center must be informed immediately.   Amendments affecting only administrative aspects 
of the study do not require formal protocol amendments or IRB approval but the IRB must be 
kept informed of such administrative changes. Examples of administrative changes not 
requiring formal protocol amendments and IRB approval include:


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1.
changes in the staff used to monitor trials 
2.
minor changes in the packaging or labeling of study drug.
9
Data management
9.1
Data collection
The DF/HCC QACT will develop a set of electronic case report forms (eCRFs).  These forms 
are designed to collect data for each study.  The CRCs designated at each institution will enter 
data on the eCRFs, and data will be reviewed by the Overall PI.   
10
Statistical methods
10.1
Sample size and power calculation
The study is designed with a total accrual goal of up to 44 patients (up to 12 in Cohorts 1/2 
and up to 32 in Cohort 3).  If no toxicity is observed in the first two cohorts of patients, a total 
of 32 patients in Cohort 3 will be treated at the full dose of each drug (RAD001 at the MTD 
plus temozolomide).
A two-stage design will be employed for the patients treated at the full doses of each drug: 17 
patients in the first stage and 15 patients in the second stage.  The research plan incorporates 
anticipated response rate into the early stopping rule. At the end of the first stage of accrual 
(17 patients) data will be reviewed to decide if the study should be terminated due to 
inactivity of the treatment. Thus, the design protects patients from inappropriate treatment. 
The investigators would wish to conclude that the regimen is worthy of further pursuit if the 
clinical response rate is 20% or greater, and conclude that the regimen is not worthy of pursuit 
if the response rate is 5% or less (Please refer to Section 1.2). The proposed design is based on 
the following criteria:
1. In the first stage, 17 patients will be treated
2. If there are 0 responses, the study will be terminated
3. If there are 1 or more responses, the study will proceed to the second stage, accruing an 
additional 15 patients to a total of 32
4. If the second stage is completed with a total of 3 or more responses, then it will be 
concluded that the treatment deserves further study
5. Conversely, it the responses total 2 or fewer, then the treatment will not be recommended 
for further study.
With this design, the probability of terminating the study after 17 patients is 0.42 if the true 
but unknown response rate is 5%, but 0.02 if the true but unknown response rate is 20%. The 
study will have overall power of 0.95, and overall type I error of 0.18. Allowing for a 5% rate 
of ineligibility, the overall accrual goal will be 32 patients.


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10.2
Statistical analysis
For the primary objective, we will estimate the response rate and provide the associated 95% 
confidence interval. For the secondary objectives, we will use the Kaplan-Meier method to 
estimate the distributions of time to response and progression-free survival. We will apply 
multivariate analysis to further examine effects of factors that are potentially related to these 
outcomes.
11
Registration Procedures
General Guidelines for DF/HCC and DF/PCC Institutions
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.
11.2
Registration Process for DF/HCC and DF/PCC Institutions
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM 
to 5:00 PM Eastern Standard Time. In emergency situation when a participant must 
begin treatment during off-hours or holidays, call the QACT registration line at 
617-632-3761 and follow the instructions for registering participants after hours.  
Registrations received after 5pm EST aren’t processed until the next business 
morning.
The registration procedures are as follows:
1. Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments.


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2. Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and 
ancillary studies will not be completed if eligibility requirements are not 
met for all studies. 
3. Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 617-632-2295.
Exception: DF/PCC Affiliate sites must fax the entire signed consent form 
including HIPAA Privacy Authorization and the eligibility checklist to the 
Network Affiliate Office. The Network Affiliate Office will register the 
participant with the QACT. 
4. The QACT Registrar will (a) validate eligibility, (b) register the participant 
on the study, and (c) randomize the participant when applicable. 
5. The QACT Registrar will send an email confirmation of the registration 
and/or randomization to the person initiating the registration immediately 
following the registration and/or randomization. Treatment can not be 
initiated until after receipt of registration confirmation.
11.3
Registration Process for Other Participating Institutions
Please see section 5.7 in DSMP, Appendix B
12
Data and Safety Monitoring
12.1
Data Reporting 
12.1.1
Method 
The QACT will collect, manage, and monitor data for this study. 
12.1.2
Data Submission 
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows:


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Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with QACT
On Study Form
Within 14 days of registration
Baseline Assessment Form
Within 14 days of registration
Treatment Form
Within 10 days of the last day of the cycle
Adverse Event Report Form
Within 10 days of the last day of the cycle
Response Assessment Form
Within 10 days of the completion of the 
cycle required for response evaluation
Off Treatment/Off Study 
Form
Within 14 days of completing treatment or 
being taken off study for any reason
Follow up/Survival Form
Within 14 days of the protocol defined 
follow up visit date or call
12.2
Safety Meetings
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.
12.3
Monitoring
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 


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designated by the Principal Investigator (or Protocol Chair) or DF/HCC. The purpose 
of these audits or inspections is to examine study-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, 
and accurately reported in accordance with the protocol, institutional policy, Good 
Clinical Practice (GCP), and any applicable regulatory requirements.
All data 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. 
13
References
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14
Procedures and instructions
14.1
Publication of results
Any formal presentation or publication of data from this trial may be published after review 
and comment by Novartis and prior to any outside submission.  Novartis must receive copies 
of any intended communication in advance of publication (at least fifteen working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations.  Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the 
interests of Novartis and, in accord with the trial contract and shall not permit disclosure of 
Novartis confidential or proprietary information.
14.2
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.
14.3
Discontinuation of study
Novartis reserves the right to discontinue any study under the conditions specified in the 
clinical trial agreement.
14.4
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:
1.
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community.
2.
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations).
3.
Declaration of Helsinki 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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14.4.1
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.
14.4.2
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.
14.4.3
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.


















































1
DFCI IRB Protocol #: 07-325 
APPENDIX  B 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 


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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 ……………………… 7 
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 
5.3 Informed Consent Requirements 
5.4 IRB Documentation 
 
 
5.5 IRB Re – Approvals 
 
 
5.6 Participant Confidentiality and Authorization 
5.7 Participant Registration 
 
 


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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 
        9.1 Ongoing Monitoring of Protocol Compliance 
 
            9.2 Evaluation of Participating Institution Performance 
 
            9.3 On-Site Auditing 
 
 
            9.4 Substandard Performance 
 


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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, 
submission, and approval of a protocol as well as its subsequent amendments per the DFCI IRB 
and applicable regulatory guidelines (CTEP, FDA, OBA 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 (ie.CTEP Protocol and Information Office (PIO), FDA, OBA 
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 (i.e. CTEP Multi-Center Guidelines).  In addition to the Lead 
Institution, the Quality Assurance Office for Clinical Trials (QACT) provides support services to 


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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
Protocol Chair (DF/HCC Principal Investigator) 
The Protocol Chair, Jennifer Ang Chan, MD will accept responsibility for all aspects of the 
Multi-Center Data and Safety Monitoring Plan to: 
Oversee the coordination, development, submission, and approval of the protocol as well as 
subsequent amendments.    
Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the protocol. 
Assure all participating institutions are using the correct version of the protocol. 
Monitor progress and overall conduct of the study at all participating institutions.
Ensure all DFCI IRB, DF/HCC and other applicable (i.e.  FDA)- reporting requirements are 
met.  
Review data and maintain timely submission of data for study analysis.  
Act as the single liaison with FDA (sponsor-investigator IND trials) , as applicable. 
Identify participating institutions and obtain accrual commitments. The Protocol Chair will also 
submit a protocol attachment labeled as “Participating Investigators” to the DFCI IRB and if 
applicable, FDA,that provides 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 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: 
Assist in protocol review. 
Maintain copies of Institutional Review Board (IRB) approvals from all 
participating institutions. 
Maintain updated roster of participants.
Verify eligibility. 
Verify response. 
Collect data on protocol specific CRFs. 
Prepare all submitted data for review by the Protocol Chair. 
Maintain documentation of Serious Adverse Event (SAE) reports submitted by 


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Participating Institutions and submit to Protocol Chair for timely review.   
Distribute external Serious Adverse Event safety reports.
Monitor and audit Participating Institutions either by on-site inspection of selected 
participant records and/or with submitted 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: 
Develop protocol specific case report forms (CRF/eCRFS). 
QA/QC data of protocol specific CRFs.
Provide Central Participant Registration. 
Confirm eligibility and consent.  
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: 
Commit to accrual to the Lead Institution’s (DF/HCC) protocol. 
Submit protocol and/or amendments to their local IRB. 
Update Coordinating Center (Lead Institution or designee) with research staff changes on 
       a timely basis. 
Register participants through the QACT.
Submit source documents, research records, and CRFs per protocol specific                       
       submission guidelines to the Coordinating Center (Lead Institution or designee).  
Submit Serious Adverse Event reports directly to the Coordinating Center (Lead                
      Institution or designee)..
Submit deviations and violations to the Coordinating Center (Lead Institution or     
            designee). 
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 ASSURANCE OFFICE FOR CLINICAL TRIALS 
The DF/HCC QACT is a unit that has been developed to collect, 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.  


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3.1
Organizational Structure 
The DF/HCC Quality Assurance Office for Clinical Trials administrative structure consists of: 
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.  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:
Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the 
protocol as an appendix. 
Identify participating institutions and obtain accrual commitments. The Protocol Chair 
will also submit a protocol attachment labeled as “Participating Investigators” to the 
DFCI IRB and if applicable FDA, that provides the names and contact information for 


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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.  
Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the Protocol Chair. 
Ensure that there is only one version of the Protocol and that all Participating 
Institutions use the correct version.
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: 
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. 
Provide necessary administrative sections, including paragraphs related to 
registration logistics, data management schedules, and multi-center guidelines.  
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.
Derivation of the study calendar, if applicable. 
Assistance in preparation and maintenance of case report forms.  
Maintain and document communication with all participating institutions.  
5.0 PROTOCOL MANAGEMENT 
The Coordinating Center (Lead Institution of designee) 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 (Lead Institution or designee) will distribute the final approved protocol 
and any subsequent 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 


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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 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. 
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.  All participating sites must follow this policy. 
5.4 IRB Documentation 
The following must be on file with the DF/HCC Lead Institution or designee prior to participant 
registration:
Approval Letter of the institution's IRB (An Expedited IRB first approval is NOT 
acceptable)
IRB approval for all amendments 
It is the individual institution's responsibility to notify its IRB of protocol revisions.  Participating 
institutions will have 90days from receipt to provide the DH/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:  


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Change of eligibility (inclusion/exclusion) criteria 
Change in design of protocol 
Change in statistical section 
Change in sample size/accrual (e.g., doubling the sample size) 
Change in informed consent 
Change of estimated dropout rate 
Change of treatment or intervention 
Change of device 
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-
Center Protocol, with the approval from the DFCI IRB and if applicable NCI/CTEP, 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
To register a participant, the following documents should be completed by the DF/HCC Multi-


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Center Protocol participating site and faxed to the Lead Institution’s study coordinator at (617) 
582-7988. : 
Copy of required laboratory tests [Hematology, Chemistry, Lipid Panel and 
Secretory Proteins] 
Signed informed consent form 
HIPAA authorization form (if separate from the informed consent document)
Other appropriate forms including the Eligibility Screening Worksheet,and 
Pathology Report confirming diagnosis, ) 
The research DF/HCC Multi-center Protocol participating site will then call or e-mail the Lead
Institution or designee to verify eligibility. To complete the registration process, the Lead
Institution or designee will: 
Register the participant on the study with the DF/HCC Quality Assurance Office       
       for Clinical Trials (QACT)
Fax or e-mail the participant case number, and if applicable the dose treatment 
level, to the participating site 
Call the research nurse or data manager at the participating site and verbally 
confirm registration 
5.8 DF/HCC Multi-center Protocol Case Number 
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 DF/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 


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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.  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: 
COMMON FORMS & REPORTS 
Eligibility Checklist, (Informed Consent/ Participant Authorization for the Release 
             of Personal Health Information) 
On-study Form 
Baseline Assessment Form (Baseline disease assessment/measurement) 
Treatment Forms 
Adverse Event Forms 
Response Assessment Form (Follow-up disease assessment/Measurement) 
Off-Treatment/Off Study Form 
Follow-Up/Survival Forms 
Note: It is necessary to send only ONE copy of all paper Case Report Forms.
Please see section 12.1.2 of the protocol  for schedule of data submission.
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: 
Lab tests required for eligibility must be completed within 14 days prior to study 
enrollment by the QACT.
For protocols requiring measurable disease, lab baseline measurements must be 
completed within  28 days prior to study enrollment by the QACT. Examples: tumor 
markers and hormones ( Chromogranin A, Gastrin, VIP).
Non-lab tests required for eligibility must be performed within  28 days prior to 
study entry. Example: radiological scans


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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:
Demographic data
Prior therapy
Past medical and surgical history
Description of participant’s physical status at protocol registration
Disease site specific data
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.  
5.10.4 Treatment Form 
Purpose - Records the following information related to the time the participant receives 
protocol treatment: 
Participant, Protocol, Affiliate information
Protocol treatment and supportive therapy per treatment cycle 
Protocol specific laboratory values per treatment cycle 
All medications other than protocol chemotherapy agents used to treat 
concomitant    diagnoses, if applicable 
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.
5.10.6 Response Assessment Form
Purpose – Documents objective and subjective response as defined by the protocol. 
Records all pertinent radiographic and laboratory measurements of disease utilized in 


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determining response evaluations.  
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. 
5.10.8    Follow up / Survival Form
Purpose - Summarizes participant status at a given point in time after being removed 
from treatment.  
 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?
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 


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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.   
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 will be supplied the investigational agents by the DF/HCC Lead Institution. 
Participating sites will contact Lead Institutions Research Pharmacy by email or phone and drugs   
will be shipped overnight via FedEx to the shipment address provided by participating sites. Drug 
should be stored as specified in section 4.5 of the protocol. It is the responsibility of the Participating 
sites to contact Lead Institutions Research Pharmacy. A log should be kept of all investigational drug 
dispensed on the NCI drug accountability forms. 
The local IRB should be kept informed of who will supply the agent (i.e., NCI or a 
pharmaceutical company) so that any regulatory responsibilities can be met in a timely fashion.  


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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 
assigned to the protocol (CTCAE Version 3.0) 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 
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. 
Unless otherwise specified in the protocol, the study will utilize the Cancer Therapy Evaluation 
Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 for 
Toxicity and Adverse Event reporting.  A copy of the CTC or CTCAE Criteria can be 
downloaded from the CTEP home page (http://ctep.info.nih.gov).
7.2 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is delineated in 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.  
The Lead Institution will maintain documentation of all Adverse Event Reporting and be 
responsible for communicating all SAEs to all Participating sites. 
7.3 Guidelines for Processing IND Safety Reports


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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.
IND Safety Reports: The Protocol chair at the Lead Institution. will be sent a copy of expedited 
adverse events reports.. Within 7 business days of receipt of the notification, the Lead Institution 
or designee will forward the letters by email to the Participating sites with protocol specific 
instructions for IRB submissions, participant notifications, etc. For routine IND Safety Reports, 
that do not require an immediate revision to the protocol and/or model informed consent 
documents should be filed with their protocol and a copy of the report sent to  theirIRB 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 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 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 and Lead 
Institution 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 
policy.
Protocol violations occurring at a participating institution will be submitted to that site’s own 
IRB.   A copy of the participating institution’s IRB report and determination will be forwarded 
to the DF/HCC Lead Institution or designee by facsimile, within 10 business days after the 
original submission.  
Coordinating Center:  Upon receipt of the violation/deviation report from the participating 


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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 
1) 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. 
9.3 On-Site Auditing
9.3.1 DF/HCC Sponsored Trials 
.
For all DF/HCC sponsored protocols: 
The participating institutions are required to submit subject source documents to the 
DF/HCC Lead Institution or designee for monitoring. Participating sites will be asked to 
submit material for the first patient after completion of 2 cycles. Thereafter, subjects will be 
selected at random for on-site monitoring conducted by the DF/HCC Lead Institution or 
designee. Participating sites will be notified 28 days prior to monitoring visit.  


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DF/HCC Lead Institution requires the participating site to submit all relevant source 
documentation after the frist patient is enrolled and has completed their 1st restaging scan. 
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 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, DFCI IRB and the NCI for CTEP trials, is charged with considering the 
totality of an institution’s performance in considering institutional participation in the DF/HCC 
Multi-Center Protocol. 
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.