Conditions: Adult Diffuse Astrocytoma Adult Mixed Glioma Adult Oligodendroglioma Adult Subependymal Giant Cell Astrocytoma Recurrent Adult Brain Neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 58
Healthy volunteers: no

Brief summary:
This phase II trial studies how well everolimus works in treating patients with recurrent low-grade glioma. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.

Detailed description:
PRIMARY OBJECTIVES:

1\. To determine progression-free survival at 6 months associated with use of RAD001 (everolimus) in patients initially diagnosed with low-grade glioma who undergo biopsy or subtotal resection at the time of recurrence with pathologic evidence of recurrent low-grade glioma (LGG).

SECONDARY OBJECTIVES:

1. To further delineate the safety profile of RAD001 in patients with recurrent LGG.
2. To assess overall survival (OS) in patients treated with RAD001.
3. To assess the objective response rate (ORR) in patients treated with RAD001.
4. To assess the correlation of protein kinase B (PKB)/Akt and phosphatase and tensin homolog (PTEN) expression with response, progression status by 6 months, and OS in patients treated with RAD001.

Arms:
arm 1: Single-arm study with patients receiving Everolimus orally once daily dosing of 10 mg continuously from Day 1 of study until progression of disease or unacceptable toxicity. In addition archival tissue will be analysed for markers of P13K/mTOR pathway activation.

Interventions: intervention 1: Everolimus intervention 2: Archival Tissue Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Phase II Trial of RAD001 in Patients with Recurrent Low Grade 
Glioma 
RAD001 
 
Study number: CRAD001CUS58T  
 
 
Author(s): 
Daphne Haaskogan, MD  
Susan Chang, MD  
 
 
Version 
7.0 
Version date 
3/15/2011 
 
 


 
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Table of contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 3 
1 
Introduction ......................................................................................................................... 6 
1.1 
RAD001 (everolimus) ............................................................................................. 6 
1.1.1 
mTOR pathway and mechanism of action .............................................. 6 
1.1.2 
Preclinical studies .................................................................................... 7 
1.1.3 
Clinical experience ................................................................................ 10 
2 
Study objectives ................................................................................................................. 18 
3 
Investigational plan ........................................................................................................... 18 
3.1 
Overall study design .............................................................................................. 18 
3.2 
Study population .................................................................................................... 19 
3.2.1 
Patient population.................................................................................. 19 
3.2.2 
Inclusion and exclusion criteria ............................................................ 19 
3.2.3 
Interruption or discontinuation of treatment ......................................... 22 
3.2.4 
Monitoring of RAD001 suspected toxicities......................................... 24 
3.2.5 
Known Undesirable Side Effects of RAD001 ...................................... 24 
3.3 
Treatments ............................................................................................................. 29 
3.3.1 
RAD001 Administration ....................................................................... 29 
3.3.3 Concomitant therapy ..................................................................................... 30 
3.3.4 
Treatment compliance ........................................................................... 35 
3.4 
Visit schedule and assessments ............................................................................. 35 
3.4.1 
Visit schedule ........................................................................................ 35 
3.4.2 
Efficacy assessments ............................................................................. 40 
3.4.3 
Safety assessments ................................................................................ 43 
3.4.4 
Novartis instructions for rapid notification of serious adverse 
events ..................................................................................................... 45 
3.4.5 
Drug levels and pharmacokinetic assessments ..................................... 49 
4 
Protocol amendments, or changes in study conduct .......................................................... 49 
5 
Data management .............................................................................................................. 50 
5.1 
Data collection ....................................................................................................... 50 
6 
Statistical methods ............................................................................................................. 50 
6.1 
Statistical methods ................................................................................................. 50 
7 
References ......................................................................................................................... 54 
8 
Procedures and instructions ............................................................................................... 59 
8.1.1 
Publication of results ............................................................................. 59 


 
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8.1.2 
Disclosure and confidentiality............................................................... 59 
8.1.3 
Discontinuation of study ....................................................................... 59 
8.2 
Ethics and Good Clinical Practice ......................................................................... 59 
8.2.1 
Institutional Review Board/Independent Ethics Committee ................. 59 
8.2.2 
Informed consent ................................................................................... 60 
8.2.3 
Declaration of Helsinki ......................................................................... 60 
 
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 


 
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HER 
Human Epidermal Receptor 
HUVECS 
human umbilical endothelial cells 
IC50 
Inhibitory concentration at 50% 
IEC 
Independent Ethics Committee 
IGF1-R 
Insulin-like Growth Factor 1 Receptor 
IHC 
immunohistochemistry 
INN 
International Non-proprietary Name 
INR 
International Normal Ratio 
IRB 
Institutional Review Board 
LC-MS 
liquid chromatography method with mass spectrometry 
LDL 
Low-density lypoproteins 
LLOQ 
Lower limit of quantification 
MAPK 
Mitogen Activated Protein Kinase 
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 


 
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TSC2 
Tuberous Sclerosis Complex 2 
TUNNEL 
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin 
Nick End Labeling 
ULN 
upper limit of normal 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
total white blood cell count 
WHO 
World Health Organization 


 
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1 
Introduction 
1.1 
RAD001 (everolimus) 
RAD001 (everolimus) is a novel oral derivative of rapamycin.  
RAD001 has been in clinical development since 1996 as an immunosuppressant in solid organ 
transplantation and has obtained marketing authorization (Certican®) for prophylaxis of 
rejection in renal and cardiac transplantation in a number of countries, including the majority 
of the European Union. RAD001 has been in development for patients with various 
malignancies since 2002. RAD001 2.5mg, 5mg and 10mg tablets were approved under the 
trade name Afinitor® for patients with advanced renal cell carcinoma (RCC) after failure of 
treatment with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU and several other 
countries and is undergoing registration in other regions worldwide. Afinitor® was also 
recently approved for the treatment of patients with subependymal giant cell astrocytoma 
(SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are 
not candidates for curative surgical resection. 
RAD001 is being investigated as an anticancer agent based on its potential to act: 
 Directly on the tumor cells by inhibiting tumor cell growth and proliferation  
 Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent 
inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced proliferation 
of endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is 
well established, and the mTOR pathway has been implicated in the regulation of tumor 
production of proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
1.1.1 
mTOR pathway and mechanism of action 
At cellular and molecular levels, RAD001 acts as a signal transduction inhibitor. RAD001 
selectively inhibits mTOR (mammalian target of rapamycin), a key and highly conservative 
serine-threonine kinase, which is present in all cells and is a central regulator of protein 
synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. mTOR 
is the only currently known target of RAD001 (Reviewed in Boulay and Lane 2007). 
mTOR is downstream of the PI3K/AKT pathway, a pathway known to be dysregulated in a 
wide spectrum of human cancers (e.g. through loss/mutation of the PTEN negative regulator; 
through PI3K mutation/amplification; through AKT/PKB overexpression/overactivation; 
through modulation of TSC1/TSC2 tumor suppressors). In addition, activation of the 
PI3K/AKT/mTOR pathway is frequently a characteristic of worsening prognosis through 
increased aggressiveness, resistance to treatment and progression.  
The main known functions of mTOR include the following (Bjornsti and Houghton 2004; 
Boulay and Lane, 2007): 
 mTOR functions as a sensor of mitogens, growth factors and energy and nutrient levels, 
facilitating cell-cycle progression from G1 to S phase in appropriate growth conditions. 


 
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 The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors.  
 Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and 
activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates translation of 
important messages, including those encoding the HIF-1 proteins, c-myc, ornithine 
decarboxylase, and cyclin D1, as well as ribosomal proteins themselves.  
 The activation of mTOR pathway leads to increased production of pro-angiogenic factors 
(i.e., VEGF) in tumors and to cell growth and proliferation of tumor, endothelial, and 
smooth muscle cells. 
 The regulation of mTOR signaling is complex and involves positive regulators, such as 
AKT that phosphorylate and inactivate negative regulators such as the Tuberous Sclerosis 
Complex (TSC1/TSC2). 
mTOR is represented by two structurally and functionally distinct multiprotein signaling 
complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR 
complex 2, rapamycin insensitive) (Wullschleger et al. 2006).  
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also known as PKB, 
protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2) (Bjornsti and Houghton 
2004). Activated AKT phosphorylates TSC2, which leads to the dissociation of TSC1/TSC2 
complex, thus inhibiting the ability of TSC2 to act as a GTPase activating protein. This allows 
Rheb, a small G-protein, to remain in a GTP bound state and to activate mTORC1. AKT can 
also activate mTORC1 by PRAS40 phosphorylation, thereby relieving the PRAS40-mediated 
inhibition of mTORC1 (Manning and Cantley 2007; Wang, et al. 2007).  
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly 
by receptor tyrosine kinase (RTK) signaling (Manning and Cantley 2007). It has been 
suggested that mTORC2 phosphorylates and activates a different pool of AKT that is not 
upstream of mTORC1. PHLPP phosphatase plays a role of a negative regulator. mTORC2 is 
rapamycin insensitive and is required for the organization of the actin cytoskeleton 
(Wullschleger et al. 2006). 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone rapamycin 
and its derivatives, such as RAD001. Once these agents bind to the 12 kDa cytosolic FK506-
binding protein immunophilin FKBP12, the resulting rapamycin-FKBP12 complexes bind to 
a specific site near the catalytic domain of mTORC1 and inhibit phosphorylation of mTOR 
substrates. As a consequence, downstream signaling events involved in regulation of the G1 
to S-phase transition are inhibited. This mechanism is thought to be responsible for the 
immunosuppressive effects of rapamycin as well as its putative antineoplastic activity 
[Reviewed in (Sabatini 2006)]. As many cancers are characterized by dysregulation of G1 
transit (for example, overexpression of cyclin or cyclin-dependent kinases), inhibition of 
mTOR becomes an intriguing target for inducing cytostasis (Bjornsti and Houghton 2004).  
1.1.2 
Preclinical studies 
Everolimus acts as an inhibitor of interleukin and growth-factor-dependent proliferation of 
cells. The only currently known target of everolimus is mTOR, a key regulatory protein 


 
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affecting cell growth (Boulay and Lane, 2007). Everolimus exerts its activity through high 
affinity interaction with an intracellular receptor protein, the immunophilin FKBP12. The 
FKBP12/everolimus complex subsequently interacts with the mTOR protein kinase, inhibiting 
downstream signaling events involved in regulation of the G1 to S-phase transition.  
The main known functions of mTOR include: 
• Function as a sensor of mitogens, growth factors, energy and nutrient levels, facilitating cell-
cycle progression from G1 - S phase in appropriate growth conditions. 
• Regulation of protein synthesis important for tumor cell proliferation and angiogenesis 
through inactivating eukaryotic initiation factor 4E binding proteins and activating the 40S 
ribosomal S6 kinases (e.g. p70S6K1). For example, activation of the mTOR pathway leads to 
a) increased production of pro-angiogenic factors (e.g. VEGF) in tumors b) tumor, endothelial 
and smooth muscle cell growth and proliferation. 
The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors. The regulation of 
mTOR signaling is complex and involves positive regulators such as AKT that phosphorylate 
and inactivate negative regulators such as the Tuberous Sclerosis Complex (TSC1/TSC2). In 
summary, mTOR has pleiotropic functions; hence, the activities of everolimus may vary 
depending upon cell type. 
The mTOR inhibitory activities presumably contribute to the antiproliferative activity of 
everolimus against tumor cell lines. However, everolimus may also exert an antitumor effect 
through the inhibition of angiogenesis. Indeed, both rapamycin and everolimus potently 
inhibit proliferation of endothelial cells (Francesc 1999, Yu 1999, Lane et al 2009) and have 
antiangiogenic activity in vivo (Guba 2002, Tsutsumi 2004, Mabuchi et al 2007, Lane et al 
2009). Exactly which molecular determinants predict responsiveness of tumor cells to 
everolimus is still unclear. Currently, the activation status of the PI3K/AKT/mTOR/p70 S6K 
pathway may be indicative of responsiveness to rapamycins. For example, preclinically, loss 
of PTEN or constitutive/hyper-activation of AKT has been suggested to sensitize tumors to 
the effects of inhibition of mTOR (Reviewed in Boulay and Lane, 2007, Mabuchi et al 2007). 
Also, clinically, it has been suggested that high p70S6K activation in baseline GBM tumor 
samples may predict a patient population more likely to derive benefit from mTOR inhibition 
(Galanis, et al 2005). 
Everolimus is a highly specific inhibitor of mTOR, which is afforded by high-affinity binding 
to the protein FKBP-12 (IC50 of 5.3 nM) similar to that of rapamycin. Similar potency of 
rapamycin and everolimus was also demonstrated at forming the mTOR / FKBP-12 tertiary 
complex in vitro. Specificity was demonstrated by a lack of inhibitory activity against 10 
other protein kinases at concentrations up to 10 μM. 
 
The antiproliferative effects of everolimus were investigated in a mixed panel of 48 different 
tumor cell lines (including breast, colon, epidermoid, glioblastoma, lung, melanoma, prostate 
and renal). The majority of tumor cell lines were highly sensitive to the anti-proliferative 
effects of everolimus while a few others appeared intrinsically insensitive, or „resistant‟ (IC50 
range 0.2 to 4125 nM) (O‟Reilly and McSheehy, 2009). The median IC50 value of the 48 cell 


 
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lines was 0.5 nM. Similar findings have been observed for rapamycin (Huang and Houghton 
2002). Everolimus was also shown to have activity in human pancreatic neuroendocrine cells, 
where induction of apoptosis was reported (Zitzmann, et al 2007), as well as in acute myeloid 
leukemia cells (Zeng, et al 2007), mantle cell lymphoma cells (Haritunians, et al 2007), adult 
T-cell leukemia cells (Ikezoe, et al 2007), diffuse large B cell lymphoma cells (Wanner, et al 
2006), pancreatic tumor cells (Tuncyurek, et al 2007), ovarian cancer cells (Treeck, et al 2006, 
Mabuchi, et al 2007) and hepatocellular carcinoma cells (Sieghart, et al 2007). 
Everolimus was also evaluated in a clonogenic assay using cells derived from 81 patient 
derived tumor xenografts never cultured in vitro (11 human tumor types with 3 to 24 tumors 
each: bladder, colon, gastric, NSCLC, SCLC, breast, ovary, pancreatic, renal, melanoma, and 
pleuramesothelioma). Everolimus inhibited colony formation in a concentration-dependent 
manner (mean IC50: 175 nM). In addition, normal hematopoetic stem cells were found to be 
relatively insensitive to everolimus, with an IC50 about 15 fold higher than the tumor lines. 
Everolimus is a highly specific inhibitor of mTOR, which is afforded by high-affinity binding 
to the protein FKBP-12 (IC50 of 5.3 nM) similar to that of rapamycin. Similar potency of 
rapamycin and everolimus was also demonstrated at forming the mTOR / FKBP-12 tertiary 
complex in vitro. Specificity was demonstrated by a lack of inhibitory activity against 10 
other protein kinases at concentrations up to 10 μM. The antiproliferative effects of 
everolimus were investigated in a mixed panel of 48 different tumor cell lines (including 
breast, colon, epidermoid, glioblastoma, lung, melanoma, prostate and renal).  
Everolimus was also shown to have activity in human pancreatic neuroendocrine cells, where 
induction of apoptosis was reported (Zitzmann, et al 2007), as well as in acute myeloid 
leukemia cells (Zeng, et al 2007), mantle cell lymphoma cells (Haritunians, et al 2007), adult 
T-cell leukemia cells (Ikezoe, et al 2007), diffuse large B cell lymphoma cells (Wanner, et al 
2006), pancreatic tumor cells (Tuncyurek, et al 2007), ovarian cancer cells (Treeck, et al 2006, 
Mabuchi, et al 2007) and hepatocellular carcinoma cells (Sieghart, et al 2007). Everolimus 
was also evaluated in a clonogenic assay using cells derived from 81 patient derived tumor 
xenografts never cultured in vitro (11 human tumor types with 3 to 24 tumors each: bladder, 
colon, gastric, NSCLC, SCLC, breast, ovary, pancreatic, renal, melanoma, and 
pleuramesothelioma). Everolimus inhibited colony formation in a concentration-dependent 
manner (mean IC50: 175 nM). In addition, normal hematopoetic stem cells were found to be 
relatively insensitive to everolimus, with an IC50 about 15 fold higher than the tumor lines. 
 
Everolimus was effective and well tolerated against subcutanuous (s.c.) tumors established 
from a variety of tumor cell lines of diverse histotypes (NSCLC, pancreatic, colon, melanoma, 
epidermoid), including a PgP170-overexpressing, multi-drug resistant tumor line. Typically, 
the antitumor activity of everolimus was that of reduction of tumor growth rates rather than 
producing regressions or stable disease although, in the case of A549 and NCI-H596 lung and 
ARJ42 pancreatic tumors, regressions could be obtained. These effects occurred within the 
dose range of 2.5 to 10 mg/kg, p.o., once per day. The change in tumor volume of the treated 
mice divided by the change in tumor volume of control mice (T/C) typically ranged from 
approximately 15 to 50% at optimal doses. A marked loss of antitumor activity occurred when 
tumor-bearing mice were treated with everolimus once per week, but improved moderately 


 
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with twice per week dosing. Antitumor activity of everolimus has also been demonstrated in 
mouse models of ovarian (Mabuchi, et al 2007), breast (Lu, et al 2007, Torres-Arzayus, et al 
2007) and gastrointestinal stromal tumors (Rossi, et al 2006). 
 
Pre-clinical safety 
In safety pharmacology studies, everolimus was devoid of relevant effects on vital organ 
functions including the cardiovascular, respiratory and nervous systems. Everolimus had no 
effects on QT interval. Furthermore, everolimus showed no antigenic potential. Although 
everolimus passes the blood-brain barrier, there was no indication of relevant changes in the 
behavior of rodents, even after single oral doses up to 2000 mg/kg or after repeated 
administration at up to 40 mg/kg/day. 
The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys, 
and rabbits. The major target organs were male and female reproductive systems (testicular 
tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several 
species; lungs (increased alveolar macrophages) in rats and mice; and eyes (lenticular anterior 
suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of 
age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse 
(exacerbation of background lesions). There was no indication of kidney toxicity in monkeys 
or minipigs. 
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of 
clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not 
indicate any oncogenic potential in mice and rats up to the highest doses, corresponding 
respectively to 4.2 and 0.2 times the estimated clinical exposure. In reproduction studies, 
everolimus was toxic to the conceptus in rats and rabbits, and was considered potentially 
teratogenic in rats. It is therefore recommended that women of childbearing potential should 
use effective contraceptive measures during the entire treatment period and for 8 weeks 
thereafter. 
 
 
More pre-clinical information is provided in the [Investigator‟s Brochure]. 
1.1.3 
Clinical experience 
1.1.3.1 
RAD001 Pharmacokinetics 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The steady-state AUC0-τ is 
dose-proportional over the dose range between 5 to 70 mg in the weekly regimen and 5 and 
10 mg in the daily regimen. Steady-state was achieved within two weeks with the daily dosing 
regimen. Cmax is dose-proportional between 5 and 10 mg for both the weekly and daily 
regimens. At doses of 20 mg/week and higher, the increase in Cmax is less than dose 
proportional. In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 
mg (as measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat 


 
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meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the 
post absorption phase concentration-time profile. 
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 
5 to 5,000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is 
approximately 20% at blood concentrations observed in cancer patients given everolimus 10 
mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients 
with moderate hepatic impairment.  
Everolimus is a substrate of CYP3A4 and a substrate and moderate inhibitor of PgP. 
Following oral administration, everolimus is the main circulating component in human blood 
and is considered to contribute the majority of the overall pharmacologic activity.  No specific 
excretion studies have been undertaken in cancer patients; however, data available from the 
transplantation setting found the drug to be mainly eliminated through the feces. There was a 
significant correlation between AUC0-τ and pre-dose trough concentration at steady-state on 
the daily regimen. The mean elimination half-life of everolimus is approximately 30 hours. 
 
Table 3-3 (Section 3.3.3) lists examples of clinically relevant CYP3A inhibitors and inducers. 
Please refer to Section 3.3.3 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications. 
More information on RAD001 pharmacokinetics is provided in the [Investigator‟s Brochure]. 
1.1.3.2 
RAD001 Pharmacodynamic studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the biomarker p70S6 
kinase 1 [S6K1] in peripheral blood mononuclear cells [PBMC]) suggests that 5-10 mg daily 
should be an adequate dose to produce a high-degree of sustained target inhibition ([Study 
C2101] / [Study 2102], Lane et al 2003). In molecular changes in tumor were evaluated 
through serial biopsying before and during treatment. Biopsying on treatment took place in 
week 4 (pharmacokinetic steady-state). All patients underwent a 24-hour post-dose biopsy. 
Patients following the weekly regimen had a further biopsy on Day 4 or 5 of the same week. 
Molecular activity was measured by immunohistochemistry. In the absence of a reliable 
technique for measuring mTOR phosphorylation, the phosphorylation status of downstream 
markers S6 and eIF4G, for which reliable antibodies exist, was selected as reflecting the 
immediate pharmacodynamic effect of everolimus. Also measured were changes in the 
phosphorylation status of upstream AKT and the proliferation index Ki67. Fifty-five patients 
were treated and the results revealed a dose and schedule dependent inhibition of the mTOR 
pathway with a near complete inhibition of pS6 and pelF-4G at the  10 mg/day and 50 mg/wk 
schedules. In addition, pAKT was upregulated in 50% of the treated tumors. In the daily 
schedule, there was a correlation between everolimus plasma trough concentrations and 
inhibition of peIF4G and p4E-BP1. There was good concordance of mTOR pathway 
inhibition between skin and tumor. ([Study C2107], Tabernero, 2008) 
More information is provided in the [Investigator‟s Brochure]. 


 
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1.1.3.3 
Clinical experience with RAD001 
Everolimus has been in clinical development since 1996 as an immunosuppressant in solid  
organ transplantation and was approved in Europe in 2003 under the trade name Certican®, 
for the prevention of organ rejection in patients with renal and cardiac transplantation. 
Additional non-oncologic indications currently being explored are wet age-related macular 
degeneration (AMD) and autosomal dominant polycystic kidney disease (ADPKD). Clinical 
experience of everolimus in the transplant indication is summarized in a separate 
Investigator‟s Brochure.  
In oncology, everolimus has been in clinical development since 2002 for patients with various 
hematologic and non-hematologic malignancies as a single agent or in combination with 
antitumor agents. Please note that safety pharmacology and toxicology studies as well as some 
human pharmacology studies which have been conducted in support of the transplant 
indication, are described in the oncology IB due to the relevance of these data for the 
oncology indication. Malignancies that are currently being evaluated in Novartis sponsored 
studies include the following: metastatic renal cell carcinoma (mRCC), breast cancer, 
gastroenteropancreatic neuroendocrine tumors (GEP-NET), mantle cell lymphoma and diffuse 
large B cell lymphoma (DLBCL), hepatocellular cancer (HCC), gastric cancer, and lung 
cancer. In addition, treatment of patients with Tuberous Sclerosis Complex (TSC) associated 
subependymal giant cell astrocytoma (SEGA) and Angiomyolypoma is also being evaluated. 
Colorectal cancer (CRC) is no longer being evaluated. 
 
Everolimus 2.5mg, 5mg and 10mg tablets were approved under the trade name Afinitor® for 
patients with advanced renal cell carcinoma in the US, EU and several other countries and is 
undergoing registration in other regions worldwide. Recent approval was granted in the US 
for the treatment of patients with subependymal giant cell astocytoma (SEGA) associated with 
tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for 
curative surgical resection. 
. 
Phase I dose escalating studies, exploratory Phase I/II studies with everolimus as single agent 
or in combination with other anti-cancer agents, Phase II/III studies of everolimus in 
indications, and Phase III double-blind studies are contributing to the extensive database. 
Approximately 12,700 cancer patients have been treated with everolimus as of 30 SEP 2010: 
• 5559 patients in Novartis-sponsored clinical trials 
• 712 patients in the single patients use IND program for renal cell cancer 
• 5474 in investigator-sponsored studies. 
• In addition, healthy volunteer subjects have participated in the clinical pharmacology 
studies as described in Section 5.2. 
As of 30 SEP 2010, there are a total of 11 Phase III trials ongoing in the indications mRCC 
(1), advanced NET (2), breast cancer (3), TSC (2), DLBCL (1), gastric cancer (1) and 
hepatocellular carcinoma (1). One additional Phase III trial in the TCS will be starting later in 


 
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2011. In addition, the Phase II SEGA in Tuberous Sclerosis study remains ongoing for follow-
up.   
Recent approvals of everolimus (Afinitor®) were based upon a Phase III, international, 
multicenter randomized, double-blind, placebo-controlled study [C2240] in patients with 
metastatic renal cell carcinoma (mRCC) whose disease had progressed despite prior treatment 
with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor) 
therapy. Progression-free survival (PFS) assessed via a blinded, independent central review, 
was the primary endpoint. Secondary endpoints included safety, objective tumor response 
In the pivotal, Phase III study [C2240], which included patients with advanced renal cell 
carcinoma, the most common adverse reactions (incidence ≥10%) were stomatitis, rash, 
fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, vomiting, pneumonitis, 
cough, peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnea. The most 
common grade 3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, fatigue, and 
pneumonitis. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including 
Everolimus and some of these cases have been severe and on rare occasions, fatal outcomes 
have been observed. Everolimus has immunosuppressive properties and may predispose 
patients to bacterial, fungal, viral or protozoan infections, including infections with 
opportunistic pathogens. Localized and systemic infections, including pneumonia, other 
bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis and viral 
infections including reactivation of hepatitis B virus, have been described in patients taking 
everolimus. Some of these infections have been severe (e.g. leading to respiratory or hepatic 
failure) and occasionally have had a fatal outcome 
 
The 
most 
common 
laboratory 
abnormalities 
(incidence 
≥50%) 
were 
anemia, 
hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased 
creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were 
lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths 
due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were 
observed on the everolimus arm. The rates of treatment-emergent adverse reactions resulting 
in permanent discontinuation were 7% and 0% for the everolimus and placebo treatment 
groups, respectively. Safety data from study [C2240] are described in detail in Section 6.5. 
Overall, safety data available from completed, controlled and uncontrolled studies are 
consistent with the aforementioned findings of the Phase III trial. Everolimus is generally well 
tolerated at weekly and daily dose schedules. The safety profile is characterized by 
manageable adverse events (AEs). These AEs are generally reversible and non-cumulative. 
 
 
Further detailed information regarding RAD001 clinical development, safety and efficacy is 
provided in the [Investigator‟s Brochure]. 
 


 
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1.1.3.4 
Gliomas 
 
 
The incidence of primary brain tumors in the United States (US) is about 17,000 per year, 
with a case fatality of about 10,000 per year.  Gliomas account for up to 80% of primary brain 
tumors and they account for significant mortality.  Gliomas can be classified as either high-
grade (or malignant), or low-grade.  The low-grade gliomas (LGG) themselves are a diverse 
group of glial tumors with an annual incidence in the US is about 1800 cases (CBTRUS: 
Statistical Report 2002). Histologic subtypes of LGG include diffuse astrocytomas (WHO 
grade II astrocytomas), oligodendrogliomas and mixed oligoastrocytomas Ashby et al. 2004).  
The majority of these tumors are of mixed histology.   
 
Despite medical management with surgery and irradiation the median 10-year survival rates 
for LGG range from 17-49%.  Survival is limited by recurrence and progression of LGG to 
high-grade gliomas. Factors influencing survival in these patients include histologic subtype, 
age, extent of surgical resection, and presence of 1p 19q status (Pignatti et al 2002; Yeh et al. 
2005; Smith et al. 2000.  One particular subtype of LGG, the pilocytic astrocytomas, usually 
occurs in the cerebellum of children. These tumors are often completely resectable and are 
associated with a 10-year survival of >80%.  For the purposes of this project only 
supratentorial non-pilocytic LGG in adults will be considered.  
 
The management of patients with residual low grade glioma following surgical resection is 
not standardized (Lang et al. 2006).  Options include surveillance scans and treatment at the 
time of tumor progression, versus the use of radiation therapy soon after the surgical 
procedure.  Adjuvant chemotherapy following radiation is not considered a standard approach 
(Grier and Batchelor, 2003).    
 
Low grade gliomas are diffuse in nature and the treatment fields for radiation therapy can be 
large. The potential complications of radiation therapy to the brain include seizures, cognitive 
decline, endocrinopathies, necrosis and vasculopathies.  In addition, any of a number of 
secondary malignancies may arise after radiation treatment including meningiomas, gliomas 
and sarcomas.  Given the potential for long term survival of patients with LGG and the 
morbidity associated with radiation therapy, alternative approaches in this setting are 
appealing and are being evaluated (Grier and Batchelor, 2003).     
 
In an effort to reduce the use of radiotherapy, several studies have evaluated the use of 
chemotherapy as initial treatment of LGG.  Tumor  regressions using a combination of 
procarbazine, lomustine and vincristine in patients with an oligodendroglial component has 
been demonstrated (Buckner et al. 2003; Stege at al. 2005).  More recently, temozolomide 
showed activity as treatment for recurrent LGG.  However, the role of chemotherapy as up-
front treatment of LGG continues to be evaluated (Grier and Batchelor, 2003; Hoang-Xaun et 
al. 2004; Brada et al. 2003). 
 
The role of chemotherapy in adult patients with recurrent LGG has also not been extensively 
investigated (Quinn et al. 2003; Pace et al. 2003; Soffietti et al. 1998).  Nitrosourea based 
chemotherapy and temozolomide have both been evaluated. In small studies, temozolomide 


 
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appears to have response rates ranging from 47-61% and 1 year progression free survival from 
39-76% (Quinn et al. 2003; Pace et al. 2003).  Although these numbers appear promising for 
the treatment of recurrent LGG with chemotherapy, other treatment strategies are needed for 
this patient population, especially in the setting of progression to malignant glioma.  With a 
better understanding of the signaling pathways important for tumor growth and invasion, 
novel targeted therapies are being evaluated. 
 
1.1.3.5  PTEN methylation and PKB/Akt phosphorylation in gliomas 
 
Alterations in the tumor suppressor protein PTEN are common in gliomas and result in 
activation of the PI3K pathway, as evidenced by phosphorylation of PKB / Akt.  Whereas 
mutation of PTEN is common in de novo malignant gliomas (Choe et al. 2003; Rasheed et al. 
1997; Ermoian et al. 2002), methylation of the PTEN promoter is thought to be the underlying 
mechanism of PTEN alteration found in low-grade gliomas and secondary malignant gliomas 
(Wiencke et al. 2007).   
 
In fact, methylation of the PTEN promoter occurs frequently in low-grade gliomas.  Whereas 
there is no evidence of PTEN promoter methylation in normal brain and only 9% methylation 
in de novo glioblastiomas, low-grade tumors displayed methylation of PTEN promoter in 43-
67% of low-grade glioma cases, and in 68-82% of secondary high grade glioma cases. The 
differences in PTEN promoter methylation frequencies for low-grade gliomas were highly 
statistically significant (P<0.001) (Wiencke et al 2007).   
 
Not only is methylation of the PTEN promoter frequent and associated specifically with low-
grade gliomas and secondary malignant gliomas, there is evidence that PTEN methylation 
also leads to functional activation of the PI3K pathway, which is thought to be important for 
tumor transformation and growth (Wiencke et al. 2007).  Furthermore, a retrospective study of 
43 LGG (grade II) tumor specimens from newly diagnosed patients show a trend towards 
decreased overall survival in low grade glioma patients with PTEN promoter methylation 
compared to those without methylation (McBride et al. 2007).   
 
Because of the clinical significance of PTEN promoter methylation and its effects on the PI3K 
pathway, therapies that target tumors with PI3K activity may be of clinical benefit in low-
grade gliomas.  The mammalian target of rapamycin (mTOR) is downstream to the (PI3K) / 
PTEN-AKT survival pathway and is therefore an ideal target for low-grade glioma and 
secondary malignant glioma patients with PTEN promoter methylation (Choe et al. 2003; Xu 
et al. 2004; Neshat et al. 2001).  In fact, there is evidence that tumors expressing activated 
PKB/Akt appear particularly sensitive to mTOR inhibition (Gera et al. 2004; Noh et al. 2004).   
 
 
1.1.3.6 Clinical experience with mTOR inhibitors for gliomas 
 
There is extensive clinical experience with mTOR inhibitors including the evaluation in the 
treatment of patients with malignant glioma (Reardon et al. 2006).  Perhaps most exciting are 
recent studies in which patients with Tuberous Sclerosis Complex (TSC) and low-grade 


 
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gliomas were treated with an mTOR inhibitor (rapamycin most commonly), resulting in tumor 
regression in every treated patient.  In one patient treatment was interrupted, resulting in 
tumor re-growth, followed by further regression when treatment with the mTOR inhibitor 
resumed (Franz et al. 2006). The success of this approach adds credence to our plan to treat 
low-grade gliomas with RAD001 because of the genetic underpinnings of low-grade gliomas 
in TSC patients.  In brief, mutations in either hamartin or tuberin, the tuberous sclerosis gene 
products, result in elevated mTOR signaling.  As a result, afflicted individuals develop 
hamartomatous growths in multiple organs, and 5-15% of TSC patients develop low-grade 
central nervous system neoplasms in the form of subependymal giant cell astrocytomas 
(SEGAs).  Although SEGAs rarely respond to radiation or chemotherapy, striking tumor 
regressions were documented after treatment with mTOR inhibitor in these TSC patients. 
 
1.4       Rationale 
 
We have shown that methylation of the PTEN promoter occurs frequently in low-grade 
gliomas and secondary glioblastomas, and is associated with PI3K signaling and PKB/Akt 
phosphorylation (Wiencke et al. 2007).  Given these findings, and the link between (mTOR) 
and the (PI3K) / PTEN-AKT survival pathway, we hope that RAD001 will also prove 
efficacious in the treatment of low-grade gliomas and secondary malignant gliomas as 
delineated in the study proposed herein.   
 
In this study, molecular features, including PTEN status and PKB/Akt phosphorylation will be 
assessed prospectively in this trial to test the hypothesis that those tumors with PTEN 
methylation and consequent PKB/Akt phosphorylation will preferentially respond to mTOR 
inhibition. 
 
1.5       Rationale for additional radiographic imaging as an exploratory aim 
 
Standard anatomic MRI in conjunction with clinical evaluation such as neurologic status and 
corticosteroid use, remains the key determinant of response to therapy and the evaluation of 
tumor recurrence for LGG (Just and Thelen 1988; Dean et al. 1990; Ginsberg et al. 1996). 
Increase in contrast enhancement, worsening cerebral edema, and mass effect are universal 
traits of malignant transformation. Acquiring tissue samples to confirm tumor upgrade, 
although considered the “gold standard” for determining the presence of viable tumor, can 
result in both false positives and negatives that relate to sampling error (Earnest et al. 1988; 
Kleihues et al. 1993). Recent studies using MR spectroscopic imaging (MRSI) suggest that in 
vivo levels of metabolites such as choline, creatine, N-acetylaspartate, lactate and lipids 
provide more-reliable measures of the presence of recurrent tumor. Perfusion-weighted 
imaging (PWI) and diffusion-weighted imaging (DWI) have been explored for patients with 
newly diagnosed glioma, but only on a limited basis for patients with recurrent LGG. 
Techniques to characterize the molecular morphology of pre-specified areas in addition to 
neuroimaging parameters may better define the biologic behavior of such lesions. 
 
Many of the newer drugs being studied in neuro-oncology target specific aberrant pathways 
and are cytostatic rather than cytotoxic. Examples include anti-invasive and anti-angiogenic 


 
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agents. These agents may cause stability of the tumor rather than regression, and surrogate 
biomarkers are important in the assessment of these types of agents.  Pending funding 
availability, we will prospectively incorporate metabolic and physiologic imaging to this trial 
to allow us to assess the ability of the key parameters to predict clinically relevant endpoints 
such as treatment related radiographic response, time to progression and survival. 
 


 
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2 
Study objectives 
Primary 
To determine progression-free survival at 6 months associated with use of RAD001 in 
patients initially diagnosed with low-grade glioma who undergo biopsy or subtotal resection 
at the time of recurrence with pathologic evidence of recurrent low-grade glioma. 
Secondary 
1.   To further delineate the safety profile of RAD001 in patients with recurrent LLG. 
 
2. To assess overall survival (OS) in patients treated with RAD001. 
 
3.   To assess the Objective Response rate (ORR) in patients treated with RAD001. 
 
4. To assess the correlation of phosphorylated PKB/Akt and PTEN expression with response, 
progression status by 6 months, and OS in patients treated with RAD001. 
Exploratory 
1. To determine progression-free survival at 6 months associated with use of RAD001 in 
patients initially diagnosed with low-grade glioma who have already received 
radiotherapy, and who undergo biopsy or subtotal resection at the time of recurrence with 
pathologic evidence of high-grade glioma. 
 
2. Pending adequate funding, to assess the ability of metabolic and physiologic imaging 
parameters such as MR spectroscopy, perfusion-weighted imaging, and diffusion-
weighted imaging to predict clinically-relevant endpoints such as time to progression and 
survival. 
 
3 
Investigational plan 
3.1 
Overall study design 
 
A single-arm, one-stage phase II trial of RAD001 will be undertaken.  Sixty patients will be 
enrolled.  The target population will be patients with a diagnosis of low-grade glioma who 
experience a recurrence and who undergo a biopsy or subtotal resection at the time of 
recurrence with pathologic evidence of recurrent glioma.  The purpose of this study is to 
accrue patients to evaluate a pharmacologic agent.  


 
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3.2 
Study population 
3.2.1 
Patient population 
 
It is anticipated that most low-grade glioma patients completing surgical resection for 
recurrence will be eligible for enrollment and will choose to participate.  Based on current 
patient volume in the UCSF neurologic-oncology clinic, it is expected that a minimum of 3 
patients per month will be enrolled.  Therefore, accrual can be completed in a 20 month 
period.  Patients will be recruited with no preference to gender.   Minorities will actively be 
recruited to participate.  In order to evaluate our primary objective, enrollment will continue 
until at least 40 low-grade glioma patients have enrolled. 
3.2.2 
Inclusion and exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and 
must meet all inclusion and exclusion criteria. Results of all baseline evaluations, which 
assure that all inclusion and exclusion criteria have been satisfied, must be reviewed by the 
Principal Investigator or his/her designee prior to enrollment of that patient. In addition, the 
patient must be thoroughly informed about all aspects of the study, including the study visit 
schedule and required evaluations and all regulatory requirements for informed consent. The 
written informed consent must be obtained from the patient prior to enrollment. The following 
criteria apply to all patients enrolled onto the study unless otherwise specified. 
3.2.2.1 
Baseline Characteristics Inclusion criteria  
 
 Patients must have a Karnofsky performance status of > 60 
 Patients must have a life expectancy > 8 weeks 
 Patients must be ≥ 18 years old 
 All patients must sign an informed consent document indicating that they are aware of the 
investigational nature of this study 
 Patients must sign an authorization for the release of their protected health information 
 Patients must have an MRI scan performed within 14 days prior to initial protocol 
treatment 
 Patients must be registered in the UCSF Neuro-Oncology database prior to treatment with 
study drug 
 Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, 
Hb >9 g/dL 
 Adequate liver function as shown by: 
 serum bilirubin ≤ 1.5 x ULN 
 INR < 1.5  (Anticoagulation is allowed if target INR  1.5 on a stable dose of 
warfarin or on a stable dose of LMW heparin for > 2 weeks at the time of registration) 
 ALT and AST ≤ 2.5x ULN  


 
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 Adequate renal function: serum creatinine ≤ 1.5 x ULN 
 Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 
x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only 
be included after initiation of appropriate lipid lowering medication. 
 
3.2.2.2 
Histologic Inclusion Criteria 
 
 Patients must have histologically proven intracranial low-grade glioma at initial diagnosis. 
Low-grade gliomas include: astrocytoma, oligodendroglioma and mixed 
oligoastrocytoma.  Pilocytic astrocytomas are excluded 
 Patients must have unequivocal evidence for tumor recurrence or progression by histology 
as determined by review of pathology by an attending neuro-pathologist at UCSF  
 If most recent histology shows progression to high grade glioma, patients must have had 
prior radiotherapy in order to be eligible  
 Paraffin-embedded sections of tissue acquired from surgery at the time of suspected 
recurrence must be available for analysis  
 
3.2.2.3 
Radiographic Inclusion Criteria 
 
 Patients must have evidence for tumor recurrence or progression by MRI as determined by 
radiographic review of images by an attending neuro-oncologist or neuro-radiologist at 
UCSF 
 
 If the steroid dose is increased between the date of the MRI and registration on the trial, a 
new baseline MRI is required.  This MRI must be performed after > 5 days on a stable or 
decreasing dose of steroids 
 An MRI must be used throughout the period of protocol treatment for tumor measurement 
 Patients must have evaluable disease 
3.2.2.4 
Prior Therapy Inclusion Criteria 
 Patients may have had treatment (including radiotherapy) for any number of relapses prior 
to this recurrence 
 Patients must be at least 4 weeks from the completion of any radiation therapy 
 Patients must be less than 4 months from the surgical procedure for this recurrence 
 Patients must have recovered from the toxic effects of prior therapy: 
1.  4 weeks from any investigational agent. 
2.  4 weeks from prior cytotoxic therapy (except 6 weeks from nitrosoureas, 3 weeks 
from procarbazine, 3 weeks from vincristine) 


 
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3.  3 weeks for non-cytotoxic or biologic agents e.g., interferon, tamoxifen, 
thalidomide, cis-retinoic acid, tarceva, etc.  Note a 3-week washout is required for 
prior treatment with Bevacizumab 
 
3.2.2.5 
Exclusion criteria 
 Patients, who have not recovered from the side effects of a major surgery or significant 
traumatic injury  or patients that may require major surgery during the course of the study 
 Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent. Topical or inhaled corticosteroids, and treatment with low dose 
Decadron ( 3mg daily) are allowed. 
 Other than surgery, patients may not have therapy for this recurrence (including radiation).  
Supportive care such as steroids or anti-epileptics does not constitute treatment of 
recurrence  
 Patients must not have any significant medical illnesses that in the investigator‟s opinion 
cannot be adequately controlled with appropriate therapy or would compromise the 
patient‟s ability to tolerate this therapy. 
 Patients with a history of any other cancer (except for adequately treated carcinoma of the 
cervix or basal or squamous cell carcinomas of the skin), unless in complete remission and 
off of all therapy for that disease for a minimum of 3 years are ineligible.  
 Patients should not receive immunization with attenuated live vaccines within one week of 
study entry or during study period. Close contact with those who have received attenuated 
live vaccines should be avoided during treatment with everolimus. Examples of live 
vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella and TY21a typhoid vaccines. 
 Uncontrolled brain or all leptomeningeal metastases, including patients who continue to 
require glucocorticoids for brain or leptomeningeal metastases 
 Patients who have any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as: 
  Symptomatic congestive heart failure of New York heart Association Class III or 
IV  
 unstable angina pectoris, symptomatic congestive heart failure, myocardial 
infarction within 6 months of start of study drug, serious uncontrolled cardiac 
arrhythmia or any other clinically significant cardiac disease 
 severely impaired lung function  
 uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (Note: 
Optimal glycemic control should be achieved before starting trial therapy.) 
 active (acute or chronic) or uncontrolled severe infections 
 liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).   


 
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 A Hepatitis B/C blood test must be done at screening for all patients.  Patients who test 
positive for Hepatitis C antibodies and the Hepatitis B antigen are ineligible 
 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) 
 Impaired lung function: O2 saturation 88% or less at rest on room air by Pulse Oximetry.  
If O2 saturation is ≤ 88% at rest, further pulmonary function tests (PFTs) should be 
ordered to confirm normal pulmonary function and eligibility. 
 Patients with an active, bleeding diathesis 
 Female patients who are pregnant or breast feeding, or adults of reproductive potential 
who are not using effective birth control methods. Adequate contraception  must be used 
throughout the trial and for 8 weeks after the last dose of study drug, by both sexes.   
(Women of childbearing potential must have a negative urine or serum pregnancy test 
within 7 days prior to administration of RAD001) 
 Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate 
contraception, during the study and for 8 weeks after the end of treatment 
 Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, 
temsirolimus, everolimus). 
 Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (e.g., 
sirolimus, temsirolimus) or to its excipients 
 History of noncompliance to medical regimens 
 Patients unwilling to or unable to comply with the protocol 
3.2.3 
Interruption or discontinuation of treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. If administration of 
RAD001 must be interrupted because of unacceptable toxicity, drug dosing will be interrupted 
or modified according to rules described in Table 3-1. Toxicity will be assessed using the 
NIH-NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3.0, 
(http://ctep.cancer.gov/forms/CTCAEv3.pdf)). 
 
Table 3.0   RAD001 dose level modification guidelines 
Dose level 
Dose and schedule 
0 (starting dose) 
10 mg daily 
-1 
5 mg daily 
-2 
5 mg every other day 
 


 
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Table 3-1 
Criteria for dose-modification in case of suspected RAD001 toxicity 
and re-initiation of RAD001 treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except pneumonitis – refer to Table 3-2) 
If the toxicity is tolerable to the patient, maintain the 
same dose. If the toxicity is intolerable to patient, 
interrupt RAD001 until recovery to grade 1. Then 
reintroduce RAD001 at same dose. 
If event returns to grade 2, then  interrupt RAD001 
until recovery to grade 1. Then reintroduce RAD001 
at the lower dose level. 
Grade 3 
(except hyperlipidemia*) 
(except pneumonitis – refer to Table 3-2) 
Interrupt RAD001 until recovery to grade 1. Then 
reintroduce RAD001 at the lower dose level. For 
pneumonitis consider the use of a short course of 
corticosteroids. 
Grade 4 
Discontinue RAD001. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥ 50x109/L)  
Interrupt RAD001 until recovery to grade 1 (>75 
x109/L). Then reintroduce RAD001 at initial dose. 
If thrombocytopenia again returns to grade 2,  
interrupt RAD001 until recovery to grade 1. Then 
reintroduce RAD001 at the lower dose level.  
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x10 9/L) 
Interrupt RAD001 until recovery to grade ≤1 
(platelets ≥ 75 x109/L).  Then resume  RAD001 at one 
dose level lower.  If grade 3 thrombocytopenia 
recurs, discontinue RAD001. 
Grade 4 Thrombocytopenia (platelets < 25 x109/L) 
Discontinue RAD001. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt RAD001 until recovery to grade 1 ( 
neutrophils ≥ 1.5 x 109/L). Then resume RAD001 at 
the initial dose.  If ANC again returns to Grade 3, 
hold RAD001 until the ANC ≥ 1.5 x 109/L.  Then 
resume RAD001 dosing at the lower dose level.  
Discontinue patient from study therapy for a third 
episode of grade 3 neutropenia. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt RAD001 until recovery to grade  1  
(neutrophils ≥ 1.5 x 109/L). Then resume RAD001 at 
the lower dose level. If grade 3 or grade 4 
neutropenia occurs despite this dose reduction, 
discontinue RAD001. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt RAD001 until resolution of fever and 
neutropenia to grade ≤ 1. Hold further RAD001 until 
the ANC ≥ 1,500/mm3 and fever has resolved. Then 
resume RAD001 at the lower dose level. If febrile 
neutropenia recurs, discontinue RAD001. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue RAD001. 
Any hematological or non-hematological toxicity requiring 
interruption for ≥ 28 days.   
Discontinue RAD001 
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be 
managed using medical therapies (see Sec. 3.2.5.2). 


 
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3.2.4 Monitoring of RAD001 suspected toxicities  
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value suspected to be related to RAD001 must be followed at least 
weekly until the adverse event or abnormal laboratory resolves or returns to grade 1. If a 
patient requires a dose delay of > 28 days from the intended day of the next scheduled dose, 
then the patient must be discontinued from the study. 
3.2.5 
Known Undesirable Side Effects of RAD001 
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a 
randomized phase III study for the treatment of metastatic renal cell carcinoma. In total, 165 
patients were exposed to everolimus 10 mg/day for ≥4 months. The median age of patients 
was 61 years (range 27 to 85). The most common adverse reactions (incidence ≥10%) were 
stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal inflammation, 
vomiting, cough, peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnoea. The 
most common grade 3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, 
fatigue, and pneumonitis. 
The median duration of blinded study treatment was 141 days (range 19 to 451) for patients 
receiving everolimus and 60 days (range 21 to 295) for those receiving placebo. The rates of 
treatment-emergent adverse reactions resulting in permanent discontinuation were 7% and 0% 
for the everolimus and placebo treatment groups, respectively. Most treatment-emergent 
adverse reactions were grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse 
reactions were reported in 39% versus 7% of patients receiving everolimus and placebo, 
respectively. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal 
failure (0.4%) were observed on the everolimus arm. 
 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoan infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis or candidiasis and viral infections including 
reactivation of hepatitis B virus, have been described in patients taking everolimus. Some of 
these infections have been severe (e.g. leading to respiratory or hepatic failure) and 
occasionally have had a fatal outcome. 
 
Physicians and patients should be aware of the increased risk of infection with everolimus. 
Treat pre-existing infections prior to starting treatment with everolimus. While taking 
everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation of 
everolimus. If a diagnosis of invasive systemic fungal infection is made, discontinue 
everolimus and treat with appropriate antifungal therapy. 
 
Reactivation/flare of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have also been seen in 


 
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this setting with everolimus. Use of antivirals during anti-cancer therapy has been shown to 
reduce the risk of Hepatitis B virus reactivation and associated morbidity and mortality 
(Loomba 2008). A detailed assessment of Hepatitis B/C medical history must be done for all 
patients at screening, with testing performed prior to the first dose of everolimus.  
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, 
dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or 
without respiratory impairment) have been observed with everolimus. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting a patient on everolimus. Mouth ulcers, 
stomatitis and oral mucositis have been seen in patients treated with everolimus. In such cases 
topical treatments are recommended, but alcohol- or peroxide-containing are not allowed. 
 
Elevations of serum creatinine, usually mild, have been reported in clinical trials. Monitoring 
of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, 
is recommended prior to the start of everolimus therapy and periodically thereafter. 
Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported in clinical 
trials. Monitoring of complete blood count is recommended prior to the start of everolimus 
therapy and periodically thereafter. 
Everolimus is not recommended in patients with severe hepatic impairment, (Child-Pugh class 
C). 
The use of live vaccines and close contact with those who have received live vaccines should 
be avoided during treatment with everolimus. 
 
 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have been reported as 
serious adverse reactions. Electrolytes should be monitored in patients treated with RAD001. 
Table 3-1 provides general recommendations for the management of patients, with suspected 
drug toxicities while on treatment with RAD001 as single-agent therapy. 
More detailed information regarding RAD001 reported suspected toxicities and individual 
cases is provided in the [Investigator‟s Brochure]. 
3.2.5.1   Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to RAD001 should be treated using local 
supportive care.  
When described, the disorder has been identified as inflammation or ulcers in the mouth. If 
exam reveals mouth ulcers, rather than a more general inflammation of the mouth, please 
classify the adverse event as „mouth ulcers‟. If inflammation is limited to the mouth without 
ulcers please use the term „stomatitis‟ rather than the less specific term „mucositis‟. 


 
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If the disorder is elsewhere than the mouth please describe the location as well as any specific 
procedures carried out for exploration (e.g. endoscopy).   
Please use the Grading according to the NIH-NCI Common Terminology Criteria for Adverse 
Events, Version 3.0 (CTCAEv3.0; http://ctep.cancer.gov/forms/CTCAEv3.pdf). 
Grade 1: 
minimal symptoms; normal diet 
Grade 2: 
symptomatic but can eat and swallow modified diet 
Grade 3: 
symptomatic and unable to adequately aliment or hydrate orally 
Grade 4: 
symptoms associated with life-threatening consequences  
Recommendations 
1. To help avoid these effects patients should brush their teeth with a very soft toothbrush and if 
gums bleed patients should be instructed to brush their teeth with gauze instead, use an 
alcohol-free mouthwash up to 3 times a day, eat soft bland foods like puddings milkshakes 
and cream soups, avoid spicy, crunchy, acidic and very hot foods. 
2. 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. 
3. 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% (e.g. Kenalog in Orabase®). 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. Antifungal agents must be avoided unless 
a fungal infection is diagnosed. In particular, systemic imidazole antifungal agents 
(ketoconazole, fluconazole, itraconazole, etc.) should be avoided in all patients due to their 
strong inhibition of RAD001 metabolism, therefore leading to higher RAD001 exposures. 
Therefore, topical antifungal agents are preferred if an infection is diagnosed. Similarly, 
antiviral agents such as acyclovir should be avoided unless a viral infection is diagnosed. 
3.2.5.2   Management of hyperlipidemia and hyperglycemia  
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state.. 
Hyperlipidemia and hypertriglyceridemia should be treated according to local best clinical 
practice. Patients should be monitored clinically and through serum chemistry for the 
development of rhabdomyolysis and other adverse events as required in the product label/data 
sheets for HMG-CoA reductase inhibitors. 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum glucose is 
recommended prior to the start of everolimus therapy and periodically thereafter. Optimal 
glycemic control should be achieved before starting trial therapy. 
 


 
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3.2.5.3   Management of Hepatitis B reactivation 
If any patients experience reactivation of hepatitis B during treatment, the patient will be 
removed from study protocol and referred to the appropriate specialist for management of 
Hepatitis B.   
3.2.5.4   Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in patients taking 
everolimus (see Section 5 Adverse drug reactions). Some of these have been severe and on 
rare occasions, a fatal outcome was observed.  
A diagnosis of non-infectious pneumonitis should be considered in patients presenting with 
non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or 
dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been 
excluded by means of appropriate investigations. Patients should be advised to report 
promptly any new or worsening respiratory symptoms.  
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have 
few or no symptoms may continue everolimus therapy without dose alteration. If symptoms 
are moderate (Grade 2), consideration should be given to interruption of therapy until 
symptoms improve. The use of corticosteroids may be indicated. Everolimus may be 
reintroduced at a reduced dose until recovery to Grade 1 or better.  
For cases where symptoms of non-infectious pneumonitis are severe (Grade 3), everolimus 
therapy should be discontinued and the use of corticosteroids may be indicated until clinical 
symptoms resolve. Therapy with everolimus may be re-initiated at a reduced dose depending 
on the individual clinical circumstances. 
 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious 
pneumonitis (grade 2 = not interfering with activities of daily living or grade 3 = interfering 
with activities of daily living and oxygen indicated) have been noted in patients receiving 
RAD001 therapy. Non-infectious pneumonitis has been associated with RAD001 and other 
mTOR inhibitors (Atkins 2004). In order to monitor for asymptomatic (grade 1) pulmonary 
infiltrates, a chest X-ray is required if a CT scan of chest is not used for bi-monthly disease 
evaluations. Additional chest CT scans may be performed, when clinically necessary. If non-
infectious pneumonitis develops, a consultation with a pulmonologist should be considered. If 
the patient develops grade 3 pneumonitis, treatment with RAD001 should be interrupted and 
the patient should be treated as medically indicated (short course corticosteroids, oxygen, 
etc).Management of non-infectious pneumonitis suspected to be associated with RAD001 and 
dose modifications instructions are provided in Table 3-2  
 


 
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Table 3-2 
Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
RAD001 Dose Adjustment 
Grade 1 
CT scans with lung windows 
and pulmonary function 
testing including: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat chest x-ray/CT scan 
every 2 Cycles until return to 
baseline. 
No specific 
therapy is 
required 
Administer 100% of RAD001 dose. 
Grade 2 
CT scan with lung windows 
and pulmonary function 
testing including: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat each subsequent 
Cycle until return to 
baseline. Consider 
bronchoscopy *  
Symptomatic 
only. Prescribe 
corticosteroids if 
cough is 
troublesome. 
Reduce RAD001 dose until 
recovery to ≤ Grade 1. RAD001 
may also be interrupted if 
symptoms are troublesome. 
Patients will be withdrawn from the 
study if they fail to recover to ≤ 
Grade 1 within 3 weeks.  
Grade 3 
CT scan with lung windows 
and pulmonary function 
testing including: 
spirometry, DLCO, and room 
air O2 saturation at rest.; 
Repeat each subsequent 
Cycle until return to 
baseline. Bronchoscopy is 
recommended * 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Hold treatment until recovery to ≤ 
Grade 1. May restart protocol 
treatment within 2 weeks  at a 
reduced dose (by one level) if 
evidence of clinical benefit. 
Patients will be withdrawn from the 
study if they fail to recover to ≤ 
Grade 1 within 2 weeks. 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. 
Repeat each subsequent 
Cycle until return to 
baseline. Bronchoscopy is 
recommended *. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 
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. After administration of 24 cycles 
2. adverse event(s) including re-activation of Hepatitis B 
3. abnormal laboratory value(s) 
4. abnormal test procedure result(s) 


 
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5. disease progression 
6. protocol violation 
7. subject withdrew consent 
8. lost to follow-up 
9. administrative problems 
10. Medical or psychiatric illness which in the investigator's judgment renders the patient 
incapable of further therapy. 
11. Death 
12. Treatment delay due to toxicity greater than 28 days measured from the start of the 
preceding cycle. 
3.3 
Treatments 
3.3.1 
RAD001 Administration 
The study drug RAD001 will be self-administered (by the patients themselves). The 
investigator will instruct the patient to take the study drug exactly as specified in the protocol. 
RAD001 will be administered orally as once daily dose of 10 mg (two 5 mg tablets) 
continuously from study day 1 until progression of disease or unacceptable toxicity. Patients 
will be instructed to take RAD001 in the morning, at the same time each day.  
RAD001 may be taken with or without food. 
If vomiting occurs, no attempt should be made to replace the vomited dose.  
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded. 
Medication labels will comply with US legal requirements and be printed in English. They 
will supply no information about the patient. The storage conditions for study drug will be 
described on the medication label. 
RAD001 will be provided by Novartis. RAD001 is formulated as tablets for oral 
administration of 5 mg and 10mg strength. Tablets are blister-packed under aluminum foil in 
units of 10 tablets (16 units per box), which should be opened only at the time of 
administration as drug is both hygroscopic and light-sensitive. 
 
3.3.2 Duration of Therapy 
 
In the first year of therapy, patients will receive therapy continuously for approximately 2 four 
week cycles.  At the end of every 2 cycles during the first year, patients will receive an MRI 
and return to clinic for clinical evaluation.  The frequency of MRI‟s is based on clinical 
practice at the Neuro-oncology department at UCSF for patients on active therapy.  Upon re-
evaluation, patients who have not experienced excess toxicity or disease progression will 
continue on protocol therapy.  
 
 


 
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In the second year of therapy, patients will receive therapy continuously for approximately 3 
four week cycles.  At the end of every 3 cycles during the second year, patients will receive an 
MRI and return to clinic for clinical evaluation.  Upon re-evaluation, patients who have not 
experienced excess toxicity or disease progression will continue on protocol therapy. 
 
After administration of RAD001 for 2 years, patients will receive an MRI and return to clinic 
for clinical evaluation.  At that time, they will be offered the opportunity to continue treatment 
if they have not experienced excess toxicity or disease progression.  Patients will continue to 
be followed at three month intervals if after two years they continue to take RAD001. 
 
The study will be terminated for the patient if treatment is delayed due to toxicity greater than 
28 days measured from the last dose of RAD001.   
 
3.3.3 Concomitant therapy 
 
All concomitant medications administered within 14 days of enrollment through treatment 
termination should be reported to the investigator and recorded in the Case Report Form 
(CRF).  In particular, corticosteroid dosing will be recorded as use of corticosteroids may 
affect the appearance of T2 changes on MRI imaging.  In addition, the definition of response 
is based on corticosteroid use (see section 3.42).   
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At 
each visit, the investigator will ask the patient about any new medications he/she is or has 
taken after the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be 
recorded. 
The following restrictions apply during the entire duration of the study: 
 No other investigational therapy should be given to patients. 
 No anticancer agents other than the study medication should be given to patients. If such 
agents are required for a patient then the patient must first be withdrawn from the study. 
 Oral contraceptives in preclinical and clinical data have shown everolimus to have 
CYP3A4 inhibitory activity rather than induction activity, induction of metabolism of 
contraceptive hormones by everolimus is unlikely. Consequently, administration of 
everolimus should not reduce the efficacy of oral contraceptives. 
Inhibitors of CYP3A4 and/or PgP 
 Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, 
ritonavir) or P-glycoprotein (PgP) should be avoided  


 
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 Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity. These 
juices are potent CYP3A4-inhibitors. Concomitant use should be avoided  
 Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or 
PgP inhibitors should be used with caution.  If patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of RAD001 to 2.5 mg 
daily. Additional dose reductions to every other day may be required to manage toxicities. 
If the inhibitor is discontinued the RAD001 dose should be returned to the dose used prior 
to initiation of the moderate CYP3A4/PgP inhibitor after a washout period of 2 to 3 days. 
Inducers of CYP3A4 and/or PgP 
Avoid the use of strong CYP3A4 inducers. If patient requires co-administration of strong 
CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, Phenobarbital, St. 
John‟s wort), an increase in the dose of everolimus from 10mg daily to 20mg daily, using 5mg 
increments. Enzyme induction usually occurs within 7-10 days, therefore everolimus dose 
should be increased by one increment 7 days after the start of the inducer therapy.  If no safety 
concerns are seen within the next 7 days, the dose can be increased again one additional 
increment up to a maximum of twice the daily dose used prior to initiation of the strong 
CYP3A4 inducer.  This dose adjustment of RAD001 is intended to achieve similar AUC to 
the range observed without inducers.  However, there are no clinical data with this dose 
adjustment in patients receiving strong CYP3A4 inducers.  If the strong inducer is 
discontinued the RAD001 dose should be returned to the dose used prior to initiation of the 
strong CYP3A4/PgP inducer.  
 
 No chronic treatment with systemic steroids (at a dose equivalent of greater than 20 mg 
prednisone per day) or other immunosuppressive agents. Topical or inhaled corticosteroids 
are allowed. 
 
 The use of live vaccines and close contact with those who have received live vaccines 
should be avoided during treatment with everolimus. Examples of live vaccines include 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and 
TY21a typhoid vaccines. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
RAD001 is expected. However, drug-drug interaction studies between macrolide antibiotics 
and warfarin have produced mixed outcomes and the disparity in these findings has led to the 
conclusion that multiple factors may alter the clearance of warfarin. The coadministration of 
RAD001 and oral anticoagulants is possible but should be subject to verification of 
coagulation (INR) once steady state is reached (after one week‟s treatment). 
Examples are provided in Table 3-3 (CYP3A4 inhibitors/inducers) and Table 3-6 (Drug 
interactions mediated by P-glycoprotein). A comprehensive list of cytochrome P450 
isoenzymes and CYP3A4 inhibitors, inducers, and substrates can be found at 


 
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http://medicine.iupui.edu/flockhart.  This website is continually revised and should be 
checked frequently for updates. 
 


 
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Table 3-3 Examples of clinically relevant drug interaction: substrates, inducers and 
inhibitors of isoenzyme CYP3A.  
Substrates (competitive inhibition) 
 
Antibiotics1: 
 
clarithromycin* 
 
erythromycin  
 
telithromycin* 
Anti-arrhythmics: 
 
quinidine 
Benzodiazepines: 
 
alprazolam 
 
diazepam 
 
midazolam 
 
triazolam 
Immune Modulators: 
 
cyclosporine 
 
tacrolimus (FK506) 
HIV Protease Inhibitors: 
 
indinavir* 
      nelfinavir 
 
ritonavir* 
 
saquinavir* 
Prokinetic: 
 
cisapride 
Antihistamines: 
 
astemizole 
 
chlorpheniramine 
   terfenadine 
Calcium Channel Blockers: 
 
amlodipine 
 
diltiazem 
 
felodipine 
      lercanidipine 
 
nifedipine 
 
nisoldipine 
 
nitrendipine 
 
verapamil 
HMG CoA Reductase Inhibitors2:  
 
 
 
cerivastatin 
 
lovastatin 
 
simvastatin 
Miscellaneous: 
 
Alfentanil, aprepitantaripirazole, buspirone, cafergot, 
caffeine,      cilostazol, cocaine, codeine-N-
demethylation, dapsone, dexamethasone, 
dextromethorphan,    docetaxel domperidone, 
eplerenone, fentanyl,   finasteride, Gleevec/imatinib, 
haloperidol irinotecan, LAAM, lidocaine, methadone 
nateglinide, ondansetron, pimozide propranolol, 
quetiapine, quinine risperidone, salmeterol 
sildenafil 
sirolimus, sorafenib, sunitinib 
 
tamoxifen taxol, terfenadine, torisel, 
 
trazodone,  
vincristine zaleplon, ziprasidone, 
zolpidem 
Inducers 
Barbiturates, 
Carbamazepine 
Glucocorticoids 
modafinil, oxcarbazepine, 
Phenobarbital 
Phenytoin*, pioglitazone, 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
efavirenz, nevirapine 
Inhibitors 
Strong Inhibitors:  
indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir, telithromycin 
Posaconazole (Krishna et al, 2009) 
 
Moderate inhibitors:  
aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil 
 
Weak inhibitors: 
Cimetidine, Seville orange (Malhotra et al, 2001) 
Unclassified as per the Indiana University DDI listing: 


 
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Ciprofloxacin, delaviridine, troleandamycin, mibefradil, amiodarone, chloramphenicol, diethyldithiocarbamate, 
fluvoxamine, starfruit, gestodene, imatinib, mifepristone, norfloxacin, norfluoxetine, voriconazole* 
 
 
 
 
Based on http://medicine.iupui.edu/clinpharm/ddis/table.asp as of  December 01, 2009  
* Voriconazole (unclassified as per the Indiana University DDI table) 
Strong inhibitor according to the following reference: 
(http://www.nature.com/clpt/journal/v80/n5/pdf/clpt2006438a.pdf) 
 
1.   
 
Table 3-7   Clinically relevant drug interactions mediated by PgP 
PgP Substrates 
PgP Inhibitors in vivo 
PgP Inducers 
digoxin, fexofenadine,  
indinavir, vincristine, 
colchicine, topotecan, 
paclitaxel 
amiodarone, azithromycin, 
captopril, carvedilol, 
clarithromycin, conivaptan, 
cyclosporine, diltiazem, 
elacridar, erythromycin, 
felodipine, (GF120918), 
itraconazole, ketocoanzole, 
lopinavir, (LY335979), 
mibefradil, nifedipine, 
nitrendipine, (PSC833), 
quinidine, ranolazine, 
ritonavir, talinolol, valspodar, 
verapamil 
rifampin, St John‟s wort 
Reference: 
Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Dec. 2, 2009, which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies, the University of Washington’s Drug Interaction Database, and Indiana 
University School of Medicine's Drug Interaction Table. "  
NOTES:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM072101.pdf 
**This list of clinically relevant drug interactions is updated as of December 02, 2009** 


 
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3.3.4 Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to 
return all unused study medication. 
3.4 
Visit schedule and assessments 
3.4.1 
Visit schedule 
3.4.1.1 
Screening Assessments 
 
Written informed consent must be obtained and documented in the medical record 
before starting protocol therapy.  After receiving a subject‟s agreement to participate 
in the study and verifying that the subject eligibility criteria, the study site will begin 
further pretreatment evaluation as follows: 
 
 Clinical Evaluation: A complete history and neurological examination                
( including clinical assessment of Karnofsky Performance Status, Neurological 
function, neurologic exam score, Vital signs, Physical, and Mental Status ) is to 
be done within 14 days of initial protocol treatment. 
 
 Radiographic Evaluation: An MRI scan must be performed within 14 days prior to 
initial treatment on a dose of steroids that has been stable or decreasing for 5 days or 
more.  MR spectroscopy are optional. 
 
 Vital Signs: Height, pulse, blood pressure, respiration rate, temperature and 
weight.  Blood pressure, pulse and respiration rate should be measured on 
patients.  
 
 Laboratory Evaluation:  Blood tests may be performed at the UCSF GCRC, at 
the UCSF Neuro-oncology clinic, or at a local laboratory.  Pre-study 
laboratory tests must be obtained with 14 days prior to initial protocol 
treatment.  Pre-study laboratory tests shall include: 
 
o CBC, platelets, differential, PT (INR) 
o Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, 
albumin, total protein, BUN, serum creatinine 
o T. bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus,  
o Fasting serum lipid profile (total cholesterol,triglycerides, HDL and 
LDL 
o serum pregnancy test for women of childbearing potential (performed 
within 7 days of initial protocol treatment).  
 


 
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 Electrocardiogram (ECG): A standard 12 lead ECG is to be performed within 
14 days of initial protocol treatment and significant findings must be recorded. 
 
 Lung function: Pulse Oximetry and Chest X-ray must be performed within 14 
days prior to initial protocol treatment  
 
Hepatitis B/C testing: Patients will be tested for the following hepatitis serologic markers: 
HBsAg, HBs Ab, HBc Ab Total, HBc IgM Ab and HCV antibodies.  
 
3.4.1.2. 
Assessments During Treatment 
 
 Clinical Evaluation: Clinical assessments will be required every 2 months for 
the first 12 months, then every 3 months for the next 12 months.  After 4 
weeks of treatment, a toxicity check will be performed with a local MD or 
telephone.  Whenever possible, all assessments at each scheduled time-point 
will be completed in a single clinic visit.  Performance of a full clinical 
evaluation should take between 1-1.5 hours.  Clinical assessments performed 
at required visits will include the following: 
 
 
Karnofsky performance status (Appendix 17.2) 
 
 
 
Neurological function / Neurologic exam (see below) 
 
 
 
Physical Examination 
 
 
Pulse Oximetry measurements 
 
Neuro Exam: Neurologic status should be recorded at each patient visit 
according to the scale below (compared to baseline, defined as 
neurologic exam at time of screening). 
 
+2 
Definitely better 
+1 
Possibly better 
0 
Unchanged 
-1 
Possibly worse 
-2 
Definitely worse 
 
Vital Signs: pulse, blood pressure, respiration rate, temperature and 
weight.  Blood pressure, pulse and respiration rate should be measured 
on patients  
 
  Radiographic Evaluation: An MRI will be required every 2 months for 12 
months and every 3 months for the next 12 months. MR spectroscopy scans at 
these time points are optional.  A research MRI/MRS scan maybe performed 
during Cycle 1 week 3.  Required assessments will include measurement of bi-


 
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directional diameters for patients who continue to have measurable disease.  
Uni-dimensional maximal diameter will also be recorded. MRI will be 
evaluated by Central Radiology review by both a neuro-oncology attending.  
 
 Chest X-ray: A chest x-ray is required every 2 months for 12 months and every 
3 months for the next 12 months.  
 
Course Response: This will be recorded every time a patient has an 
imaging study.   
 
+3 
= 
Disappearance of tumor (CR) 
+2 
= 
Definitely better (PR) 
+1 
= 
Possibly better 
0 
= 
Unchanged 
-1 
= 
Possibly worse 
-2 
= 
Definitely worse (PD) 
-3 
= 
Development of a new lesion (PD) 
 
 Laboratory Evaluation:  Laboratory tests except serum pregnancy tests shall be 
performed every 2 weeks during the first 2 months of treatment, and then 
monthly thereafter: 
 
o CBC, platelets, differential 
o Sodium, potassium, chloride, bicarbonate, calcium, fasting glucose, 
albumin, total protein, BUN, serum creatinine 
o T. Bilirubin, AST, ALT, alkaline phosphatase, uric acid, phosphorus 
o Fasting serum lipid profile (total cholesterol, triglycerides, HDL and 
LDL) 
o Serum pregnancy test: for women of childbearing potential every 2 
months for 12 months and then every 3 months while on protocol 
therapy and 12 weeks after discontinuing protocol therapy. 
o Note the coadministration of RAD001 and oral anticoagulants is 
possible but should be subject to verification of coagulation (INR) once 
steady state is reached (after one week‟s treatment). 
 
 Hepatitis B testing: Patients who test positive for hepatitis B antibodies 
without receiving prior vaccination will be monitored for HBsAg every 4 
weeks.  
 
 Medication Evaluation: All relevant information regarding drug doses, 
concomitant medications and doses, evaluable lesions with measurements, 
tumor response, laboratory examinations, and treatment-related toxicities shall 
be documented in the patient‟s medical record and flow sheets. Patients will 
maintain a treatment diary while on therapy. The Treatment Diary will be 
initiated on Day 1 of therapy and continue throughout treatment. Treatment 


 
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Diaries will be collected from the patient at 1 week, and then every 2 months 
for the first 12 months, then every 3 months until the patient discontinues 
therapy.  
 
3.4.1.3    Follow-Up Assessments 
 
 Protocol Completion Assessment:  
o After administration of RAD001 for two years, patients will be offered 
the opportunity to continue treatment.  There is no limit to the course of 
treatment an individual patient may receive.  However, the patient will 
continue to be evaluated at 3 month intervals while on RAD001 and a 
decision to discontinue treatment after 2 years of therapy will be made 
on clinical grounds. 
o All patients must be observed for safety for 30 days following the last 
dose of RAD001 prior to withdrawal from study.  This defines study 
completion.   
o Physical examination and comprehensive neurologic examination and 
grading, vital signs including weight, Karnofsky Performance status,  all 
laboratory values, and MRI of the brain must be repeated within 2 weeks 
of the last day of study only if these have not been evaluated within 14 
days, inclusive, prior to the date of withdrawal from study. 
 
 Long-term Follow-up: 
o Patients will be followed according to routine clinical practice after 
removal from protocol therapy or until death, whichever occurs first.   
o Patients removed from protocol therapy for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse 
event.   
o All patients will be followed for PFS and OS while on protocol therapy 
and while still receiving subsequent routine clinical care.  Patients off 
protocol therapy will continue to be followed for PFS and OS only.  
 
3.4.1.4    Summary of Assessments  
 
 
Initial 
Screen 
1-month 
Assessment 
Assessments 
every 8 weeks 
 (+3/-7days 
unless otherwise 
noted) for year 
1 of therapy 
 
Assessments 
every 12 weeks  
(+3/-7days 
unless otherwise 
noted)  after 
first year of 
therapy 
 
30 days 
after 
completing 
protocol 
therapy 
Procedure: 
Clinical 
Evaluation 
X 
 
X 
X 
 


 
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Vital Signs 
X 
 
X 
X 
 
Neurologic 
Exam 
X 
 
X 
X 
 
Toxicity 
Check 
X 
X 
X 
X 
X 
Chest X-Ray 
X 
 
X  
Q 8 weeks 
 (+/-7days) 
X 
Q 12 weeks 
 (+/-7days) 
 
Pulse 
Oximetry 
X 
 
X 
X 
 
ECG 
X 
 
 
 
 
Laboratory/ 
Diagnostic 
Tests: 
Serum 
pregnancy for 
women of 
child-bearing 
potential 
X 
 
X  
Q 8 weeks 
 (+/- 3 days)   
X 
Q 12 weeks 
 (+/- 3 days)   
 
CBC with diff 
and platelts 
 
 
Laboratory evaluation at baseline, 
Q 2 weeks (+/- 3 days) for the first two months, 
then Q 4 weeks (+/- 3 days)  while on therapy. 
 
Chemistries 
Liver function 
tests 
Fasting 
cholesterol / 
triglycerides 
MRI of the 
brain 
X 
 
X 
X 
 
Hepatitis B/C 
testing 
 
HBsAg, HBs Ab, 
HBc Ab Total, 
HBc IgM Ab and 
HCV antibodies 
X 
Patients who test positive for HBV antibodies 
without prior vaccination will be tested for HbsAg 
every 4 weeks (+/- 7 days) for re-activation 
 
Translational 
Research: 
Archival 
tumor tissue 
X 
 
     
 
 
Study Drug: 
RAD001 
starting dose: 
 
10mg 
 
 


 
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3.4.2 
Efficacy assessments 
 
3.4.2.1 Response Definitions 
 
Standard anatomic MRI in conjunction with clinical evaluation such as neurologic status and 
corticosteroid use, remains the key determinant of response to therapy and the evaluation of 
tumor recurrence for low grade gioma. Increase in contrast enhancement, worsening cerebral 
edema, and mass effect are traits of malignant transformation. Acquiring tissue samples to 
confirm tumor upgrade, although considered the “gold standard” for determining the presence 
of viable tumor, can result in both false positives and negatives that relate to sampling error.  
Evaluating response in low-grade glioma by radiographic imaging is an accepted means of 
determining response and is the standard by which NIH grant-funded brain tumor consortiums 
operate. 
 
One of the secondary endpoints will be response rate, based on the best response achieved (see 
below for definition of best response).  In order to ensure comparability of data from this trial 
with data from earlier trials, this trial will retain the traditional evaluation definition as the 
primary way to define response.  Response will be determined by the bi-dimensional 
diameters.  However, RECIST criteria will be collected and used for secondary evaluation.   
 
Definitions of Response  
 
Measurable Disease: Bidimensionally measurable lesions with clearly defined margins 
by MRI scan.  A measurable lesion must be 1 mm or larger in longest diameter. 
 
Evaluable Disease: Unidimensionally measurable lesions, masses with margins not 
clearly defined. 
 
Objective Status, To Be Recorded at Each Evaluation: If there are too many lesions to 
measure at each evaluation, choose the largest two to be followed before a patient is 
entered on study.  The remaining lesions will be considered evaluable for the purpose 
of objective status determination.  Unless progression is observed, objective status can 
only be determined when ALL measurable and evaluable sites and lesions are 
assessed. 
 
Complete Response (CR):  Complete disappearance of all measurable and evaluable 
disease.  No new lesions.  No evidence of non-evaluable disease.  All measurable, 
evaluable and non-evaluable lesions and sites must be assessed using the same 
techniques as baseline.  Patients must be on minimal or no steroids. 
 
Partial Response (PR):  Greater than or equal to 50% decrease under baseline in the 
sum of products of perpendicular diameters of all measurable lesions.  No progression 
of evaluable disease.  No new lesions.  All measurable and evaluable lesions and sites 
must be assessed using the same techniques as baseline.  Responders must be on the 
same or decreasing doses of dexamethasone. 
 
Partial Response, Non-Measurable (PRNM): Not applicable. 
 


 
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Stable / No Response (NR) / No Change (NC): Does not qualify for CR, PR, or 
progression.  The designation of Stable/No Response requires a minimum of 8 weeks 
duration.  All measurable and evaluable sites must be assessed using the same 
techniques as baseline. 
 
Progression: 25% increase in the sum of products of all measurable lesions over 
smallest sum observed (over baseline if no decrease) using the same techniques as 
baseline, OR clear worsening of any evaluable disease, OR appearance of any new 
lesion/site, OR failure to return for evaluation due to death or deteriorating condition 
(unless clearly unrelated to this cancer). 
 
Unknown: Progression has not been documented and one or more measurable or 
evaluable sites have not been assessed. 
 
Best Response: This will be calculated from the sequence of objective statuses. 
 
For patients with all disease sites assessed every evaluation period, the best response 
will be defined as the best objective status as measured according to the previously 
noted definitions.  Best response is unknown if all objective status determinations 
before progression are unknown. 
 
Neurological Exam: Although not used for determining response, it is useful to 
evaluate improvement in the neurologic exam that should coincide with objective 
measurement of tumor size. 
 
+2 
Definitely better 
+1 
Possibly better 
0 
Unchanged 
-1 
Possibly worse 
-2 
Definitely worse 
(compared to baseline)  
 
Time to Death: From date of registration to date of death due to any cause. 
 
 
3.4.2.2. 
Pathology Review 
 
Pathology must be reviewed in the UCSF pathology department.   
 
Obtaining tissue samples: 
 
 
The UCSF Neurosurgery Tissue Bank has a general consent that patients sign to 
authorize release of their samples from previous surgeries at outside institutions.  
 Slides and tissue blocks, along with a path report, are sent to UCSF -- c/o one of the 
NeuroOnc study coordinators or directly to the Neurosurgery tissue bank manager 
(currently Cynthia Cowdrey)  
 
Preparation of tissue samples: 
 


 
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 Once received, samples are logged into the Pathology computer system and assigned 
an SF#.   
 If H&E slides are not provided, the tissue bank manager (currently Cynthia Cowdrey) 
will prepare unstained slides from paraffin blocks.   
 The unstained slides will be staining at the UCSF Core lab. 
 
Review of tissue samples: 
 
 
Pathology Materials Required for Review: 
o A copy of the Pathology Reports and the Operative Reports. 
o A Protocol Specific Pathology Submission Form. 
 A neuropathologist () will review all H&E slides and will determine if the histology 
corresponds to the report and if it is adequate / appropriate for the study.   
 The neuropathologist will also choose the blocks from which to prepare unstained 
slides for additional analysis.  
 In general, one to two representative H&E stained slides from a pre-registration 
biopsy and when available from the original surgery will be reviewed. 
 
Immunohistochemical assays: 
 
All antigens to be assayed in this protocol are cytoplasmic or membranous and will be 
scored using a semi-quantitative scale as described herein: 
 
To examine whether the PTEN promoter is methylated in glioma specimens, we will 
use methylation-specific primers that had previously been used to demonstrate 
methylation of the PTEN promoter in a subset of non-small-cell-lung cancer samples. 
These primers amplify a 181 base pair region of the PTEN promoter that starts 2477 
nucleotides from the translation start site. The methylation-specific PCR (MSP) assay 
is sensitive to approximately 5% methylated product. 
 
The designated neuropathologists will identify areas on the glass slide that are 
appropriately stained with the antibody, and will review the positive and negative 
control samples.  The neuropathologist will then determine the ratio of tumor cells 
staining positive to those staining negative for the particular antibody. This 
interpretation does not consider intensity of staining per cell, but defines as “positive” 
all cells staining in a similar fashion to positive control cells. Based on this 
interpretation, the results are categorized into four groups: 
 
0- 
negative staining = no staining in any of the tumor cells 
1- 
focal positive staining = staining similar to positive control in less than one 
quarter of the tumor cells as determined by review of the entire slide and visual 
estimate. 
2- 
Intermediate positive staining = staining similar to positive control in greater 
than one quarter but less than three quarters of tumor cells as determined by the 
review of the entire slide and visual estimate. 
3- 
Diffuse positive staining = staining similar to positive control in greater than 
three quarters of the tumor cells as determined by the review of the entire slide and 
visual estimate. 


 
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Visual estimation may be aided by dividing the interpretable areas of the tissue on the 
slide into four quadrants using a tissue marker. It is beneficial to provide a visual scale 
in the form of a figure for the initial publications that will utilize the grading system. 
The results of this scoring can be reported as either a number representing each 
category, or descriptively using the terms negative, focal, intermediate, and diffuse. 
 
Table 1: Summary of Assays to evaluate Phosphorylated Akt pathway 
 
Molecular feature 
Assay (reagents) 
Phosphorylated PKB/Akt (phospho-
PKB/Akt) expression 
IHC: Polyclonal antibody Ser473; Cell 
Signaling Technology, Inc., Beverly, MA 
PTEN promoter expression 
IHC 
Ribosomal S6 phosphorylation 
IHC: phospho-specific antibody. 
PRAS40 
IHC 
 
3.4.2.3 
Radiology review 
  
All objective responses must be reviewed by a neuro-oncologist at UCSF.  Images will be 
viewed on the WebPACs system and comparison will be made between the most recent MRI image 
and the previous MRI image.  Measurements and responses are judged based on criteria outlined in 
section 9.1.  Discrepancies between measurements will be adjudicated by another neuro-oncologist at 
UCSF.  
 
 
 
 
3.4.3 
 
Safety assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and 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 
CTC 
http://ctep.cancer.gov/forms/CTCAEv3.pdf. 
3.4.3.1 
Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug even if the event is not considered to 
be related to study drug. Medical conditions/diseases present before starting study drug are 
only considered adverse events if they worsen after starting study drug. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or symptoms, 
are considered clinically significant, or require therapy. 


 
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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]. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
3.4.3.2 
Serious adverse events 
Information about all serious adverse events will be collected and recorded. To ensure patient 
safety each serious adverse event must also be reported to Novartis within 24 hours of 
learning of its occurrence. A serious adverse event is an undesirable sign, symptom or medical 
condition which: 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 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 
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 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 
3.4.4 
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 Drug Safety and Epidemiology Department (DS&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 
DS&E Department within 24 hours of learning of its occurrence. This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. 
All deaths during treatment or within 30 days following completion of active protocol therapy 
must be reported within 5 working days. 
Any serious adverse event occurring after the patient has provided informed consent and until 
4 weeks after the patient has stopped study participation must be reported. This includes the 
period in which the study protocol interferes with the standard medical treatment given to a 
patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed dose 
of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
3.4.5 
Data Safety Monitoring Plan  
3.4.5.1 Oversight and Monitoring Plan 
 
The UCSF-CCC Data Safety Monitoring Committee (DSMC) is responsible for monitoring 
data quality and patient safety for all UCSF-CCC institutional clinical studies.  A summary of 
DSMC activities for this study includes:  
 
 Review of subject data in each cohort  
 Quarterly review for progress and safety 
 Review of all serious adverse events  
 Minimum of a yearly audit  
3.4.5.2 Monitoring and Reporting Guidelines 
 
Investigators will conduct continuous review of data and patient safety at monthly study 
group or site committee meetings where the results of each patient‟s treatment are discussed 
and the discussion is documented in the minutes. The discussion will include the number of 
patients, significant toxicities as described in the protocol, doses adjustments, and observed 
responses. Quarterly summaries will be submitted to the DSMC for review.  All grade 3-5 


 
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AE‟s and SAE‟s will be entered in the CCC Oncore database.   
 
3.4.5.3 Review and Oversight Requirements 
 
3.4.5.4 Adverse Event Monitoring  
 
Adverse Events (AEs) will be recorded on the Oncore database, all grade 3-5 expected and 
unexpected AEs will be recorded and updated at each visit.    
 
Serious Adverse Event Reporting  
 
Serious Adverse Event reporting will be in accordance with the UCSF- Committee on Human 
Research Regulations and Code of Federal Regulation Title 21 Volume 5 Part 312.32.  
 
UCSF CHR website for guidance in reporting serious adverse events 
http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.pdf 
  
 
FDA website for guidance in reporting serious adverse events  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 
 
MedWatch forms and information:  
http://www.fda.gov/medwatch/getforms.htm 
 
 
Serious Adverse events will be reported on the MedWatch form. A copy of the MedWatch 
report and CHR forms must be sent to CCC- DSMC at Box 1297.   The date the SAE was sent 
to all required reporting agencies will be documented in Oncore, and hard copies of the report 
will be maintained in the regulatory files. 
 
If the SAE is death and determined to be possibly, probably or definitely related to the 
investigational drug or any research related procedure the event must be reported to the 
DSMC Chair, or his designee with in 24 business hours.   The reporting procedure is by 
personal communication via phone or in person with written documentation of the 1:1 
communication via e-mail with a copy of the e-mail to DSMC Administrator and DSMC 
Coordinator. 
If any of the above action occurs in multiple-institutional clinical trial coordinated by 
the UCSF-CCC, the Study Coordinator will insure that all participating sites are 
notified.   
 


 
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3.4.6 
Review of Adverse Event Rates 
 
If the study has an increase of unexpected or expected Adverse Events grade 3 or 4 above the 
rate reported in the Investigational Brochure or package insert, the increase rate of AEs will 
be reported to the DSMC at the time of Identification. The Chair and PI will discuss the 
finding and proceed with a written course of action. Each quarterly report will indicate if the 
AE incidence is within the scope of the investigational brochure or package insert.  If at any 
time the Investigator stops enrollment or stops the study due to safety issues the DSMC Chair 
and Administrator must be notified within 24 business hours via e-mail.  The DSMC must 
receive a formal letter within 10 business days and the CHR must be notified.  
 
If any of the above action occurs in multiple-institutional clinical trial coordinated by the 
UCSF-CCC, the Study Coordinator will insure that all participating sites are notified. 
 
3.4.7 
Study Progress – Quarterly Review 
 
Principal Investigators are required to submit quarterly study progress reports to determine 
whether accrual projections are being met, to summarize grade 3 and 4 toxicities (expected 
and unexpected) and SAE reports. This report will also indicate if the rate of all grade 3-5 
AE‟s are above the AE rates documented in the Investigational Brochure or package insert. In 
addition, a progress report on recruitment and subjects known responses to the investigational 
therapy must be submitted. At this time also send the committee all external DSMB reports 
and formal audit reports. 
 
These quarterly reports are reviewed at Data Safety Monitoring Committee meetings.  These 
reports are required:  February 1, May 1, August 1, and October 1.   Failure to submit such 
reports may result in trial suspension.  Send reports to: DSMC Box 1297. 
 
 
Data Safety Monitoring Committee Contacts: 
DSMC Chair:  Alan Venook, MD 
Phone  
(415) 353-2745 
Email  
venook@cc.ucsf.edu 
Box 
 
1705 
 
DSMC Administrator: Diane Davies, RN 
Phone  
(415) 353-9510 
Email  
ddavies@cc.ucsf.edu 
Box 
 
1297 
 
 
 
In addition all SAEs must be reported to:  
Include the Pharmaceutical Company contact for SAE reporting in this section. 


 
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3.4.7.1 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects, congenital abnormalities or maternal and newborn complications. 
3.4.7.2 
Laboratory evaluations 
 
please see section 3.4.1 for schedule for initial assessment and during follow up 
Hematology 
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential. PT (INR) evaluation will be included for baseline evaluations. 
Blood chemistry 
Blood chemistry must include sodium, potassium, chloride, bicarbonate, calcium, glucose, 
creatinine, blood urea nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total 
bilirubin, alkaline phosphatase, uric acid, phosphorus, serum lipid profile (triglycerides, total 
cholesterol, HDL and LDL). 
Because accurate serum glucose and lipid measurements are required, patients should be 
fasting at the time of the blood sampling. 
Hepatitis B Virus testing 
Patients will be tested for the following hepatitis B serologic markers prior to enrolling on the 
trial: HBsAg, HBs Ab, and HBc Ab Total, and HBc IgM Ab.  
HbsAg monitoring should be performed every 4 weeks if a patient tests positive for the 
hepatitis B antibodies without prior vaccination  
Hepatitis C Virus  testing 
Patients with be tested for HCV Ab prior to enrolling on the trial.  
3.4.7.3 
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  


 
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3.4.7.4 
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). 
 
Please see 3.4.1 for detailed neurological assessment. 
 
Significant findings made after the start of study drug which meet the definition of an Adverse 
Event must be recorded. 
3.4.7.5 
ECG 
A standard 12 lead ECG is to be performed during screening and significant findings must be 
recorded. 
3.4.7.6 
Performance status 
Performance status will be assessed. 
 
Karnofsky score as outlined in 3.4.1. 
3.4.7.7 
Special tests 
 
MRI as outlined in 3.4.1; neurological evaluatiuon as outlined in 3.4.1 
3.4.8 
Drug levels and pharmacokinetic assessments 
 Drug levels will not be monitored 
4 
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.  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 


 
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investigator and is implemented for safety reasons Novartis must be notified and the IRB at 
the center must be informed immediately.   Amendments affecting only administrative aspects 
of the study do not require formal protocol amendments or IRB approval but the IRB must be 
kept informed of such administrative changes. Examples of administrative changes not 
requiring formal protocol amendments and IRB approval include: 
1. 
changes in the staff used to monitor trials  
2. 
minor changes in the packaging or labeling of study drug. 
5 
Data management 
5.1 
Data collection 
 
Investigators must record the information required by the protocol. 
6 
Statistical methods 
6.1 
Statistical methods 
 
6.1.1. Stopping Rules 
 
If the discontinuation rate due to toxicity is 20% or greater and the lower bound for the one-
tailed 95% confidence interval is > 10%, this strategy would not be considered feasible.  At 
the time we observe any toxicity that requires permanent discontinuation of drug, we will 
estimate, with confidence intervals, the rate of toxicity.  If there is a greater than 20% rate for 
discontinuation of drug during therapy the study will stop and we will assess the study design.  
Because the confidence interval may be calculated multiple times, the actual confidence level 
will be overstated.  This increases the likelihood of rejecting the therapy due to toxicity.  
However, this is felt to be an acceptable risk in order to prevent continuation of a therapy that 
may have a toxicity rate that precludes its routine use. 
 
If there is any treatment related mortality event, the study accrual will be suspended until all 
data pertaining to the event is reviewed by the Study Chair and co-investigators. 
 
6.1.2. Endpoint Definitions and Sample Size 
 
The following definitions will be used for statistical analysis: 
 
 
Response: Response is based on the best response.  The best response is defined as 
the best objective status as measured by the sum of products of perpendicular 
diameters of all measurable lesions.  
 
Progression-free survival: Number of days from the day the patient was enrolled to 
the day the patient experiences an event of disease progression or recurrence or to 
the date of death if disease progression or recurrence is not reached.  All events of 
disease progression or recurrence will be included, regardless of whether the event 


 
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occurred while the patient was still taking drug or had previously discontinued 
study drug.  All events of death will be included for patients who had not 
experienced disease progression or recurrence.  If the patient does not have an 
event of disease progression or recurrence nor as the patient died, the patient‟s data 
will be censored at the date of last contact with the patient. 
 
Overall survival: Number of days from the day the patient was enrolled until the 
date of death.  If the patient is lost to follow-up, the patient‟s data will be censored 
at the date of last contact with the patient.  
 
For this single-arm phase II trial, the primary endpoint will be 6-month 
progression-free survival (PFS-6).  Patients will be analyzed based on intention to treat. 
The primary determination of treatment success will be based on the results for those 
patients who are shown to still be low-grade.  The intent is to perform the primary 
analysis at the time the 6 month PFS is known for all patients. 
 
Precise documentation of prognosis among recurrent low grade glioma 
patients treated with targeted therapy is limited in literature.  A recent study based on 
the experience of the North American Brain Tumor Consortium (NABTC) was 
conducted to assess whether progression status at 6 months predicts survival from that 
time among recurrent high-grade glioma adult patients (Lamborn, Yung et al. 2008). In 
that study, it was reported that the estimated PFS-6 among recurrent grade III glioma 
patients who were not treated with temozolomide, a chemotherapy which is part of the 
standard of care for newly diagnosed gliomas, is approximately 17%.  Since we expect 
patients with recurrent low grade gliomas to have better prognosis than grade III 
patients, we consider the lower threshold for the probability of 6-month PFS to be 17%.  
The calculation of sample size is based on a binary endpoint with the goal to increase 6-
month PFS rate to 40%. This translates into a hazard ratio of 0.52 
(experimental/historical).  40 patients will provide over 90% power using a one-sided 
test with alpha of 0.05.  
6.1.3. Accrual Objectives 
 
  
The study plan is to accrue 60 patients.  It is anticipated that most recurrent 
low-grade glioma patients completing surgical resection will be eligible for enrollment 
and will choose to participate.  Based on current patient volume in the UCSF 
neurologic-oncology clinic, it is expected that a minimum of 3 patients per month will 
be enrolled.   
 
6.1.3.        Estimated Duration of Study 
 
With enrollment of 3 patients per month, accrual can be completed in a 20 
month period.  With up to an additional 6 months of treatment to assess best response 
for the last accrued patient, the approximate duration of study is 26 months.  
Based on review of UCSF historical data, we expect approximately one-third 
of recurrent low-grade glioma patients to present with high-grade gliomas.  Therefore, 
we should be able to complete enrollment of 40 low-grade glioma patients and 20 


 
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secondary malignant glioma patients at approximately the same time.  In order to 
evaluate our primary objective, enrollment will continue until at least 40 low-grade 
glioma patients have enrolled. 
 
6.1.4 
Analyses Time-points and planned analysis 
  
  
Primary end-point – 6-month PFS: 
 
  
Analyses will be performed after all enrolled patients have completed 6 
months on study drug, or whenever the progression status of all patients has been 
established, whichever comes first.  The primary analysis will be based on Kaplan-
Meier method.  Kaplan-Meier estimates and the associated 95% CIs will be calculated 
for the 6-month PFS separately for low-grade glioma patients and secondary malignant 
glioma patients. The Cox proportional hazards model will also be used to allow for 
adjustment of the prognostic factors including age, KPS, extent of resection, and 
number of prior chemotherapy regimens.  
 
Secondary end-point – overall survival and objective response rate: 
The method described above for the analysis of PFS-6 will be applied to the analysis of 
OS. Response is based on the best response, defined as the best objective status as 
measured by the sum of products of perpendicular diameters of all measurable lesions. 
The point estimate and the associated 2-sided 95% CI for the response rate will be 
calculated separately for low grade and secondary malignant tumors. 
 
Secondary end-point – biologic correlates: 
 
The endpoints of overall survival,objective response rate and progression status at 6 
months will be evaluated for impact of phosphorlyated PKB/Akt status.  We anticipate 
that the response rate may be more dependent on phosphorylated PKB/Akt status than 
on current tumor grade.  We also expect approximately 50% of the low-grade tumors to 
be phosphorylated PKB/Akt positive and 75% of the higher-grade tumors to be positive. 
This will result in approximately 20 phosphorylated PKB/Akt positive low-grade cases 
and 15 phosphorylated PKB/Akt positive high-grade cases for secondary analyses.  A 
consideration of phosphorylated PKB/Akt status as a predictor of response will use the 
Cochran Mantel-Haenzel test stratified by grade.  If the number of responses is 
sufficient, logistic regression will be used to evaluate the potential impact of 
phosphorylated PKB/Akt status on the likelihood of response adjusting for grade. 
Estimates of the odds ratio and its associated 95% confidence interval will be calculated 
to determine if future studies of RAD001 should require prior assessment of 
phosphorylated PKB/Akt status.  The same methods will be used to determine if 
phosphorylated PKB/Akt status predicts progression status at 6 months stratified by 
grade.  The impact of phosphorylated PKB/Akt status on OS will be assessed using the 
proportional hazards models adjusting for grade. Estimates of the hazard ratio and its 
associated 95% confidence interval will be calculated. We will repeat these analyses on 
patients based on PTEN promoter methylation status. 


 
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Exploratory analysis – radiographic responses: 
 
We will determine if the pretreatment imaging and changes from pre-treatment 
to first post-treatment scan correlate with the clinical endpoints of time to tumor 
progression and survival.  A scoring system will be developed for predicting outcome 
based on the initial, pretreatment scan. Since all of these patients will have surgery, it 
will be possible to prospectively determine if the imaging score can predict grade as 
assessed by the neuropathologist. However, since most patients do not have surgery at 
time of progression, and time to progression varies even among those with the same 
tumor grade, we want to determine how useful this score will be beyond the current 
histology information. We plan to test the usefulness of this score in predicting PFS and 
survival using Cox regression. If the number of patients with responses is sufficient we 
will also assess the ability of the imaging score to predict response using logistic 
regression. The models will include, in addition to the imaging score, age, KPS, extent 
of resection, time since diagnosis, and initial diagnostic histology scored as 
oligodendroglioma only vs. those with an astrocytoma component. Because PKB/Akt 
phosphorylation status is predicted to impact outcome for this particular therapy, this 
will also be included in the model. The inclusion of these additional variables is to 
adjust for known or potential confounding risk factors. The primary hypothesis test will 
focus on the ability of the prediction score to add information beyond what would have 
been known based on the clinical data. 
 
The patients will initially be categorized as predicted upgraded (Yes/No) 
consistent with the primary question posed. For supplementary analyses the prediction 
score will be included as a continuous variable, or we may create a score – based, for 
example, on the quartiles of the values observed in the previously studied cases – to 
determine if a further refinement in prediction of outcome can be achieved. A further 
analysis will include the known current histologic grade to determine if the score 
provides information even adjusted for this variable. Based on preliminary data we 
expect 1/3 of low-grade patients to be upgraded to high-grade glioma on recurrence. If 
we make the assumption that the predicted distribution will be the same, then we will be 
comparing 20 predicted high grade vs. 40 predicted low grade patients for the overall 
assessment. Because these patients are being treated at time of progression, we 
anticipate that we will know the progression time for most of them at the time of the 
analysis. Assume that the analysis is done when 50 of the 60 event times are known and 
alpha=0.05 one-tailed. There would be over 80% power to detect the difference if the 
hazard ratio was 2.2.   
 
The analysis of the change from initial to first post treatment scan will be 
performed in a similar manner except that there will be the additional covariate of 
baseline prediction score, since we will want to know if the change from baseline adds 
information beyond what was available at the initial scan. The primary endpoints will be 


 
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PFS and survival. Fewer patients will be available for this assessment since some will 
progress at the time of their first post treatment scan. The power for testing hypotheses 
within this clinical trial is limited by the number of patients enrolled on the trial. We 
plan to estimate hazard ratios together with confidence intervals to determine if the MR 
parameters continue to look promising in this treatment group. 
 
 
7 
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8 
Procedures and instructions 
8.1.1 
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. 
8.1.2 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and to request 
similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents provided by Novartis 
(investigators' brochures and other material) will be stored appropriately to ensure their confidentiality. 
The information provided by Novartis to the investigator may not be disclosed to others without direct 
written authorization from Novartis, except to the extent necessary to obtain informed consent from 
patients who wish to participate in the trial. 
8.1.3 
Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the clinical trial 
agreement. 
8.2 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good Clinical 
Practice, as described in Novartis standard operating procedures and: 
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. 
8.2.1 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and dated 
statement that the protocol and informed consent have been approved by the IRB/IEC/REB must be 
given to Novartis before study initiation. Any amendments to the protocol, other than administrative 
ones, must be reviewed by Novartis approved by this committee. 


 
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8.2.2 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved and any discomfort it may entail. Each subject must be informed that participation in the study 
is voluntary and that he/she may withdraw from the study at any time and that withdrawal of consent 
will not affect his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating it, 
and should be given a copy of the signed document. If the subject cannot read or sign the documents, 
oral presentation may be made or signature given by the subject’s legally appointed representative, if 
witnessed by a person not involved in the study, mentioning that the patient could not read or sign the 
documents. No patient can enter the study before his/her informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with it for IRB/IEC/REB approval. 
8.2.3 
Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of Helsinki. 
Copies of the Declaration of Helsinki and amendments will be provided upon request or can be 
accessed via the website of the World Medical Association at http://www.wma.net/e/policy/17-
c_e.html.