Conditions: Bladder Cancer Metastatic Transitional Cell Carcinoma
Keywords: URETER URINARY BLADDER RAD001 Everolimus Urothelium 08-123
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
The purpose of this study is to learn what effects, good and/or bad, Everolimus has on advanced urothelial cancer.

The goal of this clinical research study is to learn if the study drug Everolimus can shrink or slow the growth of urothelial cancer. The safety of this drug will also be studied. The patients physical state, changes in the size of the tumor, and laboratory findings taken while on-study will help us decide if Everolimus is safe and effective.

Detailed description:

Arms:
arm 1: Everolimus will be administered at a dose of 10 mg orally once daily continuously.

Interventions: intervention 1: Everolimus
Intervention descriptions: intervention 1: Everolimus (RAD001) is a novel oral derivative of rapamycin. Everolimus will be administered orally as a 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 Everolimus in the morning, at the same time each day. Everolimus should be taken by the patient in a fasting state or with no more than a light fat-free meal.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-123 A(8) 
Amended: 03/04/15 
1 
 
 
 
 
 
 
Phase II Study of  Everolimus (RAD001) in Metastatic Transitional Cell Carcinoma of the 
Urothelium 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal  Investigator/Department: 
Dean F. Bajorin, MD 
Department of Medicine, GU 
Co-Principal 
Investigator(s)/Department: 
Jonathan E. Rosenberg, MD 
Department of Medicine, GU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10065 


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Investigator(s)/Department: 
Robert J. Motzer, MD 
George Bosl, M.D. 
Lewis Kampel, M.D. 
Gopakumar Iyer, M.D. 
Jason Koutcher, M.D. 
Michael Morris, M.D. 
Martin Voss, M.D. 
Howard Scher, M.D. 
Susan Slovin, M.D., Ph.D. 
David Solit, M.D. 
Dana Rathkopf, M.D. 
Karen Autio, MD 
Daniel Danila, MD 
Richard Bambury, MB 
James Hsieh, MD, PhD 
Yu Chen, MD, PhD 
Rana Kaplan, M.D. 
Marcia F. Kalin, M.D. 
Satish Tickoo, M.D. 
Scott Gerst, M.D. 
Irina Ostrovnaya, PhD 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, 
Pulmonary 
Department of Medicine, 
Endocrinology 
Department of Pathology 
Department of Radiology 
Department of Biostatistics 


Memorial Sloan-Kettering Cancer Center 
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Consenting 
Professional(s)/Department: 
George Bosl, M.D. 
Dean F. Bajorin, MD 
Jonathan E. Rosenberg, MD 
Karen Autio, MD 
Daniel Danila, MD 
Richard Bambury, MB 
James Hsieh, MD, PhD 
Yu Chen, MD, PhD 
Martin Voss, M.D. 
Gopakumar Iyer, M.D. 
Lewis Kampel, M.D. 
Jason Koutcher, M.D. 
Michael Morris, M.D. 
Robert Motzer M.D. 
Howard Scher, M.D. 
Susan Slovin, M.D., Ph.D. 
David Solit, M.D. 
Dana Rathkopf, M.D. 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Department of Medicine, GU 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amended: 03/04/15 
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Memorial Sloan-Kettering Cancer Center 
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IRB#:08-123 A(8) 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ................................................................ 2 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .......................................................................... 2 
3.1 
BACKGROUND AND RATIONALE ............................................................................... 2 
3.2 UROTHELIAL CANCER ............................................................................................ 2 
3.3 RATIONALE FOR EVEROLIMUS IN UROTHELIAL CARCINOMA .................... 3 
3.4 EVEROLIMUS ................................................................................................................... 3 
3.4.1 MTOR PATHWAY AND MECHANISM OF ACTION .......................................... 4 
3.4.2 PRECLINICAL STUDIES ........................................................................................ 5 
3.3.4 EVEROLIMUS PHARMACOKINETICS ................................................................ 7 
3.3.5 EVEROLIMUS PHARMACODYNAMIC STUDIES .............................................. 8 
3.3.6 CLINICAL EXPERIENCE WITH EVEROLIMUS .................................................. 8 
3.3.7 RATIONALE FOR THE STUDY POPULATION ................................................... 9 
3.3.8 RATIONALE FOR A PFS ENDPOINT .................................................................. 10 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................... 11 
4.2 
DESIGN ................................................................................................................ 11 
4.3 
INTERVENTION ................................................................................................. 11 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS ..................................................................... 11 
5.2 INVESTIGATIONAL DRUG DESCRIPTION ......................................................... 11 
5.3 DRUG DISPENSING/ADMINISTRATION .............................................................. 12 
5.4 STORAGE AND STABILITY ................................................................................... 12 
5.5 SOURCE OF DRUG................................................................................................... 12 
5.6 DRUG ACCOUNTABILITY ..................................................................................... 12 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 13 
6.2 
SUBJECT INCLUSION CRITERIA .................................................................... 13 
6.3 
SUBJECT EXCLUSION CRITERIA ....................................................................... 15 
7.0 
RECRUITMENT PLAN ................................................................................................... 16 
8.0 
PRETREATMENT EVALUATION ................................................................................ 16 
9.1 
TREATMENT/INTERVENTION PLAN ......................................................................... 17 
9.2 SCHEDULE AND DOSE ADMINISTRATION ....................................................... 17 
9.3 DOSE MODIFICATIONS .......................................................................................... 18 
9.4 MONITORING OF EVEROLIMUS SUSPECTED TOXICITIES ............................ 20 
9.4.1 MANAGEMENT OF STOMATITIS/ORAL MUCOSITIS/MOUTH ULCERS . 20 
9.4.2 MANAGEMENT OF HYPERLIPIDEMIA AND HYPERGLYCEMIA .............. 21 
9.4.3 MANAGEMENT OF NON-INFECTIOUS PNEUMONITIS ................................. 21 
9.5 TREATMENT COMPLIANCE .................................................................................. 25 
9.6 CONCOMITANT MEDICATIONS ........................................................................... 25 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ......................................... 29 
11.0 
TOXICITIES/SIDE EFFECTS ......................................................................................... 32 
12.1 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ............... 34 
12.2 DEFINITIONS ................................................................................................................ 34 
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12.3 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE .................... 34 
12.4 RESPONSE CRITERIA ................................................................................................ 34 
12.4.1 EVALUATION OF TARGET LESIONS .............................................................. 34 
12.4.2 EVALUATION OF NON-TARGET LESIONS .................................................... 35 
12.4.3 EVALUATION OF BEST OVERALL RESPONSE ............................................ 35 
12.4.4 CONFIRMATION OF RESPONSE ...................................................................... 36 
12.4.5 DURATION OF OVERALL RESPONSE/ PROGRESSION FREE SURVIVAL 
........................................................................................................................................... 36 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 36 
14.0 
BIOSTATISTICS .............................................................................................................. 37 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ............................................................................................................................. 38 
15.2 RESEARCH PARTICIPANT REGISTRATION ................................................... 38 
16.1 
DATA MANAGEMENT ISSUES ....................................................................................... 38 
16.2 
QUALITY ASSURANCE .................................................................................... 38 
16.3 
DATA AND SAFETY MONITORING ............................................................... 39 
16.4 PROTOCOL AMENDMENTS OR CHANGES IN STUDY CONTACT ............... 39 
17.1 
PROTECTION OF HUMAN SUBJECTS ........................................................................ 40 
17.2 
PRIVACY ............................................................................................................. 40 
17.3 SERIOUS ADVERSE EVENT (SAE) REPORTING .............................................. 40 
17.3.1 SERIOUS ADVERSE EVENT (SAE) REPORTING TO THE IRB .................... 40 
17.3.2 SERIOUS ADVERSE EVENT (SAE) REPORTING TO NOVARTIS ................ 41 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................ 42 
19.0 
REFERENCE(S) ............................................................................................................... 43 
20.1 
APPENDICES .................................................................................................................. 46 
A. PROCEDURES AND INSTRUCTIONS ................................................................... 46 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is an open-label Phase II study of Everolimus (RAD001) in patients with progressive 
advanced/metastatic urothelial carcinoma that have progressed despite treatment with prior 
cytotoxic chemotherapy. The primary objective of the study is to measure the 2-month PFS rate 
of Everolimus (RAD001) as determined by RECIST. Everolimus will be administered at a dose 
of 10 mg orally once daily continuously. Intra-patient dose reduction may be required depending 
on the type and severity of the individual toxicity encountered. Re-staging imaging studies will 
be performed after every two cycles of treatment (one cycle = 4 weeks) during the first five years 
of treatment, and after every 3-6 cycles of treatment thereafter. Patients may continue on study 
as long as they are tolerating therapy and are free of disease progression. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary 
• To measure PFS of Everolimus (RAD001) as determined by RECIST 
• To determine the safety and toxicity of Everolimus (RAD001) in this patient population. 
 
Secondary 
• To determine the response rate of Everolimus (RAD001) in patients with progressive 
urothelial cancer who have received prior cytotoxic chemotherapy 
• To assess markers for activated mTOR pathway (including phospho-S6 and phsopho-4E 
BP1) in all pre-treatment specimens and correlate with response to treatment and PFS. 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 Urothelial Cancer 
 
In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common 
malignancy in men and the ninth most common in women with an estimated 67,160 new cases 
(50,040 men and 17,120 women) and 13,750 deaths (9,630 men and 4,120 women) for the year 
2007[1].  Although UC is a chemosensitive malignancy with response proportions of over 50% 
with conventional cytotoxic regimens, the response durations are short and the median survival 
of patients with metastatic disease is approximately 14 months [2]. Second-line trials with 
cytotoxic agents have generally yielded discouraging response rates (see table below) with a 
median progression-free survival between 2 to 3 months and a median survival in the range of 6 
to 9 months[3-6].  Furthermore, many patients receive these agents as part of first-line therapy 
leaving few available options for patients with progressive or recurrent disease. There is no 
FDA-approved drug for this setting and no standard conventional chemotherapy agent(s) have 
demonstrated a survival benefit in patients with metastatic urothelial cancer that has progressed 
after first line platinum-based chemotherapy.  This highlights the need for the development of 


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novel therapies for the treatment of patients with metastatic UC. 
 
Table 1. Results with cytotoxic agents in patients with metastatic urothelial 
carcinoma who had received prior chemotherapy 
Agent 
Activity 
Overall Response 
95% CI 
Paclitaxel[4, 7, 8] 
9% 
0-17% 
Docetaxel[3, 9] 
13% 
4-30% 
Ifosfamide[10-12] 
20% 
10-32% 
Gemcitabine[13, 14] 
23% 
8-38% 
 
 
3.3 Rationale for Everolimus in Urothelial Carcinoma 
 
At Memorial Sloan-Kettering Cancer Center (MSKCC), we performed an immunohistochemical 
(IHC) study to assess whether mTOR pathway markers are expressed in high-stage bladder 
urothelial carcinomas.  The study was carried out on a tissue microarray of 92 cases of invasive 
urothelial carcinoma of the bladder (≥ pT2) using antibodies against phospho-S6 and phospho- 
4E BP1, both markers for an activated mTOR pathway. Staining was graded as 0 to 3+ (0=0- 
5%; 1+=6-25%; 2+=26-50%; and 3+=>50% tumor cells positive) for phsopho-S6 (cytoplasmic) 
and phospho-4E BP1 (cytoplasmic and/or nuclear). Presence of at least two evaluable cores  
from each tumor was required for inclusion in the final evaluation.  The results of 
immunoreactivity in tumor cells demonstrated that mTOR pathway markers are overexpressed in 
invasive urothelial carcinoma of the bladder with correlation of expression seen within molecules 
of the mTOR pathway using Spearman’s correlation coefficient (rho=0.411) (see table below). 
This suggests that m-TOR targeted therapies may have activity in patients with urothelial 
carcinoma. 
 
 
Table 2. Tumor cell immunoreactivity 
Antibody (# 
cases) 
Grade 0 
(%) 
Grade 1+ 
(%) 
Grade 2+ 
(%) 
Grade 3+ 
(%) 
p-S6 (85) 
45 (53) 
11 (13) 
9 (11) 
20 (23) 
p-4E BP1 (84) 
25 (30) 
10 (12) 
17 (20) 
32 (38) 
 
 
 
 
3.4 Everolimus 
Everolimus is a novel oral derivative of rapamycin. 
Everolimus 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 


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European Union. Everolimus has been in development for patients with various malignancies 
since 2002. 
Everolimus 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. 
 
 
3.4.1 mTOR pathway and mechanism of action 
 
At the cellular and molecular level, Everolimus acts as a signal transduction inhibitor. 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), a key and a highly 
conservative serine-threonine kinase, which is present in all cells and is a central regulator of 
protein synthesis and ultimately cell growth, cell proliferation, angiogenesis and cell survival. 
mTOR is the only currently known target of Everolimus (reviewed in Boulay and Lane, 2007). 
mTOR is downstream of PI3K/AKT pathway, a pathway known to be dysregulated in a wide 
spectrum of human cancers (e.g. through loss/mutation of the PTEN negative regulator; through 
PI3K mutation/amplification; through AKT/PKB overexpression/overactivation; through 
modulation of TSC1/TSC2 tumor suppressors). In addition, activation of the PI3K/AKT/mTOR 
pathway is frequently a characteristic of worsening prognosis through increased aggressiveness, 
resistance to treatment and progression. 
The main known functions of mTOR include the following (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. 
• The PI3K-mTOR pathway itself is frequently activated in many human cancers, and 
oncogenic transformation may sensitize tumor cells to mTOR inhibitors. 
• Through inactivating eukaryotic initiation factor 4E binding proteins (4E-BP1) and activating 
the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR regulates translation of important 
massages, including those encoding the HIF-1 proteins, c-myc, ornithine decarboxylase, and 
cyclin D1, as well as ribosomal proteins themselves. 
• The activation of mTOR pathway leads to the increased production of pro-angiogenic factors 
(i.e., VEGF) in tumors and to tumor, endothelial and smooth muscle cell growth and 
proliferation. 
• The regulation of mTOR signaling is complex and involves positive regulators, such as AKT 
that phosphorylate and inactivate negative regulators such as the Tuberous Sclerosis 
Complex (TSC1/TSC2). 


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mTOR is represented by two structurally and functionally distinct multiprotein signaling 
complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and mTORC2 (mTOR complex 
2, rapamycin insensitive) (Wullschleger, Loewith and Hall 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 at 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 the role of a negative regulator. mTORC2 is rapamycin 
insensitive and is required for the organization of the actin cytoskeleton (Wullschleger, Loewith 
and Hall 2006). 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone rapamycin and 
its derivatives, such as Everolimus. 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 (Witzig, et 
al 2005). Since 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). 
 
 
3.4.2 Preclinical studies 
 
Pre-clinical investigations have demonstrated that Everolimus is a potent inhibitor of the 
proliferation of a range of human tumor cell lines in-vitro with IC50s ranging from sub/low nM 
to µM concentrations. These concentrations can be reached in patients at the doses used in 
clinical trials. 
Everolimus has proven active in human tumor cell lines originating from lung, breast, prostate, 
colon, kidney, melanoma and glioblastoma. Everolimus was also shown to have activity in acute 
myeloid leukemia cells (Zeng, et al 2007), adult T-cell leukemia cells (Ikezoe, et al 2007), 
diffuse large B cell lymphoma cells (DLBCL; Wanner, et al 2006), pancreatic tumor cells 
(Tuncyurek, et al 2007), ovarian cancer cells (Treeck, et al 2006, Mabuchi, et al 2007), 
hepatocellular carcinoma cells (Sieghart, et al 2007), and human pancreatic neuroendocrine cells, 
where induction of apoptosis was reported (Zitzmann, et al 2007). 


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As a single agent, Everolimus inhibited proliferation in three mantle cell lymphoma cell lines 
(Jeko1, SP49 and NCEB1) approximately 40–65% compared to control cells. This was 
associated with G1 cell-cycle arrest and reduced phosphorylation of the mTOR downstream 
target, 4E-BP1 (Haritunians, et al 2007). 
In a clonogenic assay using cells derived from 81 patient-derived tumor xenografts  never 
cultured in vitro (11 human tumor types with 3 to 24 tumors each: bladder, colon, gastric, 
NSCLC [adeno, squamous epithelium and large cell], SCLC, breast, ovary, pancreatic, renal, 
melanoma, and pleuramesothelioma), Everolimus inhibited colony formation in a concentration- 
dependent manner. In addition, normal hematopoetic stem cells were insensitive to Everolimus, 
with an IC50 about 15 times higher than the tumor lines. 
Everolimus also inhibits the proliferation of human umbilical vein endothelial cells (HUVECS), 
with particular potency against VEGF-induced proliferation. The inhibition of endothelial 
proliferation and antiangiogenic activity of Everolimus has been confirmed in vivo, as 
Everolimus selectively inhibited VEGF-dependent angiogenic response. Mice with primary and 
metastatic tumors treated with Everolimus showed a significant reduction in blood vessel density 
when compared to controls at well-tolerated doses. Additionally, activity in a VEGF- 
impregnated s.c. implant model of angiogenesis and reduced vascularity (vessel density) of 
Everolimus-treated tumors (murine melanoma) provided evidence of in vivo effects of 
angiogenesis. 
Everolimus also inhibits tumor growth in-vivo in xenografted, syngeneic and orthotopic animal 
models, residing longer in tumor tissue than in plasma and demonstrating high tumor penetration 
in a rat pancreatic tumor model. These effects occurred within the dose range of 2.5 to 10 mg/kg 
p.o. daily. Typically, the antitumor activity of Everolimus monotherapy was that of reduction of 
tumor growth rates rather than producing regressions or stable disease. 
Everolimus, administered p.o., was a potent inhibitor of tumor growth and well tolerated in: 
• s.c. mouse xenograft model, established from a variety of tumor cell lines of diverse 
histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), including a Pgp170- 
overexpressing multi-drug resistant tumor line. 
• a series of low-passage tumor xenografts established directly from human tumor material, 
maintained only in vivo and considered highly predictive of therapeutic outcome in patients. 
These included breast (5 lines), colorectal (9 lines), gastric (3 lines), lung (22 lines including 
adenocarcinomas, epidermoid cell, large cell and small cell histotypes), melanoma (6 lines), 
ovarian (4 lines), pancreatic (3 lines) and renal (6 lines). 
• two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic melanoma). 
Taken together, these data indicate the broad antiproliferative potential of Everolimus. 
It is not clear which molecular determinants predict responsiveness of tumor cells to Everolimus. 
Molecular analysis has revealed that relative sensitivity to Everolimus in vitro correlates with the 
degree of phosphorylation (activation) of the AKT/PKB protein kinase and the S6 ribosomal 
protein. PTEN status alone may not be predictive of Everolimus relative to in vitro sensitivity, 
however in some cases (i.e., GBM) there is also a correlation with PTEN status. 


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In preclinical models, the administration of Everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated S6 (pS6) and 
p4E-BP1, and occasionally with an increase in phosphorylation AKT (pAKT). 
 
3.3.3 Pre-Clinical Safety 
 
In safety pharmacology studies, Everolimus was devoid of relevant effects on vital functions 
including the cardiovascular, respiratory and nervous systems. Everolimus had no influence on 
QT interval prolongation. 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 2000mg/kg or after repeated 
administration at up to 40 mg/kg/day. Based on these findings, the potential of Everolimus to 
affect vital functions in patients is considered low. 
Everolimus is considered to have no genotoxicity or carcinogenicity potential. All significant 
adverse events observed in preclinical toxicology studies with Everolimus in mice, rats, monkeys 
and minipigs were consistent with its anticipated pharmacologic action as an antiproliferative 
and immunosuppressant and were at least in part reversible after a 2- or 4-week recovery period 
with the exception of the changes in male reproductive organs, most notably testes. Ocular 
effects (lenticular disorders) observed in rats were not observed in any other species and are 
considered to be a species-specific disorder. 
More pre-clinical information is provided in the Investigator’s Brochure. 
 
3.3.4 Everolimus Pharmacokinetics 
 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The bioavailability of the drug is 
believed to be 11% or greater. The AUC0-τ is dose-proportional over the dose range between 5 to 
70 mg in the weekly regimen and 5 and 10 mg in the daily regimen. Cmax is dose-proportional 
between 5 and 10 mg for both the weekly and daily regimens. At doses of 20 mg/week and 
higher, the increase in Cmax is less than dose-proportional. The coefficient of variation between 
patients is approximately 50%. 
Trough levels (24 hour post-dose) correlate well with AUC0-τ at steady-state during daily 
administration. 
In whole blood, at a daily dose of 10 mg, about 20% of Everolimus is confined in plasma with 
26% being unbound. The remaining 80% is sequestered in blood cells. 
Everolimus is extensively metabolized in the liver and eliminated in the bile. Major metabolites 
are inactive. Elimination half-life is approximately 30 hours. The clearance of Everolimus is 
approximately halved in patients with mild-moderate hepatic impairment (Child-Pugh Class A or 
B), while renal impairment has little or no impact on its the pharmacokinetics. 
Age, weight and gender in the adult population do not affect the pharmacokinetics of Everolimus 
to a clinically relevant extent. The clearance of Everolimus is reduced in children. 


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Pharmacokinetic characteristics are not notably different between Caucasian and Japanese 
subjects, whereas population pharmacokinetic studies have shown an average 20% higher 
clearance in Black patients. 
A high-fat meal altered the absorption of Everolimus with a 1.3 hour delay in tmax, a 60% 
reduction in Cmax and a 16% reduction in AUC. 
Everolimus is a substrate of CYP3A4 and a substrate and moderate inhibitor of the multi-drug 
efflux pump P-glycoprotein (P-gP, MDR1, ABCB1). Hence, its metabolism is sensitive to drugs 
which modify these enzymes (substrates, inducers, or inhibitors of these enzymes). Competitive 
inhibition could occur when Everolimus is combined with drugs which are also CYP3A4 or P- 
glycoprotein substrates. 
Table 6 (Section 9.5) lists examples of clinically relevant CYP3A inhibitors and inducers. 
Please refer to Section 9.5 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications. 
More information on Everolimus pharmacokinetics is provided in the [Investigator’s Brochure]. 
3.3.5 Everolimus 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). Furthermore, molecular pharmacodynamic (MPD) studies using 
immunocytochemistry (IHC) in biopsied tumor tissue assessed the degree of inhibition and its 
duration for pS6, p4E-BP1 and pAKT expression with the daily and weekly dosing. There was 
high inhibition of the downstream markers S6K1 and 4E-BP1 at 5mg/day, which was complete 
at 10 mg/day, while preliminary results suggest an increase in pAKT expression with maximal 
effect at 10 mg daily ([Study C2107], Tabernero, et al 2005). 
More information is provided in the Investigator’s Brochure. 
 
3.3.6 Clinical experience with Everolimus 
 
Everolimus has been investigated as a component of multi-drug immunosuppression in solid 
organ transplantation since 1996 and was approved for the indication of prophylaxis of organ 
rejection in adult patients receiving an allogeneic renal or cardiac transplant on 8 Jul 2003 by the 
European Union under the trade name of Certican®. The most frequent adverse drug reactions in 
this context are highly specific to the transplant context. However, certain events are 
generalizable, most notably myelosuppression, skin disorders and increases in blood lipid levels. 
Everolimus has been in development for patients with cancer since 2002. Approximately 2586 
patients with various malignancies have been treated in either Novartis-sponsored or non- 
Novartis-sponsored clinical studies as of 31 Aug 2007. Overall, Novartis sponsored a total of 22 
studies of Everolimus administered either as a single agent (n=848) or in combination with other 
anti-tumor agents (n=663). Ongoing or completed Investigator-sponsored studies also enrolled 
over 1000 patients globally. 


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Eight single-agent Novartis sponsored trials have or are being conducted in various advanced 
malignancies. Five Phase I studies evaluated several escalating doses with either weekly or daily 
administration (Studies C2101/02, C2106, C2107, C1101) of Everolimus with the objective to 
identify an optimal regimen and dosage based on safety, pharmacokinetics, and knowledge of the 
drug’s molecular effects on various tumors. The 10 mg/day and 50-70 mg/week dosages were 
proposed for further studies when using Everolimus as a single agent and as a target maximum 
dose in combination studies. In addition, the Phase I studies conducted in prostate cancer (Study 
C2106) and in Japanese patients with advanced cancers (Study C1101) evaluated the safety and 
the molecular changes in tumors associated with the administration of Everolimus. 
Two Phase II monotherapy studies were designed to evaluate the safety and efficacy of a single 
dose of 10 mg administered daily, including Study C2235 in advanced NSCLC (n=81) and Study 
C2239 in advanced pancreatic neuroendrine tumors (n=160). 
A Phase III study (Study C2240) is ongoing and designed to demonstrate the safety and efficacy 
of Everolimus at an oral dose of 10 mg versus matching placebo in patients with metastatic 
carcinoma of the kidney, whose disease has progressed despite prior VEGF-R tyrosine kinase 
inhibitor therapy. Over 400 patients have been enrolled in this prospective, randomized, 
multicenter study, which remains blinded as of the cut-off date. 
Overall, the most frequent mild-moderate Grade 1 and 2 adverse effects have been rash, 
stomatitis, fatigue, neutropenia and, to a lesser extent, gastrointestinal disorders (nausea, 
anorexia, diarrhea, vomiting) and headache. The primary DLT has been severe (Grade 3) 
stomatitis, and occasionally fatigue, hyperglycemia, and neutropenia. Reduced blood counts, 
hyperlipidemia (mainly hypercholesterolemia), and hyperglycemia are relatively frequent 
laboratory findings. Infections have not been notably frequent or severe. Severe non-infectious 
low-Grade (Grade 1 and 2) pneumonitis has led to development of treatment guidelines for the 
disorder (Table 3-2). Preliminary indications of anti-tumor activity are encouraging. 
Refer to Section 9 for more information on known undesirable effects of Everolimus. 
Further detailed information regarding Everolimus clinical development, safety and efficacy is 
provided in the [Investigator’s Brochure]. 
 
3.3.7 Rationale for the Study Population 
The first-line treatment of patients with metastatic urothelial carcinoma varies and may involve a 
cisplatin- or carboplatin-based doublet, triplet, the four drug MVAC regimen, or a sequential 
doublet regimen. Furthermore, many patients with metastatic disease have previously received 
cytotoxic chemotherapy in the perioperative setting. Given this heterogeneity in prior exposure to 
chemotherapy, the definition of “second-line” or “third-line” chemotherapy has not been well 
characterized. As a result, we have designed the eligibility for this protocol based on the number 
of prior chemotherapeutic agents patients have received rather than the number of “lines” of 
therapy that have been administered. Second-line chemotherapy trials have typically included 
patients who have received either 1 or ≥ 1 prior regimen(s).  Clinical trials at MSKCC have 
included a maximum of 4 prior drugs because patients are treated with multiple agents in the 
community before referral.  There are no available data demonstrating that the response 
proportion in the relapsed setting is linked to the number of prior regimens; this concept has been 


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reinforced identifying Sunitinib as active in a MSKCC phase 2 trial of patients with metastatic 
urothelial cancer who have received a maximum of 4 prior drugs (J Clin Oncol 2008 Vol. 26, No 
15S, p. 270s Abstract #5082).  This prior treatment inclusion criteria will serve to enhance 
accrual and likely ultimately provide a more homogenous patient population (e.g., most patients 
will have been exposed to a platinum, gemcitabine, and a taxane at some point in their treatment 
history). Further, we do not anticipate the response to this targeted agent to be closely linked to 
the number of prior cytotoxic agents administered.  If Everolimus demonstrates activity in this 
second-line trial, future trials will include an evaluation of the combination of Everolimus with 
chemotherapy in the first- and second-line settings. 
 
3.3.8 Rationale for a PFS Endpoint 
Pertinent to the issue of discovering new drugs active in urothelial cancers is that identifying 
clinical benefit should not be limited to response. Some of the newer "targeted therapy" agents 
approved by the FDA have been approved on the basis of improved progression-free survival 
(PFS) and not response rate (e.g., sorafenib in renal cell carcinoma with a response rate of 
approximately 10% but a major impact in PFS and, eventually, an improvement in survival). 
This being said, the median progression-free survival for bladder cancer patients treated with 
chemotherapy is modest at only 2-3 months and response rates are in the 10-20% range.  In a 
second-line trial of weekly paclitaxel in 31 patients with progressive urothelial cancer, the 
median time to progression was 2.2 months[4].  In an ECOG trial evaluating the epothilone 
analog BMS-247550 in patients with relapsed urothelial cancer, the median progression-free 
survival was 2.7 months (95% CI, 1.8, 4.1)[5].  In a recently reported phase 3 randomized 
second-line trial of vinflunine versus best supportive care, the PFS for patients treated with 
vinflunine was 3.0 months (95% CI, 2.1, 4.0) (J Clin Oncol 2008 Vol. 26, No 15S, p. 257s 
Abstract #5028).  Novel therapies are desperately needed for these patients and identifying 
activity in the refractory setting by using PFS is considered an acceptable approach with these 
new targeted agents. 
 
A recently reported randomized, double-blind, multicenter trial of Everolimus versus placebo has 
demonstrated a statistically and clinically significant improvement in progression-free survival 
(HR=0.30, p <0.0001), with a favorable safety profile in patients with metastatic renal cell 
carcinoma after progression on VEGFr-TKI therapy ((J Clin Oncol 2008 Vol. 26, No 15S, p. 
256s Abstract #LBA5026).  Based on a sample size of 362 patients, this trial had a 90% power to 
detect a 33% risk reduction with a median exponential PFS improvement from 3.0 to 4.5 months. 
The PFS for Everolimus-treated patients was 4.0 months (3.7-5.5) versus 1.9 months (1.8-1.9) 
for those treated with placebo. Pertinent to this study, only 3% of patients had a partial response 
by RECIST and the majority of patients had stable disease. Also pertinent to this proposed trial 
in bladder cancer is the fact that the kidney cancer trial was also not a pure “second-line” trial; 
approximately 50% of patients had received more than one prior TKI. Everolimus was well– 
tolerated, with the most common adverse events including stomatitis, anemia and asthenia. This 
trial establishes precedent for the use of PFS as an endpoint for RAD001 trials in other diseases 
in the “second-line” setting. 


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4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is an open-label Phase II study of Everolimus in patients with progressive 
advanced/metastatic urothelial carcinoma that have progressed despite treatment with prior 
cytotoxic chemotherapy. 
 
 
The primary endpoints of this study will be: 
 
• To measure the two-month PFS rate of Everolimus (RAD001) as determined by RECIST 
• To determine the safety and toxicity of Everolimus (RAD001) in this patient population 
The secondary endpoints of this study will be: 
• To determine the response rate of Everolimus in patients with progressive urothelial cancer 
who have received prior cytotoxic chemotherapy. 
• To assess markers for activated mTOR pathway (including phospho-S6 and phsopho-4E 
BP1) in all pre-treatment tissue specimens and correlate with response to treatment and PFS. 
 
4.3 
Intervention 
 
Everolimus will be administered at a dose of 10 mg orally once daily continuously. Intra-patient 
dose reduction may be required depending on the type and severity of the individual toxicity 
encountered. Re-staging imaging studies will be performed after every two cycles of treatment 
(one cycle = 4 weeks) during the first five years of treatment, and after every 3-6 cycles of 
treatment thereafter. Patients may continue on study as long as they are tolerating therapy and 
are free of disease progression. 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 Investigational Drug Description 
 
Everolimus (RAD001) is a novel oral derivative of rapamycin. Everolimus will be administered 
orally as a 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 Everolimus in 
the morning, at the same time each day. 
Everolimus should be taken by the patient in a fasting state or with no more than a light fat-free 
meal. Dietary habits around the time of Everolimus intake should be as consistent as possible 
throughout the study. 
If vomiting occurs, no attempt should be made to replace the vomited dose. 


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5.3 Drug Dispensing/Administration 
 
Administration will be performed on an outpatient basis. Everolimus will be dispensed as tablets 
at the beginning of each treatment cycle (or, for patients who have completed five years of 
treatment, at the beginning of every other treatment cycle). In case of dose modification, patients 
will be asked to return all of their previously dispensed medication to the clinic and they will be 
dispensed with new strength capsules. 
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 will 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. 
Everolimus will be provided by Novartis. Everolimus is formulated as tablets for oral 
administration of 5mg strength. Tablets are blister-packed under aluminum foil in units of 10 
tablets, which should be opened only at the time of administration as drug is both hygroscopic 
and light-sensitive. 
 
 
5.4 Storage and Stability 
 
Current stability data permit a shelf life of either 36 months (for 5mg tablet variants based on 
solid dispersion dried by evaporation/drying oven) or 24 months (for 2.5mg, 5 mg and 10 mg 
tablet variants based on solid dispersion dried by paddle dryer), assuming correct storage below 
30oC in the original double-sided aluminium blister packaging and protected from light and 
moisture. 
 
5.5 Source of Drug 
 
Novartis, Inc. will supply Everolimus free of charge. 
 
 
5.6 Drug Accountability 
 
 
All study drug supplies must be kept in a locked room with limited access. The study drug must 
not be used outside the context of this protocol. Under no circumstances should the investigator 
or other site personnel supply study drug to other investigators, patients, or clinic, or allow 
supplies to be used other than directed by this protocol without prior authorization from 
Novartis. 
 
The pharmacist will maintain a complete drug accountability record for each capsule strength 
with lot numbers of each drug received, including the number of bottles dispensed to each 
patient, the dates drug was dispensed, and the daily dose of Everolimus the patient received. The 
prescribed dose should also be recorded in the patient’s medical records. 


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At  the conclusion  of the study, all unused Everolimus tablets will be destroyed on-site as 
described in a standard operating procedure for the destruction of chemotherapeutic waste. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
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, 
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. 
 
6.2 
Subject Inclusion Criteria 
 
• Patients must have a diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal 
pelvis, with histological confirmation at MSKCC. 
• Patients must have progressive metastatic disease. Progressive disease will be defined as new 
or progressive lesions on cross-sectional imaging. 
• Patients must have at least one measurable site of disease (according to RECIST criteria) that 
has not been previously irradiated. If the patient has had previous radiation to the marker 
lesion(s), there must be evidence of progression since the radiation. 
• Patients must have been previously treated, as defined by the following: 
• Treatment with at least one prior cytotoxic agent but not more than four prior 
cytotoxic agents.  Up to four prior chemotherapy agents are allowed, since 
conventional chemotherapy ranges from just one drug (e.g., gemcitabine) to regimens 
that contain four agents (e.g., M-VAC is a four-drug regimen containing 
methotrexate, vinblastine, doxorubicin, and cisplatin). 
• The prior therapy must have included at least one of the following: cisplatin, 
carboplatin, paclitaxel, docetaxel, or gemcitabine. 
• The prior cytotoxic agents may have been administered in the perioperative or 
metastatic setting and may have been administered sequentially (e.g., first-line 
treatment followed by second-line treatment at time of progression) or as part of a 
single regimen. 
• Pre-treatment tumor tissue available for analysis of m-TOR pathway markers 
• Age ≥ 18 years 
• Karonfsky Performance Status ≥ 60% 
• 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 


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• INR < 1.3 (or < 3 on anticoagulants) 
• ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases) 
• 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: If a patient's lipid values exceed either one of these criteria upon screening, the 
patient can only become eligible after successful initiation of appropriate lipid-lowering 
medication. After lipid-lowering therapy, patients must meet the same criteria – i.e. a fasting 
serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN – 
to be eligible for study treatment. 
• Signed informed consent 
• Testing for hepatitis B viral load and serological markers (HBV-DNA, HBsAg, HBsAb, and 
HBcAb) for the following patients: 
• All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal, or Greece 
• Patients with any of the following risk factors: 
• Known or suspected past hepatitis B infection 
• Blood transfusion(s) prior to 1990 
• Current or prior IV drug users 
• Current or prior dialysis 
• Household contact with hepatitis B infected person(s) 
• Current or prior high-risk sexual activity 
• Body piercing or tattoos 
• Mother known to have hepatitis B 
• History suggestive of hepatitis B infection, e.g dark urine, jaundice, or right upper 
quadrant pain 
• Additional patients at the discretion of the investigator 
• Testing for hepatitis C infection (using quantitative RNA-PCR) for patients with any of the 
following risk factors: 
• Known or suspected past hepatitis C infection (including patients with past interferon 
“curative” treatment) 
• Blood transfusion(s) prior to 1990 
• Current or prior IV drug users 
• Household contact of hepatitis C infected person(s) 
• Current or prior high-risk sexual activity 
• Body piercing or tattoos 
• Additional patients at the discretion of the investigator 


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6.2 
Subject Exclusion Criteria 
 
• Patients currently receiving anticancer therapies or who have received anticancer therapies 
within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, 
antibody based therapy, etc.) 
• Patients who have had a major surgery or significant traumatic injury within 4 weeks of start 
of study drug, patients who have not recovered from the side effects of any major surgery 
(defined as requiring general anesthesia), or patients who may require major surgery during 
the course of the study 
• Prior treatment with any investigational drug within the preceding 4 weeks 
• Patients receiving chronic, systemic treatment with corticosteroids or another 
immunosuppressive agent, except corticosteroids with a daily dosage equivalent to 
prednisone ≤ 20 mg. Patients receiving these corticosteroids must have been on a stable 
dosage regimen for a minimum of 4 weeks prior to the first treatment with Everolimus. 
Topical or inhaled corticosteroids are allowed. 
• Patients should not receive immunization with attenuated live vaccines within one week of 
study entry or during study period 
• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require 
glucocorticoids for brain or leptomeningeal metastases 
• 
Evidence of another active cancer, except for non-melanoma skin carcinoma, in-situ carcinoma of the 
cervix curatively treated, and adenocarcinoma of the prostate that has been surgically treated with a 
post-treatment PSA that is non-detectable. 
• 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 as evidenced by: 
• TLC <50% predicted OR 
• FVC <50% predicted OR 
• DLCO <40% predicted 
• Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN 
• Active (acute or chronic) or uncontrolled severe infections 
• Liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis 
• A known history of HIV seropositivity 
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter 
the absorption of Everolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel resection) 
• Patients with an active, bleeding diathesis 


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• Female patients who are pregnant or breast-feeding. Women of childbearing potential must 
have a negative urine or serum pregnancy test within 7 days prior to administration of 
Everolimus. 
• Adults of reproductive potential who are not using effective birth control methods. Men and 
women of childbearing potential must be willing to use effective barrier method 
contraception during the trial and for at least three months thereafter. Patients are encouraged 
to continue barrier method contraception for two years or longer after treatment. Hormonal 
contraceptives are not acceptable as a sole method of contraception. 
• Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, 
everolimus). 
• Patients with a known hypersensitivity to Everolimus (RAD001) or other rapamycins 
(sirolimus, temsirolimus) or to its excipients 
• History of noncompliance to medical regimens 
• Patients unwilling to or unable to comply with the protocol 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited from the outpatient clinics of the Genitourinary 
Oncology Service at 
Memorial Sloan-Kettering Cancer Center (MSKCC). Potential research subjects will be 
identified by a member of the patient’s treatment team, the protocol investigator, or the research 
team. If the investigator is a member of the treatment team, s/he will screen their patient’s 
medical records for suitable research study participants and discuss the study and their potential 
for enrolling in the research study. Potential subjects contacted by their treating physician will 
be referred to the investigator/research staff of the study. The patient’s initial conversation with 
the investigator/research staff and portions of the patient’s MSKCC medical records will be used 
to confirm that the patient is eligible for study participation. 
 
8.1 
PRETREATMENT EVALUATION 
 
The following will be completed within 14 days prior to initiation of treatment (unless otherwise 
indicated): 
 
• Complete history and physical examination with measurements of all palpable 
lesions and review of all concomitant medications 
 
• Height, weight, body surface area 
 
• Karnofsky Performance Status 
• Complete blood count (CBC) with differential and platelets 
 
• Comprehensive  panel,  i.e.  serum  electrolytes  including  sodium,  potassium,  chloride, 


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bicarbonate, phosphorus, calcium, glucose, blood urea nitrogen, creatinine, SGOT (AST), 
SGPT (ALT), alkaline phosphatase, total bilirubin, total protein, albumin, and uric acid 
 
• PT/PTT 
 
• Fasting Lipids include triglycerides, total cholesterol, HDL and LDL 
 
• Pregnancy test in women of childbearing age 
 
• EKG (within 30 days) 
 
• Baseline abdominal and pelvic CT scans or MRI for abdominal or pelvic indicator lesions 
(within 30 days) 
 
• In patients with osseous lesions, bone X-rays and/or bone scans should be obtained (within 
30 days) 
 
• Chest X-ray (a CT of chest may be performed instead if clinically relevant) (within 30 
days) 
 
• Pulmonary function tests (within thirty days) 
 
 
• Pre-treatment tumor tissue specimens for all patients will be analyzed using 
immunohistochemistry for markers including those of an activated mTOR pathway 
including phsopho-S6 and phospho-4E BP1. Staining will be graded as 0 to 3+ (0 = 0- 
5%; 1+ = 6-25%; and 3+ = >50% tumor cells positive) by the Core Lab of the MSKCC 
Department of Pathology. The study will not require research biopsies. 
 
• Hepatitis B testing (HBV-DNA, HBsAg, HBsAb, and HBcAb) for all patients who meet 
the hepatitis B risk criteria outlined in Section 6.1. 
 
Hepatitis C testing (quantitative RNA-PCR) for all patients who meet the hepatitis C risk 
criteria outlined in Section 6.1. 
 
 
9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 Schedule and Dose Administration 
 
The study drug Everolimus will be self-administered on an outpatient basis. The investigator 
will instruct the patient to take the study drug exactly as specified in the protocol section 5.1. 
Everolimus will be administered orally as a once-daily dose of 10 mg (Two 5 mg tablets) 
continuously from study day 1 until progression of disease or unacceptable toxicity. 


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The start of the next cycle may be delayed if additional time is required for the patient to 
recover from Everolimus-associated toxicity experienced during the previous cycle. However, 
imaging will occur at regular intervals. The study investigator may implement dose 
suspension or reduction in order to ensure patient safety (see section 9.2). 
 
9.3 Dose Modifications 
 
Patients will be monitored closely for toxicity, and the Everolimus dose may be adjusted 
according to individual patient tolerance. 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 Everolimus must be interrupted because of unacceptable toxicity, drug 
dosing will be interrupted or modified according to rules described in Table 4. Toxicity will 
be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 
3.0 (CTCAEv3.0, http://ctep.cancer.gov/forms/CTCAEv3.pdf). 
 
 
Table 3.   Everolimus 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 4. 
Criteria for dose-modification in case of suspected Everolimus toxicity and 
re-initiation of Everolimus treatment 
 
Toxicity 
Actions 
Non-hematological toxicity 
Grade 2 
(except pneumonitis – refer to Table 5 
If the toxicity is tolerable to the patient, maintain the 
same dose. If the toxicity is intolerable to patient, 
interrupt Everolimus until recovery to grade 1. Then 
reintroduce Everolimus at same dose. 
If event returns to grade 2, interrupt Everolimus until 
recovery to grade 1, then reintroduce Everolimus at 
the lower dose level. 
Grade 3 
(except hyperlipidemia*)(except pneumonitis – refer to Table 5 
Interrupt Everolimus until recovery to grade 1, then 
reintroduce Everolimus at the lower dose level. For 
pneumonitis consider the use of a short course of 
corticosteroids. 
Grade 4 
(including hyperlipidemia) 
Discontinue Everolimus. 
Hematological toxicity 
Grade 2 Thrombocytopenia (platelets <75, ≥ 50x109/L) 
Interrupt Everolimus until recovery to grade 1 (>75 
x109/L), then reintroduce Everolimus at initial dose. 
If thrombocytopenia again returns to grade 2, interrupt 
Everolimus until recovery to grade 1. Then reintroduce 
Everolimus at the lower dose level. 
Grade 3 Thrombocytopenia ( platelets <50 , ≥ 25 x 109 /L) 
Interrupt Everolimus until recovery to grade ≤1 
(platelets ≥ 75 x109/L).  Then resume Everolimus at one 
dose level lower.  If grade 3 thrombocytopenia recurs, 
discontinue Everolimus. 
Grade 4 Thrombocytopenia (platelets < 25 x109/L) 
Discontinue Everolimus. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt Everolimus until recovery to grade 1 
(neutrophils ≥ 1.5 x 109/L), then resume Everolimus at 
the initial dose.  If ANC again returns to Grade 3, hold 
Everolimus until the ANC ≥ 1.5 x 109/L, then resume 
Everolimus 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 Everolimus until recovery to grade  1 
(neutrophils ≥ 1.5 x 109/L). Then resume Everolimus at 
the lower dose level. If grade 3 or grade 4 neutropenia 
occurs despite this dose reduction, discontinue 
Everolimus. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt Everolimus until resolution of fever and 
neutropenia to grade ≤ 1. Hold further Everolimus until 
the ANC ≥ 1,500/mm3 and fever has resolved. Then 
resume Everolimus at the lower dose level. If febrile 
neutropenia recurs, discontinue Everolimus. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue Everolimus. 
Any hematological or non-hematological toxicity requiring 
interruption for ≥ 3 weeks 
Discontinue Everolimus. 
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed 
using medical therapies (see Sec. 9.3.2). 


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9.3 Monitoring of Everolimus suspected toxicities 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
an abnormal laboratory value suspected to be related to Everolimus must be followed at least 
weekly until the adverse event or abnormal laboratory value resolves or returns to grade 1. If a 
patient requires a dose delay of > 21 days from the intended day of the next scheduled dose, then 
the patient must be discontinued from the study. 
9.3.1 Management of stomatitis/oral mucositis/mouth ulcers 
 
Stomatitis/oral  mucositis/mouth  ulcers  due  to  Everolimus  should  be  treated  using  local 
supportive care. 
When described, the disorder has been identified as inflammation or ulcers in the mouth. If exam 
reveals mouth ulcers, rather than a more general inflammation of the mouth, please classify the 
adverse event as ‘mouth ulcers.’ If inflammation is limited to the mouth without ulcers, please 
use the term ‘stomatitis’ rather than the less specific term ‘mucositis.’ 
If the disorder appears elsewhere other 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. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouthwash or 
salt water (0.9%) mouthwash several times a day until resolution. 
2. For more severe toxicity (Grade 2 or 3), the suggested treatments are topical analgesic mouth 
treatments (i.e., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (e.g. Kenalog in Orabase®). 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. 
Antifungal agents must be avoided unless a fungal infection is diagnosed. In particular, systemic 
imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be avoided in 
all patients due to their strong inhibition of Everolimus metabolism (which leads to higher 
Everolimus exposures). Therefore, topical antifungal agents are preferred if an infection is 
diagnosed. Similarly, antiviral agents such as acyclovir should be avoided unless a viral infection 
is diagnosed. 


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9.3.2 Management of hyperlipidemia and hyperglycemia 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits. 
Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 or higher 
hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 or higher hypertriglyceridemia 
(>2.5 x upper normal limit) should be treated with a statin or appropriate lipid-lowering 
medication in addition to diet. Patients should be monitored clinically and through serum 
biochemistry for the development of rhabdomyolysis and other adverse events as required in the 
product label/data sheets for HMG-CoA reductase inhibitors. Patients who develop grade 4 
hyperglycemia or grade 4 hyperlipidemia will be withdrawn from study. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with 
an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, 
markedly elevated creatine kinase (CPK) levels and myoglobinuria, acute renal failure, and 
sometimes death. The risk versus benefit of using this therapy should be determined for 
individual patients based on their risk of cardiovascular complications of hyperlipidemia. 
Grade 3 hyperglycemia has been observed in patients receiving Everolimus therapy. In many 
cases in [Study Everolimus C2222] the affected patients had an abnormal fasting glucose at 
baseline. Based on this finding, optimal glucose control (indicated by fasting triglycerides ≤ 2.5 
x ULN) must be achieved before starting a patient on Everolimus. Study patients should have 
their glucose levels monitored during Everolimus therapy. 
 
9.3.3 Management of non-infectious pneumonitis 
 
Both asymptomatic radiological changes (grade 1) and symptomatic non-infectious pneumonitis 
(grade 2 = not interfering with activities of daily living or grade 3 = interfering with activities of 
daily living and oxygen indicated) have been noted in patients receiving Everolimus therapy. 
Non-infectious pneumonitis has been associated with Everolimus and other mTOR inhibitors 
(Atkins 2004). All patients are required to undergo baseline/pretreatment pulmonary function 
tests and will be excluded from study treatment if TLC <50% predicted, FVC <50% predicted, or 
DLCO <40% predicted. In order to monitor for asymptomatic (grade 1) non-infectious 
pneumonitis during study treatment, a chest CT scan or chest x-ray is required in addition to the 
monthly radiological tumor examinations. 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 Everolimus 
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 Everolimus and dose 
modification instructions are provided in Table 5. 
The attribution of changes on interval chest imaging will be recorded as related, possibly related, 
or unrelated to study drug. 


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Table 5 
Management of non-infectious pneumonitis 
 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis 
Everolimus  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 Everolimus 
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 Everolimus dose until 
recovery to ≤ Grade 1. Everolimus 
may also be interrupted if symptoms 
are troublesome. Patients will be 
withdrawn from the study if they fail to 
recover to ≤ Grade 1 within 3 weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest.; Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is 
recommended. * 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Hold treatment until recovery to 
≤ 
Grade 1. May restart protocol 
treatment within 3 weeks at a reduced 
dose (by one level) if evidence of 
clinical benefit. Patients will be 
withdrawn from the study if they fail to 
recover to 
≤ Grade 1 within 3 
weeks. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing includes:       
spirometry, DLCO, and room 
air O2 saturation at rest. Repeat 
each subsequent Cycle until 
return to baseline. 
Bronchoscopy is 
recommended. * 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
9.3.4 Management of hepatitis B 
Table 6 provides details of monitoring and prophylactic therapy according to the baseline results 
of viral load and serologic markers testing. 


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Table 6 
Action to be taken for positive baseline hepatitis B results 
 
 
 
 
 
 
 
 
 
 
 
No specific action 
 
 
 
 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug. 
For patients who have already been randomized and received study drug prior to the approval of 
the amendment, the same process should be followed at the patient's next visit. The first HBV- 
DNA result would be regarded as baseline. 
For hepatitis B reactivation, definition and management guidelines, see Table 3-2 Guidelines for 
management of hepatitis B. 
Test 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
+ or - 
and no prior HBV 
vaccination 
- 
or + with prior 
HBV vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
Recommendation 
Prophylaxis treatment should be 
started 1-2 weeks prior to first dose of 
study drug 
Monitor HBV-DNA approximately 
every 4 weeks 


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Table 7 
Guidelines for management of hepatitis B 
 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results: 
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation is defined as: 
[Increase of 1 log in HBV- 
DNA relative to baseline 
HBV-DNA value OR new 
appearance of measurable 
HBV-DNA] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral 
AND 
Interrupt study drug administration until resolution: 
• 
≤ grade 1 ALT (or baseline ALT, if > grade 1) and 
• 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, study drug should be re-started at one 
dose level lower, if available. If the patient is already receiving the lowest 
dose of study drug according to the protocol, the patient should restart at the 
same dose after resolution. Both antiviral therapies should continue at least 4 
weeks after last dose of study drug. 
If resolution occurs > 28 days, patients should discontinue study drug but 
continue both antiviral therapies at least 4 weeks after last dose of study 
drug. 
For patients with baseline 
results: 
Negative HBV-DNA and 
HBsAg 
AND 
[Positive HBs Ab (with no 
prior history of vaccination 
against HBV), OR positive 
HBc Ab] 
------------------------------------- 
reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat: Start first antiviral medication 
AND 
Interrupt study drug administration until resolution: 
• 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days, study drug should be re-started at one 
dose level lower, if available. If the patient is already receiving the lowest 
dose of study drug according to the protocol, the patient should restart at the 
same dose after resolution. Antiviral therapy should continue at least 4 
weeks after last dose of study drug. 
If resolution occurs > 28 days, patients should discontinue study drug but 
continue antiviral therapy at least 4 weeks after last dose of study drug. 
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 3.0 Metabolic 
Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator; in 
which case they should be recorded as grade 4 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral 
Re-activation). Date of viral reactivation is the date on which both DNA and ALT criteria were 
met (e.g. for a patient who was HBV-DNA positive on 01-JAN-10 and whose ALT reached ≥ 5 
× ULN on 01-APR-10, the date of viral reactivation is 01-APR-10). 
9.3.5 Hepatitis C management 
The  following  two  categories  of  patients  should  be  monitored  every  4  weeks  for  HCV 
reactivation: 
• Patients with detectable  HCV RNA-PCR test at baseline. 
• Patients known to have a history of HCV infection, despite a negative viral load test at 
baseline (including those that were treated and are considered ‘cured’) 
For definition of hepatitis C reactivation and the management guidelines, see Table 8. 


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Table 8 
Guidelines for management of hepatitis C 
 
HCV reactivation* 
For patients with baseline results: 
Detectable HCV-RNA, reactivation is defined as: 
ALT elevation x 5 ULN 
Discontinue study drug 
For patients with baseline results: 
Knowledge of past hepatitis C infection with no 
detectable HCV-RNA, reactivation is defined as: 
New appearance of detectable HCV-RNA 
Discontinue study drug 
* All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v 3.0 Metabolic 
Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator; in 
which case they should be recorded as grade 4 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral 
Re-activation). 
 
 
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 are discontinued, the reason will be recorded. 
 
9.4 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. 
 
9.5 Concomitant Medications 
 
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. 
• Growth factors (e.g.G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are not to 


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be administered prophylactically but may be prescribed by the investigator for rescue from 
severe hematologic events if this is thought to be appropriate. 
• Concurrent administration of Everolimus and strong CYP3A4 inhibitors (such as 
ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin, rifabutin) should be 
avoided. Provided there is no alternative treatment available, patients should be closely 
monitored for potential toxicities. 
• Concurrent administration of Everolimus and moderate CYP3A4 inhibitors (such as 
erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and moderate 
CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin) should also be avoided if 
possible, or used subject to caution (e.g. increased frequency of safety monitoring, temporary 
interruption of Everolimus). 
• Competitive inhibition could occur when Everolimus is combined with drugs which are also 
CYP3A4 substrates. Caution should be exercised in such cases. 
• Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be 
avoided, if possible, or used subject to caution (e.g. increased frequency of safety monitoring, 
temporary interruption of Everolimus). 
• Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity and 
should therefore be avoided. 
• In addition, patients should avoid Seville oranges and star fruit as well as the juice of these 
fruits, which are potent CYP3A4-inhibitors. 
• No chronic treatment with systemic steroids or immunosuppressive agents except 
corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg should be administered. 
Patients receiving corticosteroids must have been on a stable dosage regimen for a minimum 
of 4 weeks prior to the first treatment with Everolimus. Topical or inhaled corticosteroids are 
allowed. 
• Everolimus may affect the response to vaccinations, making the response to the vaccination 
less effective. Live vaccines should be avoided while a patient is treated with Everolimus. 
Oral anticoagulants such as warfarin are CYP2C9 substrates; as such, no interaction with 
Everolimus 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 
Everolimus and oral anticoagulants is possible but should be subject to verification of 
coagulation (INR) once steady state is reached (after one week’s treatment). 
Examples are provided in Table 6. A comprehensive list of cytochrome P450 isoenzymes and 
CYP3A4 inhibitors, inducers, and substrates can be found at http://medicine.iupui.edu/flockhart. 
This website is continually revised and should be checked frequently for updates. 


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Table 6. Examples of clinically relevant drug interaction: substrates, inducers and 
inhibitors of isoenzyme CYP3A. 
 
Substrates (competitive inhibition) 
Antibiotics1 : 
clarithromycin* 
erythromycin 
telithromycin* 
Anti-arrhythmics: 
quinidine 
Benzodiazepines: 
alprazolam 
diazepam 
midazolam 
triazolam 
Immune Modulators: 
cyclosporine 
tacrolimus (FK506) 
HIV Protease Inhibitors: 
indinavir* 
ritonavir* 
saquinavir* 
Prokinetic: 
cisapride 
Antihistamines: 
astemizole 
chlorpheniramine27 
Calcium Channel Blockers: 
amlodipine 
diltiazem 
felodipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
HMG CoA Reductase Inhibitors2 : 
atorvastatin 
cerivastatin 
lovastatin 
simvastatin 
Miscellaneous: 
aprepitant 
buspirone 
haloperidol 
methadone 
pimozide 
quinine 
sildenafil 
tamoxifen 
trazodone 
vincristine 
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin* 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Atanzavir 
Cimetidine 
Ciprofloxacin 
Clarithromycin 
Conivaptan* 
Darunavir 
Delaviridine 
Diltiazem 
Erythromycin 
Fluconazole 
Fluvoxamine* 
Grapefruit juice 
Sevilla orange 
Posaconazole* 
Indinavir 
Itraconazole* 
Ketoconazole* 
Lopinavir* 
Voriconazole* 
Posaconazole* 
Mibefradil* 
Nefazodone* 
Nelfinavir* 
Troleandomycin* 
Verapamil 
Voriconazole* 
Imatinib 
Tofisopam 
Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms, 
Naunyn Schmiedebergs Arch Pharmacol. 2004 Jan;369(1):89-104.  [http://www.medicine.iupui.edu/flockhart/clinlist.htm as 
 
of July 13, 2006], 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 
Amended: 03/04/15 
27


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* asterisk denotes strong inhibition/induction 
Please note: 
- 
strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% decrease in clearance of 
sensitive CYP substrates 
- 
moderate inhibitor implies that it can cause 2- to 5-fold increase in AUC values or 50-80% decrease in 
clearance  of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to conditions). 
1. Macrolide antibiotics:   Azithromycin is not a CYP3A substrate. Therefore, it may be employed where 
antibiotherapy with a macrolide is desirable in a patient being treated with Everolimus. 
2. Statins: Atorvastatin and pravastatin may be associated with Everolimus, since a PK interaction study has 
shown that there is no relevant PK interaction. 
 
Interaction Table. " 


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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
Table 7. Schedule of Events 
Screening 
Cycle 1 
Additional 
Cycles (Years 
1-4) 
Additional 
Cycles (Years 
5+) 
Post 
Treatment/ 
Withdrawal
7 
Survival 
Follow- 
up 
Procedure 
≤ 30 Days 
Prior to 
Dosing 
≤ 14 Days 
Prior to 
Dosing 
Day 1 
(± 3) 
Day 
14 (± 
3) 
Day 
28 (± 
3) 
Day 1 
(± 3) 
Day 28 
(± 3) 
Day 1 
(± 3) 
Day 56 
(± 3) 
Informed Consent 
X 
Medical History 
X 
Physical Examination, KPS 
X 
(X)6 
X 
X 
X15 
X 
Lab Studies 
Pregnancy Test9 
X 
Hematology1 
X 
(X)6 
X 
X 
X15 
X 
Biochemistry2 
X 
(X)6 
X 
X 
X15 
X 
PT/PTT 
X 
Fasting Lipids2 
X 
(X)6 
X 
X15 
X 
HBV-DNA, HBsAg, HBs Ab, 
HBs Ab, HCV-RNA-PCR12 
X 
HBV DNA, HCV RNA-PCR13 
X 
X 
X 
X 
Other Assessments 
12-lead EKG 
X 
Pulmonary Function Tests 
X 
Disease Assessment/Tumor 
measurements3 
X 
X3 
X14 
X 
Adverse Events4 
X 
X 
X 
X15 
X 
Concomitant Medications 
X 
X 
X 
X 
X15 
X 
Treatment compliance11 
X 
X 
X 
Everolimus8 
X → 
→ 
→ 
→ 
→ 
→ 
→ 
Survival Status5 
X 
Tumor Tissue Evaluation10 
X 
(X) – if applicable 
X → - start and continue treatment 
→ - continue treatment 


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Footnotes for Schedule of Events 
1.Complete blood count (CBC) with differential and platelets 
2. Comprehensive panel (i.e. serum electrolytes including sodium, potassium, chloride, bicarbonate, phosphorus, calcium, glucose, blood urea nitrogen, creatinine, SGOT 
(AST), SGPT (ALT), alkaline phosphatase, total bilirubin, total protein, albumin, uric acid). 
Fasting Lipids include triglycerides, total cholesterol, HDL and LDL. 
3. Disease Assessment/Tumor Measurements: Re-staging imaging studies will be performed after every two cycles of treatment (1 cycle = 4 weeks) during the first five years of 
treatment and after study completion or withdrawal. Imaging studies should be performed during weeks 7 or 8. The same imaging studies performed at baseline (e.g., CT or 
MRI) should be performed throughout the study, when possible. Baseline chest CT or chest x-ray must be performed. If chest CT or chest x-ray is not part of the disease 
assessment, it must be repeated every 2 months. Bone x-ray(s)/scan to be performed if bone metastases are present. 
4. Adverse Events: Patients must be followed for adverse events from the first day of study treatment until at least 28 days after the last on-study treatment administration, or 
until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable,” whichever is later. Serious adverse events should be monitored and 
reported as described in the protocol. 
5. Post-study survival status: Follow-up survival information will be collected for all patients by clinic visit or telephone contact approximately every 6 months for up to 2 years 
from the date of first dose of Everolimus. Patients will be followed until disease progression and/or death. 
6. Physical Examination/Hematology/Biochemistry/Fasting Lipids: Physical Examination/ Hematology/ Biochemistry/Fasting Lipids on Cycle 1 Day 1 is not required if 
performed within 7 days of Day 1 unless clinically indicated. 
7. Post Treatment/Withdrawal: This visit will take place 1 month after the last dose of study drug. Patients with ongoing study drug-related toxicities should be followed as 
dictated in footnote 4. These patients should be followed at the interval deemed appropriate by their study physician. 
8. Everolimus: Everolimus will be orally self-administered, once daily in the morning. Patients will receive a prescription for a 4-week supply of drug at the beginning of each 
cycle during their first five years of treatment. After five years of treatment, patients will receive a prescription for an 8-week supply of drug at the beginning of every other 
cycle. The Everolimus drug bottles (including any unused capsules) will be returned to the clinic for drug accountability at each study visit. 
9. Serum or urine test must be performed for all women of childbearing potential. 
10. Pre-treatment tumor tissue specimens for all patients will be analyzed using immunohistochemistry for markers including those of an activated mTOR pathway including 
phsopho-S6 and phospho-4E BP1. Note that the study will not require research biopsies. 
11.  Treatment Compliance: At the start of each cycle, patients will be given a Pill Diary and asked to record the time, date, concomitant drugs, and side-effects of each dose of 
Everolimus taken. 
12. All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis B and hepatitis C. It is highly recommended that patients with positive HBV- 
DNA or HBsAg are treated prophylactically with an antiviral for 1-2 weeks prior to receiving study drug. The antiviral treatment should continue throughout the entire study 
period and for at least 4 weeks after the last dose of study drug. Patients with viral hepatitis C risk factors should be screened for HCV RNA-PCR. 
13.  Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested for HBV-DNA  according to study visit schedule. Patients with positive HCV-RNA 
PCR or a history of past infection, even if treated and considered ‘cured’ – should be followed by HCV-RNA PCR according to visit schedule. 
 


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14. Patients who complete five years of study treatment will undergo imaging studies as directed in Footnote 3 after every 3-6 cycles of treatment as determined by their treating 
physician. 
15. Patients who complete five years of study treatment will return to clinic for physical exam, KPS, laboratory assessments, adverse events assessment, and concomitant 
medications assessment every two cycles (56 +/- 3 days). 


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11.0     TOXICITIES/SIDE EFFECTS 
 
Adverse events most frequently observed with Everolimus are rash, stomatitis/oral mucositis, 
fatigue, headache, anorexia, nausea, vomiting, and diarrhea. Infections have not been notably 
frequent or severe. Non-infectious pneumonitis has also been observed. The majority of these 
AEs have been of mild to moderate severity (CTC grade 1-2). Overall, the most frequently 
observed laboratory abnormalities include reduced blood counts and hyperlipidemia mostly 
reported as hypercholesterolemia and/or hypertriglyceridemia. 
The principal DLT in Phase 1 trials has been Grade 3 stomatitis. For guidance on management of 
stomatitis refer to Section 9.3.1 
Hyperlipidemia was reported as a serious adverse reaction. It is a recognized side-effect of 
rapamycins. Use of lipid-lowering drugs should be associated with dietary recommendations. 
Monitoring of blood lipid levels requires patients to be fasting; this aspect must be verified when 
interpreting results. For guidance on management of hyperlipidemia refer to Section 9.3.2. 
Hyperglycemia was reported as a serious adverse reaction. Again, the fasting state of patients 
should be verified when interpreting results. For guidance on management of hyperglycemia 
refer to Section 9.3.2. 
Pneumonitis is a recognized adverse effect of rapamycins (sirolimus, temsirolimus, and 
everolimus). Numerous case reports in the literature suggest that rapamycin-associated 
pneumonitis is relatively unaggressive, limited in extent, and reversible upon drug 
discontinuation. The term ‘pneumonitis’ is used here to describe radiologically evident, non- 
infectious, non-malignant infiltration in the lungs. More precise diagnosis should come after 
histocytological examination following lung biopsy, generally during bronchoscopy which may 
or may not be symptomatic. Advice on the management of pneumonitis has been provided in 
Table 5. 
In oncology studies with Everolimus, severe pneumonitis suspected as drug-related has been 
reported as a serious adverse event on 13 occasions. Additionally, it has been reported in the 
following associated preferred terms: acute respiratory distress syndrome (n=2), alveolitis (n=1), 
allergic alveolitis (n=1), interstitial lung disease (n=10), lung infiltration (n=23), cryptogenic 
organizing pneumonia, lung consolidation, pulmonary alvealoar haemorrhage, pulmonary 
toxicity, and pulmonary fibrosis (n=1 each). One fatal case of drug-related pneumonitis was 
reported for a patient with metastatic infiltrating ductal carcinoma of the breast treated with 10 
mg/day, which developed approximately two months after starting Everolimus. Cytology for 
both the pleural and pericardial fluids were positive for malignancy. The death was considered 
possibly related to the underlying late-stage tumor and study drug. Additionally, one patient 
treated with 10 mg/day died due to severe acute respiratory distress syndrome and septic shock. 
Thoracic CT scan demonstrated condensation in the majority of the left lower lobe and frosted 
glass appearance in the left upper lobe, lingula, and right lung. 
Along with the cases of non-infectious pneumonitis, serious opportunistic infections have also 
been reported in cancer patients treated with Everolimus: mycobactrium, aspergillus, fatal 
candidal sepsis, and fatal pneumocystis carnii, in particular. Because Everolimus, as other 
rapamycins,  inhibits  proliferation  of  activated  lymphocytes  and  reduces  neutrophil  counts, 


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treatment with Everolimus must be considered as predisposing patients to the risk of infection. 
This risk will be higher in patients severely immunocompromised because of their underlying 
disease and/or co-medications. Outcome may be fatal in case of serious infections. 
A reduction in blood cell counts is frequent when Everolimus therapy is initiated. Infrequently 
and without clinical significance, anemia and thrombocytopenia have been reported. In heavily 
pretreated patients with aggressive lymphoma, the incidence of grade 3 anemia, neutropenia, and 
thrombocytopenia was reported to be 11%, 16%, and 30%, respectively. Serious, suspected drug- 
related hemorrhages have been exceptional. Nevertheless, Everolimus should be considered as 
predisposing patients to hemorrhage and potentially fatal should they develop severe drug- 
related thrombocytopenia. 
Discrete, reversible changes in liver enzymes have been found to occur in numerous patients 
during treatment with Everolimus in oncology clinical studies and in a study in rheumatoid 
arthritis. In oncology studies, these changes may be evident only in patients without severe 
underlying morbidity. The increase in transaminases (AST and ALT) generally appears after 4 
weeks of treatment. In all but a few cases it does not exceed Grade 1 (≤ 2.5 x ULN). Similarly, 
mild increases in alkaline phosphatases can coexist. Spontaneous corrections or intermittent 
correction with continued treatment can occur. Serum bilirubin is not increased. In studies of 
patients with advanced cancers, clinically relevant changes in liver enzymes have been 
invariably associated with the presence of liver metastases and/or progression of the underlying 
cancer. 
Renal failure has been reported in five suspected cases to date. One patient with no alternative 
explanation made a complete recovery following study drug adjustment and no treatment/therapy 
for the event. The rest of the patients had concurrent morbidities, which may have contributed to 
the reported events. 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy (Yeo 2004). Sporadic cases of Hepatitis B reactivation have also been seen in this 
setting with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce 
the risk of Hepatitis B virus reactivation and associated morbidity and mortality (Loomba 2008). 
A detailed assessment of Hepatitis B/C medical history and risk factors must be done for all 
patients at screening, with testing performed prior to the first dose of everolimus. 
Hypophosphatemia, hypomagnesemia, hyponatremia, and hypocalcemia have been reported as 
serious adverse reactions. Electrolytes should be monitored in patients treated with Everolimus. 
Table 4 provides general recommendations for the management of patients with suspected drug 
toxicities while on treatment with Everolimus as single-agent therapy. 
More detailed information regarding Everolimus, reported suspected toxicities, and individual 
cases is provided in the [Investigator’s Brochure]. 


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12.1 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Response and progression will be evaluated in this study using the international criteria by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI, 92(3):205-216, 
2000]. Changes in the largest diameter (uni-dimensional measurement) are used in the RECIST 
criteria. Note: lesions are either measurable or non-measurable using the criteria provided 
below: 
 
12.2 Definitions 
 
Measurable lesions: lesions that can be accurately measured in at least one dimension with 
longest diameter ≥ 20 mm using conventional techniques or ≥ 10 mm with spiral CT scan. 
Non-measurable lesions: all other lesions (or sites of disease) including small lesions (longest 
diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan) are 
considered 
non-measurable 
disease. 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable. 
Target lesions: all measurable lesions – up to a maximum of five lesions per organ and 10 lesions 
in total, representative of all involved organs – should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will 
be calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
Non-target lesions: all other lesions (or sites of disease) should be identified as non-target lesions 
and should also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
 
12.3 Guidelines for evaluation of measurable disease 
 
All measurements should be taken and recorded in metric notation. The same method of 
assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. 
 
 
 
 
12.4 Response Criteria 
 
12.4.1 Evaluation of Target Lesions 


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Complete Response 
(CR): 
Disappearance of all target lesions 
Partial Response 
(PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
Progressive 
Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions 
Stable Disease 
(SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD 
since the treatment started 
 
12.4.2 Evaluation of Non-Target Lesions 
 
 
Complete 
Response (CR): 
Disappearance  of  all  non-target  lesions  and  normalization  of 
tumor marker level 
Incomplete 
Response/ 
Stable Disease 
(SD): 
Persistence   of   one   or   more   non-target   lesion(s)   or/and 
maintenance of tumor marker level above the normal limits 
Progressive 
Disease (PD): 
Appearance  of  one  or  more  new  lesions  and/or  unequivocal 
progression of existing non-target lesions (1) 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 


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Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
12.4.4 Confirmation of Response 
 
There will be no repeat imaging studies done solely for the purpose of confirming response. 
Patients will have follow-up imaging studies as outlined in the protocol and responses that are 
confirmed on follow-up scans will be noted. 
 
12.4.5 Duration of Overall Response/ Progression Free Survival 
 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started. 
Progression Free Survival will be calculated from the start of treatment until progressive disease 
or death. Patients who die before documented progression will be considered failures at their 
time of death. If the patient did not progress or die, the patient will be censored on the date of last 
follow-up. 
 
13.0    CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
▪ Completion of treatment per protocol 
▪ Disease progression 
▪ Intercurrent illness that prevents further administration of treatment 
▪ Unacceptable adverse event(s) 
▪ Patient decides to withdraw from the study, or 


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▪ General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
▪ Inability of subject to comply with study requirements 
If at anytime, the patient is found to be ineligible for the protocol as designated in the inclusion 
and exclusion criteria detailed in Section 6.0 (i.e., a change in diagnosis), the patient will be 
removed from the study. 
 
 
14.0 
BIOSTATISTICS 
 
The purpose of this study is to assess the efficacy of Everolimus in patients with progressive 
urothelial cancer who have received prior cytotoxic chemotherapy. Historically, patients in this 
setting experience a median time to progression of 2-3 months (as illustrated in Section 3.1). 
Thus, the primary endpoint of this study will be the proportion of patients who are progression- 
free after two months on-study. 
 
The sample size and stopping rules will be determined according to Simon's Minimax two-stage 
design. A two-month progression free survival rate of 50% would be considered not promising, 
while a 70% two-month PFS rate would be considered promising.  In Stage 1 of the trial, 23 
evaluable patients will be accrued to the study. If twelve or more patients demonstrate 
progression on imaging after two months on-study, the study will be terminated early and 
declared to have a negative result. If 13 or more patients are progression-free at two months, 
enrollment will be extended to accrue a total of 37 patients. If 24 or more patients are 
progression-free after their two-month scan (i.e. after Stage 2), the treatment will be declared 
effective and worthy of further testing. 
 
Patients will be considered inevaluable for the primary objective (PFS at 2 months) if they 
receive < one cycle of protocol therapy and are discontinued from protocol treatment for 
either rapid clinical deterioration related to progression of disease or adverse events 
unrelated to Everolimus. Patients with still be evaluable for toxicity assessment. 
For the purposes of this study, the Type I (false acceptance of a non-promising therapy) and  
Type II (false rejection of a promising therapy) error rates have been set at 0.05 and 0.20, 
respectively. This statistical design would effectively discriminate between two-month PFS rates 
of <50% and >70% and yields 80% probability of a positive result if the true two-month PFS rate 
is >70%. It yields 95% probability of a negative result if the true two-month PFS rate is <50%. 
The probability of early stopping under the null hypothesis is 66%. 
 
The secondary endpoint of response rate will be estimated as the proportion of patients meeting 
the criteria outlined in Section 3.4.2.3 for a complete response or partial response. 
This proportion will be reported along with its binomial confidence interval. 
 
An accrual rate of 2-4 patients per month is anticipated, and thus the expected accrual time for 
the study will be approximately 10-20 months. 


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Frequency of toxicity will be tabulated according to the NCI Common Toxicity Criteria, version 
3.0. 
 
Biological markers including phospho-S6 and phospho-4E BP1 will be evaluated in all pre- 
treatment specimens. Patients will be categorized on the basis of marker levels into three 
categories: no expression, low expression, or high expression. These levels will be correlated 
with PFS using a log rank test and will be correlated with response to treatment (complete 
response/partial response versus no response) using Fisher’s exact test.. 
 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.2 Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am 
– 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic Registration 
System (http://ppr/).  The completed signature page of the written consent/RA or verbal 
script/RA, a completed Eligibility Checklist and other relevant documents must be uploaded via 
the PPR Electronic Registration System. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordination of the activities of the 
protocol study team. 
The data collected for this study will be entered into the Clinical Research Database.   Source 
documentation will be available to support the computerized patient record. 
 
16.2 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will be 


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monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team at a minimum of two times per year, more frequently if indicated. 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data 
and 
Safety 
Monitoring 
of 
Clinical 
Trials,” 
which 
can 
be 
found 
at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring  Plans  can  be  found  on  the  MSKCC  Intranet  at:  http://mskweb2.mskcc.org 
/irb/index.htm 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education on 
clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees, Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 
 
16.4 Protocol Amendments or Changes in Study Contact 
 
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. A copy of the written 
approval of the IRB must be provided to Novartis. Examples of amendments requiring such 
approval are: 
• Increases in drug dose or duration of exposure of subjects 
• Significant changes in the study design (e.g. addition or deletion of a control group) 
• Increases in the number of invasive procedures 


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• Addition or deletions of a test procedure required for monitoring of safety 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients 
included in the trial. If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons, Novartis must be notified and the IRB at the 
center must be informed immediately. Amendments affecting only administrative aspects of the 
study do not require formal protocol amendments or IRB approval, but the IRB must be kept 
informed of such administrative changes. Examples of administrative changes not requiring 
formal protocol amendments and IRB approval include: 
• Changes in the staff used to monitor trials 
• Minor changes in the packaging or labeling of study drug 
 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
17.2 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
17.3 Serious Adverse Event (SAE) Reporting 
 
17.3.1 Serious Adverse Event (SAE) Reporting to the IRB 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. 
The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org. The report should contain the following 
information: 
Fields populated from CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 


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• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office 
 
17.3.2 Serious Adverse Event (SAE) Reporting to Novartis 
 
The principal investigator has the obligation to report all serious adverse events to the FDA, IRB, 
and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department (CS&E). 
All events must be reported, by FAX (888-299-4565), to Novartis Pharmaceuticals CS&E 
Department within 24 hours of learning of it’s occurrence. This includes serious, related, 
labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. All deaths 
during treatment or within 30 days following completion of active protocol therapy must be 
reported within 5 working days. 
Any serious adverse event occurring after the patient has provided informed consent and until 4 
weeks after the patient has stopped study participation must be reported. This includes the period 
in which the study protocol interferes with the standard medical treatment given to a patient (e.g. 
treatment withdrawal during washout period, change in treatment to a fixed dose of concomitant 
medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Novartis study drug (or therapy) is suspected. 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
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 


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or voluntary termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and newborn complications. 
 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


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19.0 
REFERENCE(S) 
 
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Culine, S., C. Theodore, et al. (2006). "A phase II study of vinflunine in bladder cancer patients 
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Dreicer, R., S. Li, et al. (2007). "Phase 2 trial of epothilone B analog BMS-247550 (ixabepilone) 
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Gad el Mawla, N., M. R. Hamza, et al. (1989). "Chemotherapy in invasive carcinoma of the 
bladder. A review of phase II trials in Egypt." Acta Oncol. 28: 73-76. 
Haritunians T, Mori A, O'Kelly J, et al (2007) Antiproliferative activity of RAD001 
(everolimus) as a single agent and combined with other agents in mantle cell lymphoma. 
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signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. 
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Ingelman-Sundberg M (2004) Human drug metabolising cytochrome P450 enzymes: properties 
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Jemal, A., R. Siegel, et al. (2007). "Cancer statistics, 2007." CA Cancer J Clin 57(1): 43-66. 
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mTOR inhibitor, RAD001, in oncology [abstract]. J Clin Oncol; 22:237A. 
Mabuchi S, Altomare DA, Cheung M, et al (2007) RAD001 inhibits human ovarian cancer cell 
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Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell; 
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Moore, M. J., I. F. Tannock, et al. (1997). "Gemcitabine: a promising new agent in the treatment 
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Witzig TE, Geyer SM, Ghobrial I, et al (2005) Phase II trial of single-agent temsirolimus (CCI- 
779) for relapsed mantle cell lymphoma. J Clin Oncol; 23(23):5347-5356. 
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124(3):471-84. 
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signaling and inhibit AKT activation in AML. Blood; 109(8):3509-3512. 
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lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 148(7): 519-28. 
Krishna G, Moton A, Lei Ma L, Savant I, Martinho M, Seiberling M, McLeod J. Effects of oral 
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20.0     APPENDICES 
A.  Procedures and instructions 
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. 
 
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. 
 
Discontinuation of study 
Novartis reserves the right to discontinue any study under the conditions specified in the clinical 
trial agreement. 
 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Novartis standard operating procedures and: 
1. 
ICH  Harmonized  Tripartite  Guidelines  for  Good  Clinical  Practice  1996.  Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice that it conforms to. 


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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. 
 
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.