Clinical trial NCT01399918
Conditions: Renal Cell Carcinoma
Keywords: Kidney Everolimus Bevacizumab 10-226 non-clear cell histology Advanced
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2011-07-01; Completion date: 2020-12-28
Enrollment: 57 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out what effects, good and/or bad the combination of two medications, everolimus and bevacizumab, has on kidney cancer. In this clinical trial we are now testing these medications in combination. We think that both together might work better that either drug alone. Importantly, both of these drugs together have been tested in patients with a different type of kidney cancer and patients tolerated the combination well.

Detailed description:

Arms: arm 1: This is a single-institution, single-arm phase II trial of everolimus in combination with bevacizumab in patients with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted therapy. A separate cohort of patients with non-clear cell RCC with papillary features will be enrolled in order to gather information regarding the efficacy given the rarity of these entities.
Interventions: intervention 1: everolimus and bevacizumab
Intervention descriptions: intervention 1: Cycle length will be defined as 28 days. Treatment will include everolimus 10mg, self administered orally once daily on a continuous schedule (days 1-28), and bevacizumab 10mg/kg, administered intravenously on days 1 and 15 of each cycle. Treatment will be continued until disease progression, major toxicity, or withdrawal from the study for any reason. Dose modification will be permitted based on toxicity. Patients that come off study before 6 months before documented progression/death will be treated as events for the 6 month PFS endpoint.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 10-226 A(22) 
Page 1 of 55 
 
 
Approval date: 29-Dec-2
A Phase II Trial of Everolimus and Bevacizumab 
Cell Cancer (RC 
PROTOCOL FACE PA 
MSKCC  THERAPEUTIC/DIAGNOS
Principal 
Darren Feldman, MD 
Investigator/Department: 
017 
in Advanced Non-clear Cell Renal 
C). 
GE FOR 
TIC PROTOCOL 
Medicine: Genitourinary Oncology Service 
Co-Principal 
Martin Voss, MD 
Investigator(s)/Department: 
Medicine: Genitourinary Oncology Service 
Investigator(s)/Department: 
Robert J. Motzer, MD 
Dean Bajorin, MD 
Lewis Kampel, MD 
Michael Morris, MD 
Dana Rathkopf, MD 
David Solit, MD 
Chung-Han Lee, MD, PhD 
Karen Autio, MD 
Wassim Abida, MD 
Gopakumar Iyer, MD 
Samuel Funt, MD 
Rohit Bose, MD, PhD 
Daniel Danila, MD 
Jonathan Rosenberg, MD 
Maria Carlo, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Marina Shcherba, DO 
Avni Desai, MD 
John Fiore, MD 
Jahan Aghalar, MD 
Juliana Eng, MD 
Jia Li, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Pamela Drullinsky, MD 
Elizabeth Won, MD 
Alice Zervoudakis, MD 
Parisa Momtaz, MD 
Abraham Hakimi, MD 
Joshua Chaim, DO 
Sujata Patil, PhD 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Surgery: Urology 
Radiology 
Epidemiology and Biostatistics 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-226 A(22) 
Approval date: 29-Dec-2017 
Page 2 of 55 
 
 
 
 
 
Victor Reuter, MD 
Satish Tickoo, MD 
Yingbei Chen, MD, PhD 
Michael Berger, PhD 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Jacqueline Bromberg, MD 
Wanqing Iris Zhi, MD PhD 
Stuart Lichtman, MD 
Carly Osborne, NP 
Maryann Carousso, NP 
Min Yuen Teo, MD 
Curtis Chong, MD 
Christine Anderson, NP 
Pathology 
Pathology 
Pathology 
Pathology 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Consenting 
Professional(s)/Department: 
Martin Voss, MD 
Robert J. Motzer, MD 
Darren Feldman, MD 
Dean Bajorin, MD 
Michael Morris, MD 
Lewis Kampel, MD 
David Solit, MD  
Dana Rathkopf, MD 
Chung-Han Lee, MD, PhD 
Karen Autio, MD 
Wassim Abida, MD 
Gopakumar Iyer, MD 
Samuel Funt, MD 
Rohit Bose, MD, PhD 
Daniel Danila, MD 
Jonathan Rosenberg, MD 
Maria Carlo, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Marina Shcherba, DO 
Avni Desai, MD 
John Fiore, MD 
Jahan Aghalar, MD 
Juliana Eng, MD 
Jia Li, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service; 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Medicine: Genitourinary Oncology Service 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 
Department of Medicine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-226 A(22) 
Approval date: 29-Dec-2017 
Page 3 of 55 
 
 
 
 
 
Zoe Goldberg, MD 
Department of Medicine 
Tiffany Troso-Sandoval, MD 
Department of Medicine 
Pamela Drullinsky, MD 
Department of Medicine 
Elizabeth Won, MD 
Department of Medicine 
Alice Zervoudakis, MD 
Department of Medicine 
Parisa Momtaz, MD 
Department of Medicine 
Philip Caron, MD, PhD 
Department of Medicine 
Jason Konner, MD 
Department of Medicine 
Serena Wong, MD 
Department of Medicine 
Azadeh Namakydoust, MD 
Department of Medicine 
Colette Owens, MD 
Department of Medicine 
Loren Michel, MD 
Department of Medicine 
Jacqueline Bromberg, MD 
Department of Medicine 
Wanqing Iris Zhi, MD PhD 
Department of Medicine 
Stuart Lichtman, MD 
Department of Medicine 
Maryann Carousso, NP 
Nursing 
Min Yuen Teo, MD 
Medicine 
Curtis Chong, MD 
Medicine 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Rockville Center 
Commack 
Westchester 
Monmouth 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-226 A(22) 
Approval date: 29-Dec-2017 
Page 4 of 55 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA.......................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS................................................................................... 5 
3.0 
BACKGROUND AND RATIONALE ........................................................................................ 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ..................................................................... 18 
4.1 Design ....................................................................................................................................... 18 
4.2 Intervention ..................................................................................................................................... 18 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .............................................................................. 18 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ................................................................................. 19 
6.1 Subject Inclusion Criteria ........................................................................................................... 19 
6.2 Subject Exclusion Criteria ......................................................................................................... 20 
7.0 
RECRUITMENT PLAN ....................................................................................................................... 22 
8.0 
PRETREATMENT EVALUATION ......................................................................................... 22 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 23 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ....................................................... 30 
11.0 
TOXICITIES/SIDE EFFECTS ........................................................................................................ 33 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................... 43 
13.0 
CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 44 
14.0 
BIOSTATISTICS .................................................................................................................. 44 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES .. 46 
15.1  Research Participant Registration ......................................................................................... 46 
15.2 
Randomization ...................................................................................................................... 46 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................... 47 
16.1 
Quality Assurance ................................................................................................................. 47 
16.2 
Data and Safety Monitoring ........................................................................................................ 47 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................... 47 
17.1 
Privacy .................................................................................................................................. 48 
17.2 
Serious Adverse Event (SAE) Reporting ................................................................................... 48 
17.3.4 Pregnancy .............................................................................................................................. 51 
18.0 
INFORMED CONSENT PROCEDURES ...................................................................................... 51 
19.0 
REFERENCES ......................................................................................................................... 52 
20.0 
APPENDICES ...................................................................................................................... 55 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-226 A(22) 
Approval date: 29-Dec-2017 
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1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single institution open-label phase II trial of everolimus and bevacizumab in patients 
with advanced non-clear cell RCC, who have not received prior VEGF-.or mTOR-targeted 
therapy. Primary endpoint will be progression free survival (PFS) after six months of 
treatment, secondary endpoints will be objective response rate (ORR) per RECIST 1.1 
(Eisenhauer, Therasse et al. 2009), and safety of this drug combination in the study 
population. Explorative endpoints will include correlation of pretreatment tissue biomarkers 
with treatment response. 
1.2 Study Schema 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective: 
o To evaluate the efficacy of combining everolimus  and bevacizumab in patients 
with advanced RCC of non-clear cell histology 
▪ 
The primary endpoint in this study will be the percent of patients alive and 
progression-free after 6 months of therapy. 
▪ 
Secondary  endpoint  will  be  the  overall  response  rate  (ORR)  per  the 
international criteria defined by the Response Evaluation Criteria in Solid 
Tumors Committee (RECIST 1.1). 
 
Secondary objectives: 
o To  investigate  the  safety  of  everolimus  and  bevacizumab  in  patients  with 
advanced RCC of non-clear cell histology. 
▪ 
Toxicity will be assessed using Common Terminology Criteria for Adverse 


Memorial Sloan Kettering Cancer Center 
IRB Number: 10-226 A(22) 
Approval date: 29-Dec-2017 
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Events (CTCAE) v4.0 (Gompertz 1825), as outlined in section 11.5. 
Toxicities will be summarized by type and grade using frequencies and 
rates. 
 
o To determine whether relevant biomarkers in tumor tissue can be predictive of 
treatment response. 
o To obtain data regarding efficacy of everolimus and bevacizumab in patient with 
non-clear cell renal cell cancer types with papillary features. 
 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.1 Epidemiology 
 
Renal cell carcinoma (RCC) is the most common malignancy of the kidney, and is expected 
to account for more than 58,000 new diagnoses of cancer and over 13,000 cancer deaths in 
the United States during 2010 (Jemal, Siegel et al. 2010). Annual incidence and mortality 
worldwide are estimated over 270,000 and 116,000, respectively (Ferlay, Shin et al. 2010). 
Incidence is rising, and RCC now make up 3.8% of new cancer diagnoses in the United 
States (Jemal, Siegel et al. 2010). It is more common in men than women with an 
approximate incidence of 1.5:1. Metastatic RCC occurs in approximately 30% of the newly 
diagnosed patients, with 1.5 to 3.5% having a solitary metastasis (Flanigan, Salmon et al. 
2001). 
 
3.2 Subtypes of RCC 
 
RCC is a heterogeneous disease, comprised several different histological types with distinct 
genetic alterations, varying clinical course, and variable responsiveness to systemic therapy. 
The current classification of RCC is based on the Heidelberg system, which identifies several 
distinct malignant histologic subtypes of RCC including clear-cell, papillary, chromophobe, 
collecting-duct (Bellini duct) with its variant medullary type carcinoma, and unclassified RCC 
(Kovacs, Akhtar et al. 1997). The most common subtype is clear cell RCC (60–80%), often 
termed conventional RCC. The remaining subtypes are often grouped as non-clear cell RCC 
(NCRCC) and differ in their incidence with the order being papillary (7–14%), chromophobe 
(6-11%), unclassified tumors (3-5%), and collecting duct RCC (<1%) (Kovacs, Akhtar et al. 
1997; Reuter and Presti 2000). Sarcomatoid features can be seen in all different subtypes of 
RCC and typically confer a more aggressive course with adverse outcome. This is thought 
due to the de-differentiation of the original epithelial malignancy (Bertoni, Ferri et al. 1987; 
Mai, Landry et al. 2001; Kourda, Zeddini et al. 2006). 
 
The prognostic significance to histologic subtype has been intensely studied. Several 
retrospective studies have suggested that stratification by histologic subtype can lend 
prognostic value (Moch, Gasser et al. 2000; Amin, Tamboli et al. 2002; Cheville, Lohse et al. 
2003).Different implications have been reported for localized and metastatic disease. 
Favorable prognosis after nephrectomy for a localized primary tumor has been seen in 
papillary and chromophobe cell types compared with the clear-cell type (Moch, Gasser et al. 
2000; Amin, Tamboli et al. 2002; Cheville, Lohse et al. 2003; Beck, Patel et al. 2004). In 


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IRB Number: 10-226 A(22) 
Approval date: 29-Dec-2017 
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metastatic disease, non-clear cell histologies have been reported to portend poor survival 
compared to conventional RCC in univariate analysis. Better outcomes have been cited for 
patients with chromophobe tumors than for those with metastatic collecting duct or papillary 
RCC (Motzer, Bacik et al. 2002). This was not confirmed by a more recent international 
multicenter retrospective analysis of >4000 cases (Patard, Leray et al. 2005), which noted no 
significant survival difference among clear-cell, papillary and chromophobe RCC when 
adjusting each histologic subgroup for TNM stage (including Stage IV disease) in multivariate 
analysis. The only exception was chromophobe histology, which resulted in better outcome 
only in high grade tumors (nuclear grade 3 and 4 tumors) (Patard, Leray et al. 2005). 
3.3 Therapy of metastatic RCC 
 
RCC is characterized by a high degree of resistance to chemotherapy. Interferon alfa-2a 
(IFN) and interleukin-2 were standard therapies for patients with metastatic RCC. Both 
achieve complete plus partial responses in 10% to 20% of patients, only a minority of treated 
patients experiences a favorable response, and few achieve long-term survival (Fyfe, Fisher 
et al. 1995; Fossa 2000). While these treatments were not prospectively evaluated in NRCC 
in dedicated trials, retrospective data suggested inferior outcome for patients with NRCC 
compared to conventional RCC (Motzer, Bacik et al. 2002). 
 
More recently, targeted agents blocking the (Yang, Haworth et al. 2003)vascular endothelial 
growth factor (VEGF) pathway or the mammalian target of rapamycin (mTOR) have emerged 
as powerful tools in the management of advanced disease and have become the standard of 
care in conventional RCC. It is important to note that the majority of Phase III clinical trials 
have predominantly enrolled patients with clear-cell histology. 
3.3.1 
The VEGF-pathway and RCC 
 
Angiogenesis, or new blood vessel formation, is critical to tumor growth, invasion, and 
metastasis (Posada, Gulley et al.). Several humoral factors stimulate angiogenesis. These 
factors act either by inducing the enzymatic breakdown of the perivascular basement 
membrane or by inducing proliferation and chemotaxis of endothelial cells. Both components 
are critical for successful neovascularization, and the inhibition of either arm has been 
hypothesized as having a potential antitumor or antimetastatic effect on malignant cells. 
Vascular endothelial growth factor (VEGF) is a 43- to 46-kd glycoprotein that induces the 
proliferation and migration of vascular endothelial cells (Rudloff, Boulay et al.). These 
activities are mediated via the two receptors for VEGF, flt-1 and KDR, which are found 
predominantly on vascular endothelial cells (Rudloff, Boulay et al.). In preclinical models, 
VEGF is a potent neovascularization agent for both normal and malignant microvasculature 
(Smeraglia). 
 
Many malignant cells produce VEGF, which serves as an autocrine factor for the induction of 
neovascularization. Several studies have demonstrated a correlation between high levels of 
VEGF and increased risk of metastatic disease and overall poor prognosis in a variety of 
malignancies including non–small-cell lung cancer and other cancers. In addition, increased 
expression of VEGF by malignant tumors is associated with a more invasive phenotype 


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(Steinbild, Baas et al. ; Higuchi, Fockler et al. 193). In preclinical animal models, the inhibition 
of VEGF was found to be associated with stabilization of established tumors (Cheung, Morley 
et al. 199). The use of anti-VEGF antibodies has been extensively studied in preclinical in  
vivo models and has demonstrated an inhibition of tumor growth in a dose-dependent  
manner (Miller, Burstein et al.). 
 
Advances in understanding the biology and genetics of RCC have led to major therapeutic 
implications. The discovery of the von Hippel-Lindau (VHL) gene and its role in regulating 
pro-angiogenic factors including VEGF, platelet-derived growth factor (PDGF), and others 
provided potential targets for novel agents (Choueiri, Bukowski et al. 2006). In clear cell 
RCC, VEGF targeted therapies, both receptor tyrosine kinase inhibitors (TKI) (sunitinib, 
sorafenib) and VEGF-A ligand antibodies (bevacizumab), were shown to have activity in the 
metastatic setting (Awada, Hendlisz et al. 2005; Motzer, Michaelson et al. 2006). However, 
VHL inactivation in RCC is almost exclusively seen in patients with clear cell histology 
(Gnarra, Tory et al. 1994). Despite this, tumor samples from patients with NCRCC can 
demonstrate high expression of VEGF (Jacobsen, Grankvist et al. 2006), making VEGF- 
targeted therapy an attractive therapeutic option. The mTOR pathway has been implicated 
as a major contributor through an autocrine loop involving VEGF, described in further detail 
below. 
3.3.2 VEGF targeted Tyrosine Kinase Inhibitors (TKI) in RCC 
 
The oral multi TKI Sunitinib demonstrated a progression-free survival (PFS) benefit over 
interferon alpha in a phase 3 pivotal trial, 11 months (95% CI 10-12) versus 5 months (95% 
CI 4-6) (Motzer, Hutson et al. 2007). PFS benefit was also demonstrated in a phase III trial 
comparing sorafenib, another oral TKI, to placebo (Escudier, Eisen et al. 2007). These 
pivotal studies were exclusively performed in patients with clear cell histology. Both drugs 
have been approved by the US Food and Drug Administration (FDA) for the treatment of 
metastatic RCC. The third approved oral TKI in RCC is pazopanib, which was tested in a 
multicenter randomized placebo-controlled phase 3 trial in both treatment naïve and cytokine 
pretreated patients (Sternberg, Davis et al. 2010). ORR was 30% for pazopanib compared 
with 3% for placebo; PFS was significantly prolonged in the overall group (median PFS 9.2 
months) as well as the treatment naïve population (median PFS 11.1 months). 
The role of VEGF targeted TKI is less clear in NCRCC. A retrospective multicenter review 
published by Choueiri and colleagues looked at 41 patients with advanced papillary and 
chromophobe RCC (Choueiri, Plantade et al. 2008). In papillary RRC patients, response 
rates were low (5%; two responders, both received sunitinib), PFS appeared longer in 
patients treated with sunitinib compared to sorafenib (11.9 vs 5.1 months, p<0.001). In 
chromophobe RCC, results were more encouraging with RR of 25% and median PFS more 
promising in sorafenib than sunitinib (27.5 vs 8.9 months, respectively). 
Prospective data for sunitinib and sorafenib in NCRCC is limited. French investigators 
presented preliminary results of a Phase II study of sunitinib in advanced type I and II 
papillary RCC (Ravaud, Oudard et al. 2009). In type II papillary RCC one of 23 patients (4%) 
achieved a Partial Response (PR), four patients (17%) had Stable Disease (SD) for 12 
weeks or more, five (22%) had progressed at the time of initial evaluation on treatment. Of 


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IRB Number: 10-226 A(22) 
Approval date: 29-Dec-2017 
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five patients with type I papillary RCC none had a PR, three (60%) had SD; the remaining 
patients had not been evaluated at the time of report. 
 
Similarly, investigators from M.D. Anderson and Fox Chase Cancer Center presented their 
phase II data for 23 patients with advanced papillary RCC treated with sunitinib at the 2010 
annual ASCO meeting (Plimack, Jonasch et al. 2010). There were no major responses. Eight 
pts had stable disease as best response. The radiologically assessed 6-month PFS rate was 
0.34 (95% CI, 0.18- 0.63); median PFS was 1.6 months (95% CI, 1.3-12), median Overall 
Survival (OS) 10.8 months (95% CI, 6.2-NE). Recent data from our own institution includes a 
single-institution phase II study of sunitinib in patients with metastatic non-clear cell RCC 
(Molina, Feldman et al. 2010). Twenty three patients were enrolled.  All patients received 
sunitinib 50 mg administered orally for four weeks followed by two weeks of rest (4/2). 
Overall, there was only one objective response (4%) in a patient with unclassified RCC: 
Sixteen (70%) had stable disease (SD) and six (26%) progressive disease (PD) at their first 
assessment. The median PFS was 5.5 months. With similarly disappointing results, these 
studies all suggest inferior benefit for sunitinib when compared to historical controls in 
conventional RCC, where robust objective responses are typically seen. 
3.3.3 VEGF targeted monoclonal antibody therapy in RCC - Bevacizumab 
 
Bevacizumab (rhuMAb) is a recombinant humanized monoclonal IgG1 antibody that 
selectively binds to and inhibits the biologic activity of human vascular endothelial growth 
factor (VEGF) in vitro and in vivo assay systems.  Bevacizumab binds VEGF and prevents 
the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. 
The interaction of VEGF with its receptors leads to endothelial cell proliferation and new 
blood vessel formation in in vitro models of angiogenesis. 
The overall safety profile of bevacizumab is based on several phase III trials treating patients 
with various malignancies such as colorectal cancer, non-small cell lung, breast cancer, 
ovarian cancer, and renal cell cancer, as well as patients with various other advanced 
malignancies in early phase trials, who received bevacizumab either as a single agent or in 
combination with chemotherapy in clinical trials. Throughout these studies, bevacizumab has 
generally been found to be well-tolerated, with the primary toxicities being hypertension 
(occurrence of grade 3/4 hypertension ranging from 2 to 16% in various studies) and 
proteinuria (1 to 2 % in colorectal cancer trials). Less frequently, it causes albuminuria, 
occasionally complicated by the nephrotic syndrome. Bevacizumab is also known to increase 
the risk for venous as well as arterial thromboembolic events, bleeding and disturbed wound 
healing, impairment of cardiac function, as well as stroke and myocardial infarction. In rare 
cases, gastrointestinal perforation, anastomotic dehiscence and pulmonary hemorrhage  
have been reported. 
The phase III multicenter double-blind AVOREN trial of bevacizumab plus interferon vs. 
interferon alone enrolled 649 patients with untreated advanced RCC and either clear-cell 
only (87% of patients) or mixed histologies (>50% clear cell, 13% of patients) (Escudier, 
Pluzanska et al. 2007). The trial demonstrated superiority to the bevacizumab arm with 
significantly longer PFS of 10.2 months vs 5.4 months in the interferon alone arm and higher 


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IRB Number: 10-226 A(22) 
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ORR (31% and 13%, respectively, p=0.0001). The primary endpoint for this study was OS, 
and only a nonsignificant trend towards improvement was seen in the final survival analysis 
(median OS 23.3 months and 21.3 months, respectively, p=0.336) (Escudier, Bellmunt et al. 
2010). It was however noted that the majority of patients in both arms received at least one 
post protocol antineoplastic therapy, likely confounding the OS analysis. 
649 patients were treated in this study in 18 countries.  Patients receiving bevacizumab and 
interferon-alfa experienced the following Grade 3/4 adverse events:  fatigue 12%, asthenia 
10%, proteinuria 7%, neutropenia 4%, and bleeding, hypertension influenza-like-syndrome, 
anorexia, anemia (all 3% each). 
 
 
Table 3.1 – Selected grade 3 / 4 adverse events from phase III study of bevacizumab 
and interferon in RCC (Escudier, et. al  (Escudier, Pluzanska et al. 2007)) 
 
 
 
Number of patients (%) 
Adverse event 
IFN + placebo 
(n=304) 
 
IFN + Bevacizumab 
(m=337) 
Any grade 3/4 adverse event 
137 
303 
Fatigue/ asthenia/malaise 
46 
76 
Proteinuria 
0 
22 
Hypertension 
2 
13 
Hemorrhage 
1 
11 
Venous  thromboembolism 
2 
6 
Gastrointestinal  perforation 
0 
5 
Arterial ischemia 
1 
4 
 
 
 
 
 
As mentioned above, AVOREN included 13% patients with mixed histologies, i.e. with non- 
clear cell component of <50%. An unplanned secondary analysis of the AVOREN data 
evaluating specifically this subgroup of patients was presented at the 2008 ASCO meeting 
(Escudier, Ravaud et al. 2008), and although patients with mixed histologies had poorer PFS 
than those with pure clear-cell RCC, the combination of bevacizumab plus interferon 
produced better results than interferon alone in the mixed-histology group (5.7 vs 2.9 
months; HR, 0.53; P<.007). The authors concluded benefit to bevacizumab, irrespective of 
tumor histology. 
 
A second Phase III study conducted and analyzed by the Cancer and Leukemia Group B 
(CALGB) in advanced clear cell RCC confirmed superiority of bevacizumab in combination 
with interferon over interferon alone (Pollack, Perou et al. 199). The median PFS was 8.5 
months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 
months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P < 
.0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P < .0001). Bevacizumab 
plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% 
[95% CI, 9.5% to 17.3%]; P < .0001). Overall toxicity was greater for bevacizumab plus IFN, 


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including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue 
(35% v 28%), and proteinuria (13% v 0%). No new safety signals related to interferon and 
bevacizumab were observed (Pollack, Perou et al. 199). 
 
3.3.4 Bevacizumab - pharmacokinetics / pharmacodynamics 
 
In phase 1 testing, bevacizumab had a low toxicity profile in most patients with no dose- 
limiting toxicity observed at doses ranging from 0.1 to 10 mg/kg (Norden-Zfoni, Manola et  
al.). Treatment did not induce antibodies to bevacizumab. Terminal elimination half-life was 
approximately 21 days. Free serum VEGF concentrations were found to be reduced and, at 
doses of  0.3 mg/kg, were below the detectable limit of the assay after the administration of 
bevacizumab and remained undetectable for the duration of the study (Norden-Zfoni, Manola 
et al.). 
 
 
3.3.5 The mTOR pathway and cancer 
The mammalian target of rapamycin (mTOR) is 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 (Schwab, 
Christensen et al. 1987). mTOR is downstream the 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 (Schwab, Christensen et al. 1987; 
Bjornsti and Houghton 2004): 
 
• 
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 et al. 2006). 
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also known as PKB, 
protein kinase B) and the tuberous sclerosis complex (TSC1/TSC2) (Bjornsti and Houghton 
2004). Activated AKT phosphorylates TSC2, which lead to the dissociation of TSC1/TSC2 
complex, thus inhibiting the ability of TSC2 to act as a GTPase activating protein. This allows 
Rheb, a small G-protein, to remain in a GTP bound state and to activate mTORC1. AKT can 
also activate mTORC1 by PRAS40 phosphorylation, thereby relieving the PRAS40-mediated 
inhibition of mTORC1 (Manning and Cantley 2007; Wang, Harris et al. 2007). 
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly 
by receptor tyrosine kinase (RTK) signaling (Manning and Cantley 2007). It has been 
suggested that mTORC2 phosphorylates and activates a different pool of AKT, which is not 
upstream of mTORC1. PHLPP phosphatase plays a role of a negative regulator. mTORC2 is 
rapamycin insensitive and is required for the organization of the actin cytoskeleton 
(Wullschleger, Loewith et al. 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, Geyer et al. 2005). As many cancers are characterized by dysregulation of G1 transit 
(for example, overexpression of cyclin or cyclin-dependent kinases), inhibition of mTOR 
becomes an intriguing target for inducing cytostasis (Bjornsti and Houghton 2004). 
3.3.6 mTOR targeted therapy in RCC 
Temsirolimus 
The mTOR inhibitor temsirolimus was approved for treatment of advanced RCC in May of 
2007. Its efficacy and safety were demonstrated in the pivotal phase 3 ARCC trial, a global, 
randomized, open-label study in 626 previously untreated patients with advanced RCC who 
had 3 or more of 6 poor prognostic factors (Hudes, Carducci et al. 2007). Patients were 
randomized to temsirolimus, interferon or both. Single-agent temsirolimus was associated 
with a statistically significant improvement in overall survival (OS) when compared to IFN 
(hazard ratio 0.73 [95% CI: 0.58, 0.92]; p= 0.0078). The median OS was 10.9 months on the 
temsirolimus arm and 7.3 months on the IFN arm. Median PFS was 5.5 months on the 
temsirolimus arm and 3.1 months on the IFN arm [hazard ratio 0.66 (95% CI: 0.53, 0.81)] in 
this poor risk population. The combination of 15 mg temsirolimus and IFN did not result in a 
significant increase in OS when compared with IFN alone and was associated with an 
increase in multiple adverse reactions. 


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Unlike all other phase 3 trials of targeted agents in RCC, this study included both patients 
with conventional and non-clear cell histologies. Patients with histologies other than clear cell 
RCC accounted for 17% and 18% in the temsirolimus and interferon group, respectively. This 
included patients of non-clear cell and indeterminate histology. Subgroup analysis for this 
patient subset suggests superior median OS and PFS for temsirolimus vs IFN with HR of 
0.49 (95% CI = 0.29,0.85) and 0.38 (95% CI = 0.23,0.62), respectively (Dutcher, de Souza et 
al. 2009). While median OS was shorter in NCRCC compared to conventional RCC, efficacy 
of temsirolimus appeared more pronounced among patients with non-clear or indeterminate 
primary cell type than among those with clear cell histology. This might be due to the fact that 
IFN has less efficacy in the former group of patients as mentioned above (Motzer, Bacik et  
al. 2002). 
Everolimus 
 
Everolimus is an oral derivative of rapamycin. It has been in clinical development since 1996 
as an immunosuppressant in solid organ transplantation and has obtained marketing 
authorization (Certican
®) for prophylaxis of rejection in renal and cardiac transplantation in a 
number of countries, including the majority of the European Union. It has been in 
development for patients with various malignancies since 2002. Everolimus has been 
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. 
Everolimus has been evaluated as a single agent and in combination with other antitumor 
agents, including cytotoxic chemotherapeutic agents, targeted therapies, antibodies and 
hormonal agents. Phase I dose escalating studies, exploratory Phase I/II studies with 
everolimus as single agent or in combination with other anti-cancer agents, Phase II/III 
studies of everolimus in several indications, and Phase III double-blind studies are 
contributing to the extensive database. 
Everolimus was recently approved under the trade name Afinitor® for patients with advanced 
RCC after failure of treatment with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU 
and several other countries and is undergoing registration in other regions worldwide. FDA 
approval was based on a pivotal phase 3 trial, an international, multicenter, randomized, 
double-blind study comparing everolimus to placebo in 410 patients pretreated with sunitinib 
or sorafenib (Motzer, Escudier et al. 2008). Prior therapy with bevacizumab, interleukin-2, or 
interferon-α was also permitted. Everolimus showed superior PFS over placebo (4.0 mo vs 
1.9 mo, HR 0.3, CI 0.22-0.40, p<0.0001). ORR was 1% for everolimus, none for placebo, 
arguing that PFS benefit is likely due to disease stabilization. This trial extended the role of 
mTOR inhibitors beyond first line therapy, and everolimus is now considered the standard of 


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care in patients  with  metastatic  conventional  RCC, whose disease has  progressed after 
treatment with VEGF-targeted therapies. 
The most common adverse reactions (incidence ≥10%) were stomatitis, rash, fatigue, 
asthenia, diarrhea, anorexia, nausea, mucosal inflammation, vomiting, pneumonitis, cough, 
peripheral edema, infections, dry skin, epistaxis, pruritus, and dyspnea. The most common 
grade 3-4 adverse reactions (incidence ≥2%) were infections, stomatitis, fatigue, and 
pneumonitis. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including 
Everolimus and some of these cases have been severe and on rare occasions, fatal 
outcomes have been observed. Deaths due to acute respiratory failure (0.7%), infection 
(0.7%), and acute renal failure (0.4%) were observed on the everolimus arm. The rates of 
treatment-emergent adverse reactions resulting in permanent discontinuation were 7% and 
0% for the everolimus and placebo treatment groups, respectively. 
The 
most 
common 
laboratory 
abnormalities 
(incidence 
≥50%) 
were 
anemia, 
hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased 
creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were 
lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. 
Overall, safety data available from completed, controlled and uncontrolled studies are 
consistent with the aforementioned findings of the Phase III trial. Everolimus is generally well 
tolerated at weekly and daily dose schedules. The safety profile is characterized by 
manageable adverse events (AEs). These AEs are generally reversible and non-cumulative. 
Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoan infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis or candidiasis and viral infections including 
reactivation of hepatitis B virus, have been described in patients taking everolimus. Some of 
these infections have been severe (e.g. leading to respiratory or hepatic failure) and 
occasionally have had a fatal outcome. 
 
3.3.7 
Everolimus Pharmacokinetics / Pharmacodynamics 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The steady-state AUC0-τ is 
dose-proportional over the dose range between 5 and 10 mg with daily administration, 
steady-state was achieved within two weeks with the daily dosing regimen. Cmax is dose- 
proportional between 5 and 10 mg daily administration. In healthy subjects, high fat meals 
reduced systemic exposure to everolimus 10 mg (as measured by AUC) by 22% and the 
peak plasma concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax 
by 42%. Food, however, had no apparent effect on the post absorption phase concentration- 
time profile. 
Following oral administration, everolimus is the main circulating component in human blood 
and is considered to contribute the majority of the overall pharmacologic activity.  No specific 
excretion studies have been undertaken in cancer patients; however, data available from the 
transplantation setting found the drug to be mainly eliminated through the feces. The mean 
elimination half-life of everolimus is approximately 30 hours. 


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Everolimus is a substrate of CYP3A4 and a substrate and moderate inhibitor of PgP. Please 
refer to Section 9.5.1 for more information on the concomitant use of CYP3A4 
inhibitors/inducers and other medications. 
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 (Kulke, 
Lenz et al. ; Maki, Fletcher et al.). 
 
 
3.3.8 
Tissue biomarkers for mTOR targeted therapy in RCC 
 
Investigating the prognostic significance of mTOR pathway components in RCC, a study of 
375 pts with resected disease (including 14% non clear-cell RCCs) observed adverse 
prognostic impact of pS6K, PTEN and Akt on disease-specific survival, independent of stage 
(Pantuck, Seligson et al. 2007). A second smaller study further suggested that pS6K and 
possibly pAkt were predictors of response to temsirolimus for advanced RCC (Cho, 
Signoretti et al. 2007). 
3.3.9 
Combining different targeted agents in RCC 
 
The approach of combining active agents with different mechanisms of action has proven 
valuable in the development of cytotoxic chemotherapy regimens in other cancers, and is 
subject of extensive investigation in targeted agents. Such treatment aims to improve 
responses, and either prevent or circumvent development of resistance. In phase I clinical 
trials, however, tolerability varies. Some combinations have required dose reductions (e.g. 
sunitinib with everolimus (Kroog, Feldman et al. 2009)), others are not considered safe to be 
given together (sunitinib with temsirolimus (Fischer, Patel et al. 2008)). 
 
In a phase I trial of 26 patients with conventional RCC, the combination of sunitinib with 
bevacizumab yielded ORR of 52% with the maximum tolerated dose (MTD) determined at 
full doses for both agents, but on further follow-up there was a high degree of treatment- 
associated hypertension, vascular and hematologic toxicities at these dose levels (Feldman, 
Baum et al. 2009). 
 
In NCRCC mutations in the VHL gene are not commonly seen, yet elevations in VEGF and 
HIF levels are thought to occur in response to the hypoxic tumor environment. Despite  
normal VHL function, some non-clear cell RCC have been found to exhibit a highly activated 
mTOR pathway (Pantuck, Seligson et al. 2007). Importantly, mTOR downstream effectors 
eIF-4E and phospho-S6 increase levels of both VEGF and HIF-1α(Azim, Azim et al. 2010). 
HIF-1α induces further increase in VEGF levels. VEGF, in turn, through its receptor, activates 
the PI3-K/Akt/mTOR axis(Agarwala and Case 2010). Inhibition of several steps in this 
autocrine loop (mTOR–HIF–VEGF-mTOR) is thought to be superior to single agents used in 
sequence(Heng and Choueiri 2009), and preclinical models have found such combinations to 
be synergistic(Ikezoe, Nishioka et al. 2006; Ikezoe, Yang et al. 2006). Our group previously 
conducted a phase I study combining VEGF and mTOR-inhibition by use of sunitinib and 
everolimus in 20 treatment-naïve patients with advanced RCC, 13 with clear cell and 7 with 


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non-clear cell histology(Kroog, Feldman et al. 2009). 5/20 patients (25%) achieved a partial 
response (PR), ten patients (50%) had stable disease. Three of the five patients with PR had 
non-clear cell histology, accounting for a RR of 43% within this subgroup; all three remained 
on protocol for more than one year, arguing in favor of combined targeting of VEGF and 
mTOR in these patients. Unfortunately, the combination was only tolerated at attenuated 
doses, and significant toxicity was observed. Treatment was associated with diverse grade 
3/4 toxicities, and the combination is not recommended for further study. 
3.3.10 Combination of Everolimus and Bevacizumab 
Preclinical studies of Everolimus plus VEGF Inhibition 
Everolimus has been studied in combination with a VEGFR tyrosine kinase inhibitor called 
PTK787/ZK222584 (vatalanib) in tumor models.   Comparisons of the effects of everolimus 
with those of PTK787/ZK222584, on angiogenic processes in vitro and in vivo, indicated 
overlapping effects on endothelial cell proliferation consistent with an integral role of the 
mTOR pathway in VEGFR signaling.  Based on this data, there is a potential for synergy 
between everolimus and VEGF inhibitors, such as PTK787/Zk222584 and bevacizumab. 
Clinical experience with Everolimus plus Bevacizumab 
Phase 1 and 2 studies have investigated the combination of everolimus and bevacizumab. 
Full dose of bevacizumab 10 mg/kg, i.v. every 2 weeks and full dose of everolimus 10 mg, 
p.o. daily given together has shown to be tolerable. 
 
A Phase 1 dose-escalation study of bevacizumab, everolimus, and erlotinib in patients with 
advanced-stage solid tumor demonstrated that the combination of everolimus and 
bevacizumab was well tolerated, allowing full doses of both agents to be administered.  The 
study included four dose levels: 
 
 
 
 
 
 
 
Bevacizumab 
Everolimus 
Erlotinib 
Dose Level 1 
10 mg/kg every 2 wks 
5 mg daily 
--- 
Dose Level 2 
10 mg/kg every 2 wks 
10 mg daily 
--- 
Dose Level 3 
10 mg/kg every 2 wks 
10 mg daily 
75 mg daily 
Dose Level 4 
5 mg/kg every 2 wks 
5 mg daily 
75 mg daily 
 
 
Fifteen patients were treated in Dose Level 2 (bevacizumab 10 mg/kg every 2 weeks and 
everolimus 10 mg daily), and no dose-limiting toxicities were seen in this dose level (Bendell, 
Gerorge et al. 2007). A total of 20 patients received bevacizumab and everolimus.  The most 
common adverse events were mild or moderate mucositis, fatigue, rash, and  
musculoskeletal pain.  In the group of patients who received everolimus and bevacizumab 
(20), there were six Grade 3 events, one of each of the following:  proteinuria, deep vein 


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thrombosis, cardiac ischemia, liver enzyme elevation, partial bowel obstruction, and rash. 
There were three Grade 4 events, one of each of the following:  proteinuria, left ventricular 
thrombus, and left ventricular systolic dysfunction (Bendell, Gerorge et al. 2007). 
 
A recent single arm phase II trial evaluated the efficacy of everolimus in combination with 
bevacizumab in 80 subjects with advanced RCC, including both untreated (Group A, 50 pts) 
and pretreated patients (Group B, 30 pts) (Hainsworth, Spigel et al. 2010). Enrollment 
required clear cell RCC, for mixed-histology tumors, the clear cell component had to 
comprise more than 75% of the biopsy specimen. Patients received bevacizumab 10mg/kg 
intravenously every 2 weeks and everolimus 10mg orally daily. Patients were evaluated for 
response after 8 weeks of treatment and continued treatment until disease progression or 
unacceptable toxicity. Median age was 63 (group A) and 64 (group B), the majority of 
patients had low or intermediate MSKCC risk scores. Among the 30 patients in group B, 16 
had previously received sunitinib treatment, 12 sorafenib treatment, 2 immunotherapy. ORR 
was 30% and 23% in un- and pretreated patients, respectively. The median PFS and OS 
were 9.1 months and 21.3 months for group A, 7.1 months and 14.5 months for group B. 
 
Table-3.2 Efficacy of Everolimus/Bevacizumab in conventional RCC, phase II data by 
Hainsworth et al.(Hainsworth, Spigel et al. 2010) 
 
Group A (N= 50) 
Group B (N= 30) 
Complete response 
1 (2%) 
1 (3%) 
Partial response 
14 (28%)  
6 (20%) 
Stable 
25 (50%) 
19 (64%) 
Progression 
3 (6%) 
3 (10%) 
Unevaluable 
7 (14%) 
1 (3%) 
Median PFS 
9.1 months 
7.1 months 
Median OS 
21.3 months 
14.5 months 
The combination was well tolerated by most patients, although grade 1 to 2 toxicities were 
relatively common. Adverse effects observed were those expected, based on the individual 
toxicity profiles of these two agents. The most common grade 3 to 4 toxicities included 
proteinuria (26%), mucositis/stomatitis (15%), fatigue (12%), and diarrhea (9%). The most 
common grade 3 to 4 toxicities included proteinuria (26%), mucositis/stomatitis (15%), 
fatigue (12%), and diarrhea (9%). The incidence of grade 3 to 4 proteinuria of 26% was  
higher than reported with single-agent bevacizumab, raising the possibility of potentiation of 
this toxicity by the combination; in most patients, grade 3 proteinuria was rapidly reversible 
when treatment with bevacizumab was interrupted, those patients were able to resume 
treatment at a later point. Twenty-five additional patients had dose adjustments of everolimus 
at some time during therapy, but were able to continue treatment with the modified dose 
regimen. 
 
Based preliminary findings from this trial, two large studies were designed, which are 
ongoing, one a first-line, large randomized phase II study comparing this regimen to the 
combination of bevacizumab and interferon (RECORD 2), and one second-line phase III post 
sunitinib study, comparing the same regime to everolimus plus placebo (proposed by the 
Cancer and Leukemia Group B). 


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3.4 Rationale for this study 
 
There is no current standard of care for the treatment of patients with metastatic NCRCC, 
and phase 2 trials of single agent VEGF targeted TKI in this group have been disappointing 
(Ravaud, Oudard et al. 2009; Molina, Feldman et al. 2010; Plimack, Jonasch et al. 2010). As 
outlined above, unplanned secondary analyses from two large phase III trials that have 
helped establish temsirolimus and bevacizumab in the treatment of conventional RCC 
suggest efficacy to both mTOR and VEGF pathway inhibition in NCRCC (Escudier, Ravaud 
et al. 2008; Dutcher, de Souza et al. 2009), however the numbers are too small to draw 
definite conclusions. There is a molecular rationale for combining agents targeting both 
pathways in NCRCC, since inhibition of several steps in an autocrine loop (mTOR–HIF– 
VEGF-mTOR) is thought to be superior to single agents used in sequence (Heng and 
Choueiri 2009). We chose everolimus over temsirolimus for two reasons: for one, since it is 
easily self-administered at home, whereas temsirolimus requires weekly visits for intravenous 
infusion of drug; secondly, since everolimus has been studied and found to be well tolerated 
in combination with bevacizumab in both the phase I and II setting, even with both drugs 
given at full doses. The purpose of this single-arm, single-center Phase II study is to 
determine the efficacy and safety of everolimus 10 mg p.o. daily dose in combination with 
bevacizumab 10 mg/kg administered intravenously every two weeks for treatment of patients 
with advanced non-clear cell carcinoma of the kidney, who have not received prior mTOR- or 
VEGF-targeted treatments. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
This is a single-institution, single-arm phase II trial of everolimus in combination with 
bevacizumab in patients with advanced non-clear cell RCC, who have not received prior 
VEGF-.or mTOR-targeted therapy. This study is designed as a single-stage trial  which 
requires a total of 34 patients. If 22 or more patients are progression-free after 6 months from 
the first day of treatment, this  regimen will be considered feasible and will merit further 
clinical study. 
 
A separate cohort of patients with non-clear cell RCC with papillary features will be enrolled 
in order to gather information regarding the efficacy given the rarity of these entities. 
 
4.3 
Intervention 
Cycle length will be defined as 28 days. Treatment will include everolimus 10mg, self- 
administered orally once daily on a continuous schedule (days 1-28), and bevacizumab 
10mg/kg, administered intravenously on days 1 and 15 of each cycle. 
 
Treatment will be continued until disease progression, major toxicity, or withdrawal from the 
study for any reason. Dose modification will be permitted based on toxicity as described in 
section 9.0. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 


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5.1 Everolimus 
Everolimus is formulated as tablets of 2.5 mg, 5 mg, and 10 mg strength, blistered  28 tablets 
per box..  Tablets should be kept in the blister packs until the time of administration as the 
drug is both hygroscopic and light-sensitive. Everolimus will be supplied through Novartis. 
5.2 Bevacizumab 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile pH6.2 solution 
for intravenous infusion.  Chemical and physical in-use stability has been demonstrated for 
48 hours at 2°C to 30°C in sodium chloride 9 mg/ml (0.9%) solution for injection. From a 
microbiological point of view, the product should be used immediately.  If not used 
immediately, in-use storage times and conditions are the responsibility of the user and would 
normally not be longer than 8 hours in the refrigerator at 36F to 46F (2C to 8C), unless 
dilution has taken place in controlled and validated aseptic conditions.  Bevacizumab should 
not be frozen. Keep the vial in the outer carton in order to protect from light. 
Bevacizumab does not contain any antimicrobial preservative; therefore, care must be taken 
to ensure the sterility of the prepared solution. Bevacizumab will be prepared and 
administered as per MSKC guidelines. 
No incompatibilities between bevacizumab and polyvinyl chloride or polyolefin bags or 
infusion sets have been observed.  Bevacizumab infusions should not be administered or 
mixed with glucose solutions. 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
1. 
Advanced renal cell carcinoma of non-clear cell histology with papillary features, 
histologically confirmed by MSKCC pathology. Advanced disease is defined as 
unresectable, locally recurrent disease or metastatic disease. Availability of additional 
tissue for correlative studies is NOT in inclusion requirement. 
2. 
Evidence of unidimensionally measurable disease per RECIST 1.1 (Eisenhauer, 
Therasse et al. 2009). 
3. 
Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to NCI 
CTCAE Version 4.0 grade 1. 
4. 
Adequate organ function as defined by the following criteria: 
• 
Absolute neutrophil count (ANC) 1,500/L 
• 
Platelets 100,000/L 
• 
Hemoglobin 9.0 g/dL 
• 
Serum calcium 12.0 mg/dL 
• 
Serum creatinine 1.5 x ULN 
• 
Total serum bilirubin  2.0 x ULN 
• 
Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase 


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[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic  
transaminase [SGPT]) 2.5 x local laboratory upper limit of normal (ULN), or AST and 
ALT 5 x ULN if liver function abnormalities are due to underlying malignancy 
• 
INR ≤1.5.  (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose for >2 
weeks at time of study entry.) 
• 
Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 
2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient 
can only be included after initiation of appropriate lipid lowering medication. 
 
5. 
Karnofsky performance status > 70 %. 
6. 
18 years of age or older. 
7. 
Ability to swallow oral medication. 
8. 
Signed and dated informed consent document indicating that the subject (or legally 
acceptable representative) has been informed of all pertinent aspects of the trial prior 
to undergoing study screening procedures. 
9. 
Subject‟s willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures. 
6.3 
Subject Exclusion Criteria 
 
1. 
Patients who have received prior systemic therapy for their RCC with VEGF pathway 
inhibitor (such as sunitinib, sorafenib, and bevacizumab) or with mTOR inhibitors 
(such as sirolimus, temsirolimus, everolimus, or deforolimus). 
2. 
Patients within 28 days post major surgery (e.g., intra-thoracic, intra-abdominal or 
intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing 
complications. Minor procedures and percutaneous biopsies or placement of vascular 
access device without complications require 48 hours prior to study entry. 
3. 
Patients who had radiation therapy within 28 days prior to start of study treatment 
(palliative radiotherapy to bone lesions allowed if completed 2 weeks prior to study 
treatment start). 
4. 
Patients with evidence or history of central nervous system (CNS) metastases or 
spinal cord compression, unless prior treatment with surgery or radiotherapy AND no 
progression of CNS disease within 6 months prior to enrollment. 
5. 
Patients with a history of abdominal fistula, gastrointestinal perforation, or intra- 
abdominal abscess within 6 months prior to study enrollment. 
6. 
Patients with proteinuria on screening urinalysis confirmed to be >1g /24h by 24 hour 
urine collection. 
7. 
Patients with inadequately controlled hypertension (defined as a blood pressure of 
> 150 mmHg systolic and/or > 100 mmHg diastolic on medication), or any prior 
history of hypertensive crisis or hypertensive encephalopathy. 
8. 
Patients receiving chronic systemic treatment with corticosteroids (dose of ≥ 10 
mg/day methylprednisone equivalent) or another immunosuppressive agent.  Inhaled 
and topical steroids are acceptable. 
9. 
Patients with a known history of HIV seropositivity. 
10. 
Patients who have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as: 


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• 
unstable angina pectoris (at any time), symptomatic congestive heart failure (NYHA 
III, IV) (at any time), serious uncontrolled cardiac arrhythmia (at any time), myocardial 
infarction, cerebrovascular accidents, or symptomatic left ventricular dysfunction ≤ 6 
months prior to first study treatment. 
• 
active bleeding diathesis 
• 
known severely impaired lung function defined as spirometry and DLCO ≤ 50% of 
normal and oxygen saturation at rest ≤ 88% on room air 
• 
symptomatic intrinsic lung disease requiring oxygen supplementation at baseline 
• 
Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) 
may be included, however blood glucose and antidiabetic treatment must be 
monitored closely throughout the trial and adjusted as necessary 
• 
any active (acute or chronic) or uncontrolled infection/disorders that impair the ability 
to evaluate the patient or for the patient to complete the study 
• 
liver disease such as cirrhosis, decompensated liver disease, or active and chronic 
hepatitis (i.e. quantifiable HBV-DNA and/or positive HBsAg, quantifiable HCV-RNA) 
11. 
Patients who have a history of another primary malignancy and are off treatment for ≤ 
3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the 
uterine cervix. 
12. 
Female patients who are pregnant or breast feeding 
13. 
Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, must use highly effective methods of contraception 
during the study and 8 weeks after. Highly effective contraception  methods include 
combination of any two of the following: 
a. 
Use of oral, injected or implanted hormonal methods of contraception or; 
b. 
Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
c. 
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; 
d. 
Total abstinence or; 
e. 
Male/female sterilization 
 
• 
Women are considered post-menopausal and not of child-bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at 
least six weeks prior to randomization. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child-bearing potential. 
 
14. 
Male patients whose sexual partner(s) are WOCBP who are not willing to use 
adequate contraception, during the study and for 8 weeks after the end of treatment. 
15. 
Patients who are using other investigational agents or who had received 
investigational drugs ≤ 4 weeks prior to study treatment start. 
16. 
Patients who have received attenuated live vaccines within one week of study entry. 
Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral 
polio, BCG, yellow fever, varicella and TY21a typhoid vaccines. 


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17. 
Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs (e.g. 
sirolimus, temsirolimus). 
18. 
Known impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of oral Everolimus. 
19. 
Patients with a history of non-compliance to medical regimens or who are considered 
potentially unreliable or will not be able to complete the entire study 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited through the outpatient clinics of the Solid Tumor Division of  
MSKCC.  Both men and women and members of all ethnic groups are eligible for this trial. 
 
Potential research subjects will be identified by a member of the patient‟s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC).  
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. 
 
8.1 
PRETREATMENT EVALUATION 
 
Prior to undergoing any study-specific procedure, subjects must read and sign the current 
Institutional Review Board (IRB)-approved informed consent form. 
 
Screening Procedures Within 28 Days: 
• 
Subject signature on current IRB-approved informed consent form 
• 
Tumor imaging including CT scan of the chest, abdomen, and pelvis and other 
applicable sites of disease. Patients who cannot receive intravenous (IV) contrast will 
undergo imaging with CT chest without IV contrast and MRI of the abdomen/pelvis. 
• 
Brain CT or MRI with contrast, if clinically indicated 
• 
Bone scan, if clinically indicated 
• 
Pulmonary Function Tests to include spirometry, DLCO and oxygen saturation at rest, 
if clinically indicated 
Screening Procedures within 14 Days Prior to Starting Treatment: 
• 
Medical history including oncologic history, history of other disease processes (active 
or resolved), concomitant illnesses and demographics 
• 
Karnofsky performance status, body weight, height, and vital signs (temperature, 
blood pressure, heart rate, respiratory rate) 
• 
Assessment of concomitant medications and treatments 
• 
Physical examination including examination of major body systems and 
• 
Hematology:  CBC, differential, platelets 


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• 
Chemistry:  Total bilirubin, AST, ALT, alkaline phosphatase, total protein, albumin, 
LDH, sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, and 
fasting glucose (patients must be fasting x 6h) 
• 
Baseline lipid panel (patients must be fasting x 6h) 
• 
PT/INR 
• 
HbA1c, only for patients with a history of diabetes mellitus (DM) 
• 
Urinalysis; (reflexive 24h urine collection for protein quantification to be obtained, if 
any degree of proteinuria seen on urinalysis [see also section 6.2]) 
• 
Serum pregnancy test, if applicable 
• 
12-lead ECG 
• 
Screening for hepatitis B. Per MSKCC standard policy for any patient receiving anti- 
cancer therapy, HB Surface Antigen and HB core Antibody will be tested with HBV 
PCR performed reflexively for any abnormal results (see appendix) 
• 
Screening for Hepatitis C. HCV RNA-PCR and Hepatitis C Antibody will be tested for 
all patients at screening. 
 
Correlative Studies: 
• 
Unstained slides will be obtained for each patient enrolled in the initial cohort only. 
Availability of such tissue specimen is not a requirement for study participation, and 
receipt of the material is not mandatory for initiation of treatment, i.e. can be obtained 
thereafter. 
9.1 
TREATMENT/INTERVENTION PLAN 
 
Cycle length is defined as 28 days. Treatment will include everolimus 10mg, self- 
administered orally once daily on a continuous schedule (days 1-28), and bevacizumab 
10mg/kg, administered intravenously on days 1 and 15 of each cycle. 
9.2 Everolimus Dosing Instructions 
 
Patients will take the first dose of everolimus at the center on Cycle 1, Day 1. Thereafter, 
patients will be instructed to swallow everolimus orally with a glass of water immediately after 
a meal, once daily at the same time each day. Any dietary habits around the time of 
everolimus intake should be as consistent as possible throughout the study.  The tablet(s) 
should not be chewed or crushed. If vomiting occurs, no attempt should be made to replace 
the vomited dose unless the everolimus tablet(s) are clearly visible. If the tablet(s) are clearly 
visible, then the patient should replace the everolimus dose. 
 
If a dose of everolimus is missed, patients will not increase the following day‟s dose. Instead, 
treatment will continue on the same schedule with no change in dosage or timing of drug 
administration. Missed doses should be documented by the patient in the pill diary in order to 
inform the treating physician at the next clinic visit. 


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Patients will continue to take everolimus until disease progression, major toxicity, or 
withdrawal from the study for any reason. 
The maximum allowed time of interruption of everolimus is 3 weeks in general, and up to 4 
weeks in the setting of Hepatitis B reactivation. 
In the event of permanent discontinuation of bevacizumab for safety reasons, everolimus 
may continue in the absence of disease progression. Patients continuing on everolimus only 
are only required to come for Day 1 visits each cycle. Other visits are not required. 
9.3 Bevacizumab  Administration 
Patients will receive an intravenous infusion of bevacizumab 10 mg/kg on Cycle 1, Day 1 and 
will return to the center every two weeks (14 days) for subsequent infusions until disease 
progression, major toxicity, or withdrawal from the study for any reason. 
The maximum allowed time of bevacizumab interruption is 8 weeks. 
In the event of permanent discontinuation of everolimus for safety reasons, bevacizumab 
may continue in the absence of disease progression. 
 
9.4 Dose Modifications 
 
Dose reductions will be performed, depending on the type and severity of the toxicity 
encountered, provided that the criteria have not been met for subject withdrawal from study. 
Recovery to acceptable levels of toxicity, as defined in the tables below, must occur within 4 
weeks to allow continuation in the study. 
 
9.4.1 Everolimus Dose Modifications 
 
9.4.1.1 Dose Modifications for Hepatic Impairment 
Patients with decompensated hepatic function or cirrhosis at baseline are not permitted to 
enter this study. See also section 6.1 for enrollment requirements of serum liver function 
tests. 
For dose adjustments  in the setting of hepatic  toxicity on study therapy, refer to section 
9.3.1.3. Note that in the setting of multiple factors indicating hepatic dysfunction, even if mild 
/ low grade, patients with Child-Pugh class B hepatic dysfunction (see appendix) should be 
dose reduced to 5mg daily per everolimus labeling (see appendix). 
9.4.1.2 Dose Modifications for Renal Impairment 
No dose modifications are recommended. 
 
9.4.1.3 Dose Modification due to Toxicity 
If treatment is interrupted due to toxicity, everolimus should not be resumed until recovery to 
 Grade 1, then reintroduce everolimus at the initial dose or lower dose level depending on 
toxicity type and Grade (Table 9.2). Both drugs (everolimus and bevacizumab) are to be held 
until the guidelines outlined below deem that both are safe to be restarted. These changes 


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must be recorded. For additional instructions on management including dose modifications in 
the setting specific toxicities, see section 11.2. 
 
 
 
 
 
 
 
 
Table 9.1 
Dose reduction steps for everolimus 
Dose Level 
Dose and Schedule 
0 (starting dose) 
10 mg, p.o. daily 
Decrease 1 dose level 
5 mg, p.o. daily 
Decrease 2 dose level 
5 mg, p.o. every other day 
If a patient has already decreased 2 dose levels, no further dose reduction is permitted. 
Patients requiring a third dose reduction must discontinue everolimus. The maximum allowed 
time of interruption of everolimus is 3 weeks in general and  up to 4  weeks in  case  of 
Hepatitis 
B 
reactivation. 
 
Table 9.2        Suspected Everolimus Toxicity – Dose Modification and Reinitiation 
 
Toxicity 
Action 
Non-hematological toxicity 
Grade 2 
(except pneumonitis - refer to table 11.1) 
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, then 
interrupt everolimus until recovery to  Grade1. Then 
reintroduce everolimus at the lower dose level. Suspend 
Bevacizumab dosing while everolimus is being held. 
Grade 3 
Interrupt everolimus and Bevacizumab until recovery to  
Grade 1. Then reintroduce Bevacizumab at starting dose and 
everolimus at the lower dose level. For pneumonitis consider 
the use of a short course of corticosteroids. 
Grade 4 
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. Suspend 
Bevacizumab dosing while everolimus is being held. 
If thrombocytopenia again returns to Grade 2, interrupt 
everolimus and bevacizumab until recovery to ≤ Grade 1. 
Then reintroduce everolimus at the lower dose level and 
resume bevacizumab at starting dose. 
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 
x109/L) 
Interrupt everolimus and Bevacizumab until recovery to ≤ 
Grade 1 (platelets ≥ 75 x109/L). Then reintroduce 
Bevacizumab at starting dose and 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 
Interrupt everolimus and Bevacizumab until recovery to ≤ 


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Toxicity 
Action 
x109/L) 
Grade 1 (neutrophil ≥ 1.5 x 109/L). Then reintroduce 
Bevacizumab at starting dose and resume everolimus at the 
initial dose. If ANC again returns to Grade 3, hold everolimus 
and Bevacizumab until the ANC ≥ 1.5 x 109/L. Then 
reintroduce Bevacizumab at the starting dose and 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 and Bevacizumab until recovery to ≤ 
Grade 1 (neutrophil ≥ 1.5 x 109/L). Then reintroduce 
Bevacizumab at starting dose and resume everolimus at the 
lower dose level. If ≥ Grade 3 neutropenia occurs despite this 
dose reduction, discontinue everolimus . 
Grade 3 febrile neutropenia (not life- 
threatening) 
Interrupt everolimus and Bevacizumab until resolution of 
fever and neutropenia to ≤ Grade 1. Hold further everolimus 
and Bevacizumab until the ANC ≥ 1,500/mm 3 and fever has 
resolved. Then reintroduce Bevacizumab at starting dose and 
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 except in 
the case of hepatitis B reactivation which is > 4 
weeks 
Discontinue everolimus. 
 
 
9.4.1.4 Dose Modifications related to CYP3A4 / P-glycoprotein (PgP) 
Everolimus is metabolized primarily by liver enzymes, in particular CYP3A4. It is also a 
moderate inhibitor of the multidrug efflux pump PGP.  Drugs or substances known to be 
inhibitors, inducers or substrates of the isoenzyme CYP3A4 or PgP should be avoided  
unless use of the drug is essential and no substitute is available. See tables 9.3 and 9.4 for a 
listing of relevant medications with effects on everolimus metabolism through CYP3A4 and/or 
PgP. 
 
▪ Inhibitors of CYP3A4 and/or PgP 
Co-administration with moderate or strong inhibitors of CYP3A4 (e.g., ketoconazole, 
itraconazole, ritonavir) or P-glycoprotein (PgP) should be avoided. Patients, who are taking 
such medications prior to enrollment, should be switched to an alternate agent without effect 
on CYP3A4 / PgP prior to or at the time of study initiation, if possible. 
If a patient requires co-administration of moderate / strong CYP3A4 or PgP inhibitor which 
cannot be discontinued or replaced, the subject will start everolimus at the standard dose 
(10mg by mouth daily). In the event that toxicity occurs, everolimus interruptions and dose 
modifications should be undertaken as outlined in section 9.3.1.3. For such patients, who 
undergo dose reductions, everolimus can be re-escalated to the previous dose, once the 
CYP3A4/PgP inhibitor is discontinued for whichever reason. 
Seville orange, grapefruit and their juices affect P450 and PgP activity.   Concomitant use 
should be avoided. 
▪ 
Inducers of CYP3A4 and/or PgP 


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Concomitant use of strong CYP3A4 inducers during study treatment should be avoided, if 
possible. Patients, who are taking such medications prior to enrollment, should be switched 
to an alternate agent without effect on CYP3A4 / PgP prior to or at the time of study initiation, 
if possible. 
If a patient requires co-administration of moderate / strong CYP3A4 or PgP inhibitor which 
cannot be discontinued or replaced, then the subject will start everolimus at the standard 
dose (10mg by mouth daily) with the aim to subsequently increase everolimus by 50%. 
Enzyme induction usually occurs within 7-10 days; therefore everolimus dose should not be 
escalated during this time. Instead, the dose will be increased to 15mg daily after at least 14 
days of concomitant therapy has been administered without safety concerns up to that point. 
No additional dose-escalations will be made. In case everolimus has been escalated to 15mg 
daily and the patient experiences toxicity that would require a dose reduction per table 9.2, 
everolimus will be dose-reduced to 10mg daily. Subsequent dose modifications should follow 
the guidelines lined out in section 9.3.1.3. 
If the strong inducer is discontinued in a patient previously dose-increased to everolimus 
15mg daily, the everolimus dose should be de-escalated to everolimus 10mg daily. 
▪ 
HMG-CoA reductase inhibitors and CYP3A4 
Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic 
interactions between everolimus and the HMG-CoA reductase inhibitors atorvastatin (a 
CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate). A population 
pharmacokinetic analysis also detected no influence of simvastatin (a CYP3A4 substrate) on 
the clearance of everolimus (taken from everolimus package insert, see appendix) 
 
Table 9.3 
Clinically relevant drug interactions: substrates / inducers / inhibitors of 
CYP3A4 
 
INDUCERS 
Barbiturates, carbamazepine, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine, 
topiramate 
INHIBITORS 
Strong inhibitors: 
clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir,  mibefradil, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, voriconazole, 
Posaconazole (Krishna et al, 2009) 
Moderate inhibitors: 
aprepitant, atazanavir, cimetidine, ciprofloxacin, darunavir, diltiazem, erythromycin, fluconazole, 
grapefruit juice, imatinib, tofisopam, verapamil, 
 
Table 9.4 
List of clinically relevant drug interactions mediated by PgP 
 
PgP substrates 
PgP inhibitors in vivo 
PgP inducers 
digoxin, fexofenadine, 
indinavir, vincristine, 
colchicine, topotecan, 
paclitaxel 
amiodarone, azithromycin, 
captopril, carvedilol, 
clarithromycin, conivaptan, 
cyclosporine, diltiazem, elacridar, 
erythromycin, felodipine, 
(GF120918), itraconazole, 
ketocoanzole, lopinavir, 
rifampin, St John’s wort 


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PgP substrates 
PgP inhibitors in vivo 
PgP inducers 
(LY335979), mibefradil, 
nifedipine, nitrendipine, 
(PSC833), quinidine, ranolazine, 
ritonavir, talinolol, valspodar, 
verapamil 
Reference: 
Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated Dec. 2, 2009, which 
summarizes DDI data from three sources including the FDA’s “Guidance for Industry, Drug 
Interaction Studies, the University of Washington’s Drug Interaction Database, and Indiana 
University School of Medicine's Drug Interaction Table. " 
**This list of clinically relevant drug interactions is updated as of December 02, 2009** 
 
 
9.3.2 Bevacizumab Dose Modifications 
 
There are no recommended dose modifications for the use of bevacizumab, other than dose 
adjustments due to change(s) in body weight (patient‟s body weight changes by ± 10% from 
baseline). Body weight at baseline will be used to calculate the required dose.  Once an 
adjustment has been made, the adjusted dose will become the new reference for potential 
further dose changes. 
If needed, bevacizumab should be either discontinued or temporarily suspended as 
described below. Hold bevacizumab whenever adverse events require temporary suspension 
of everolimus. Bevacizumab can be restarted at the original dose, once the protocol 
requirements for re-initiating everolimus are met. The maximum allowed time  of 
bevacizumab interruption is 8 weeks. 
Appropriate diagnostic and therapeutic medical treatment including accurate hypertensive 
treatment is mandatory for patients developing signs and symptoms of Reversible Posterior 
Leukoencephalopathy Syndrome (RPLS).  Bevacizumab has to be discontinued in these 
patients.  The safety of re-initiating bevacizumab in patients previously experiencing RPLS is 
not known. 
Bevacizumab should be permanently discontinued for the following toxicities: 
• 
gastrointestinal perforation 
• 
arterial thromboembolic event 
• 
Grade 3/4 hemorrhagic event 
• 
Wound dehiscence and wound healing complications requiring medical intervention 
• 
symptomatic Grade 4 thrombosis 
• 
Grade 4 hypertension or hypertensive encephalopathy 
• 
nephrotic syndrome 
For additional instructions on the management of specific toxicities, please see section 11.7. 
 
9.3.2.1 Bevacizumab and drug interactions 
No formal drug interaction studies with other agents have been conducted for bevacizumab. 


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9.4 Compliance 
 
Subjects will be required to keep a pill diary documenting daily self-administration of 
everolimus at home. Bottles of study medication must be returned at the beginning of each 
new cycle.  The number of tablets remaining will be documented and recorded.  Subjects 
who are considered non-compliant will be withdrawn from study. 
 
Patients who receive less than 50% of the recommended everolimus dose during a treatment 
cycle for reasons other than toxicity will be documented as protocol deviations and will be 
reviewed by the study PI to determine if they should be discontinued from the study. 
 
9.5 Concomitant Medication(s) 
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with/approval from the investigator. All 
medications taken within 30 days of starting study treatment must be reviewed as per the 
recommendations below. 
Patients will be instructed to notify the study center about any new medications he/she takes 
after the start of the study treatment. 
 
Investigational or commercial anticancer agents other than everolimus plus bevacizumab are 
not allowed during the study.  The initiation of any non-protocol specific anti-tumor treatment 
or surgery is considered an indication of disease progression and should be recorded 
appropriately. 
 
9.5.1 Anticoagulative agents 
Anticoagulation is allowed if target INR is ≤ 1.5 on a stable dose for >2 weeks. Similarly, in 
patients who experience thromboembolic events during study treatment, initiation of full dose 
anticoagulants is permitted. 
 
9.5.2 Palliative radiotherapy or initiation of bisphosphonates 
 
Bisphosphonate therapy for the treatment of bone lesions may be initiated before the patient 
enters the study. 
Patients who require palliative radiotherapy during treatment should be evaluated carefully 
for possible disease progression. Localized radiotherapy, for the treatment of pre-existing, 
painful bone metastases is allowed during the study only if evidence of radiological 
progression is not present. Palliative radiotherapy to bone is allowed to treat for pain, not for 
disease progression. Previously irradiated bone lesions will be evaluable for disease 
progression and stable disease only.  If palliative radiot herapy is prescribed, interrupt 
everolimus for the duration of the radiation treatment. If everolimus interruption is greater 
than 21 days, the patient must be permanently discontinued with exception of Hepatitis B 
reactivation, where a maximum of 4 weeks treatment interruption is acceptable. 
Radiotherapy for brain metastases is not permitted during the course of the study; because 
the need for CNS radiation will constitute disease progression. 
Pain medication is allowed for the patient to be as comfortable as possible. 


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9.5.3 Vaccinations 
The use of live vaccines  and close contact with those who have received live vaccines 
should be avoided during treatment with everolimus. These include, but are not limited to: 
intranasal influenza, measles, mumps, rubella, varicella, oral polio, BCG, yellow fever, and 
TY21a typhoid vaccines. 
 
10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 
Evaluation performed with scheduled follow-up at each cycle 
 
The following procedures must be performed on the days indicated for each / every other 
cycle: 
 
• 
Karnofsky performance status and Physical Examination including major body 
systems (Day 1 ± 5 days; Day 15 ± 5 days only on cycle 1) 
• 
Vital signs and weight (Day 1, 15 ± 5 days) 
• 
Assessment of adverse events and tumor-related signs and symptoms (Day 1 ± 5 
days; Day 15 ± 5 days only on cycle 1) 
• 
Assessment of concomitant medications and treatments (Day 1 ± 5 days) 
• 
Hematology: Complete blood cell count (Days 1, 15 ± 5 days) 
• 
Blood Chemistry: Total bilirubin, AST, ALT, alkaline phosphatase, total protein, 
albumin, LDH, sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, 
glucose  (Days 1 ± 5 days) 
• 
Fasting glucose once every 2 cycles [patients must be fasting x 6h] (Day 1 ± 5 days) 
• 
Lipid Panel once every 2 cycles [patients must be fasting x 6h] (Day 1 ± 5 days) 
• 
Urine chemistry once every 2 cycles: Urinalysis with dipstick will be performed for 
detection of proteinuria with reflective quantification of random protein and creatinine 
to calculate urine protein-creatinine ratio (UPCR) per section 11.2.10 (Day 1 ± 5 days) 
• 
Pre-treatment blood sample for correlative studies (Cycle 1, Day 1 only) Not 
applicable for patients enrolled in the expansion cohort. 
• 
Dispense everolimus to subject (Day 1 ± 5 days) 
• 
Administration of bevacizumab (Days 1, 15 ± 5 days) 
Table 10.1 Study Treatment Schedule 
 
 
Cycle 1 
Cycle 2 
Cycle 3+j 
Pre- 
Study
a
 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12+ 
Off 
Study
b
 
Bevacizum ab 
X 
X 
X 
X 
X 
X 


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E verolimus 
Taken orally every morning 
Tumor for pS6, pAKT, HIF- 
1α, PTENi 
X 
Research Test: blood 
sample
e
 
X 
Informed consent 
X 
Doctor‟s visit 
X 
X 
X 
X 
X 
X 
Blood testsc 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting blood draw 
(glucose and lipids) 
X 
X 
X 
X 
Urine tests 
X 
X 
X 
X 
EKG 
X 
CT or MRI scans of 
chest, abdomen and 
pel visd 
X 
E very 8weeksd 
X 
Pulmonary  Function 
Tests (PFTs) 
Xf 
Pregnancy test 
Xg 
Xh 
Xh 
Xh 
a: within 28 days before fi rst dose of treatment 
b: within 28 days after last dose of treatment 
c: you must be fasting, i.e. no calory intake for 6 hours prior to this blood-draw 
d: after 6 cycles (24 weeks), scans will be every 12 weeks. 
e: The blood sample for correlati ve studies will be taken prior to dosing on Cycle 1 Day 1 only.   Not 
applicable to patients enrolled in the expansion cohort. 
f. PFTs only if your doctor feels this is needed 
g. Serum pregnancy test 
h: Urine pregnancy test every 4 weeks 
i: Not applicable to patients enrolled in the expansion cohort. 
j: If the patient has stable or res ponding disease at the end of 13 cycles of treatment (one year) and 
continues on daily E verolim us only, repeat the procedures performed for cycle 3 day 1 only every eight 
weeks (ie: Cycle 15 Day 1, Cycle 17 Day 1, Cycle 19 Day 1, etc.). Other visits are not required. 
 
10.2 
Serial imaging while on study treatment 
 
The following imaging studies must be performed on the days and cycles indicated below. 
 
• 
Tumor imaging including CT scan of the chest, abdomen, and pelvis or CT scan of 
the chest and MRI of the abdomen and pelvis at the end of cycle 2 (Day 28 ± 7 days), 
cycle 4 (Day 28 ± 7 days), and cycle 6 (Day 28 ± 7 days). 


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• 
From cycle 6 (24wks) through cycle 12 (48wks), imaging will be repeated every three 
cycles (every 12wks), i.e. at the end of cycle 9, and cycle 12 (Day 28 ± 7 days). 
• 
After 12 cycles (48wks), imaging will be repeated every four cycles (every 16wks), i.e. 
at the end of cycle 16, 20, 24, etc. (Day 28 + 7 days) 
• 
Patients who cannot receive intravenous (IV) contrast will undergo imaging with CT 
chest without IV contrast and MRI of the abdomen/pelvis. For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI should be performed should also be based on the 
tumor type, anatomic location of the disease and should be optimized to allow for 
comparison to prior studies, if possible. 
• 
Nuclear bone scans will be obtained in patients only if clinically indicated. 
 
10.3 
End of Study Treatment/Withdrawal Procedures 
 
At the end of the study or at withdrawal, the following procedures should be performed within 
28 days of last dose of either study medication: 
 
• 
Physical examination including major body systems 
• 
Karnofsky performance status, body weight, and vital signs 
• 
Hematology:  CBC, differential, platelets 
• 
Blood Chemistry: Total bilirubin, AST, ALT, alkaline phosphatase, total protein, 
albumin, LDH, sodium, potassium, chloride, carbon dioxide, calcium, BUN, creatinine, 
fasting glucose, lipid panel [patients must be fasting x 6h] 
• 
Urine chemistry: Urinalysis will be performed for random protein and creatinine to 
calculate urine protein-creatinine ratio (UPCR). 
• 
Tumor imaging including CT scan of the chest, abdomen, and pelvis or CT scan of 
the chest and MRI of the abdomen and pelvis and other applicable sites of disease (if 
not obtained in the prior cycle). 
• 
Bone scan, if clinically indicated 
• 
Assessment of adverse events and tumor-related signs and symptoms 
• 
Assessment of study drug compliance/accountability.  Subjects must return all used 
and unused medication/containers. 
 
 
10.4 
Post-Treatment Follow-Up 
 
Subjects should continue to be evaluated for adverse effects of the study treatment up to 28 
days after the last dose of study medication.  At such post-treatment follow-up visits, the 
following procedures should be performed: 
 
• 
Assessment of adverse events and tumor-related signs and symptoms 
• 
Physical examination, Karnofsky performance status, laboratory assessments, or 
other tests necessary to follow unresolved or evaluate new adverse events 


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• 
Assessment of concomitant medications and treatments 
During this period, the outcome of adverse events with a date of onset during the study 
period should be reevaluated, and any new adverse events should be recorded. 
 
10.5 
Correlative Studies 
 
Biomarker discovery and validation will be performed to identify tumor biomarkers which may 
predict treatment response/failure to bevacizumab plus everolimus.  Genomics correlations 
and immunohistochemical (IHC) analyses will be performed. First, to identify any potential 
correlations between histologic features and treatment response, we will conduct detailed 
histologic review of architectural and cytologic features of the tumors.  In addition, to 
specifically elucidate the molecular basis of treatment response and resistance, standard  
IHC and scoring will be performed on archived paraffin tissue blocks to determine the 
underlying protein expression of key signaling molecules targeted by the treatment, including 
mTOR pathway activation markers phospho-S6 (p-S6) and phospho-4E BP1 (p-4E BP1);  
HIF pathway markers hypoxia inducible factor-1α (HIF-1α) and carbonic anhydrase IX (CA- 
IX); vascular maker CD31; and other key growth factors or regulators of interacting pathways 
such as platelet-derived growth factor receptor-β (PDGFR-β), phospho-AKT, and PTEN. 
Given the fact that the molecular underpinning of majority advanced ncRCC is largely 
unknown, the proposed IHC study is mainly limited to the pathways targeted by everolimus 
and bevacizumab. 
 
To date (11/26/2013), emerging immunohistochemical (IHC) analysis on archived tumor 
samples is encouraging and thus far suggest that markers of mTOR pathway activation such 
as phospho-4E BP1 (p-4E BP1) are high in responders and low in non-responders. 
Secondly, DNA extracted from tumors and matched normal tissue or blood specimens will be 
analyzed by the IMPACT assay, a targeted-exome capture assay with ultra-deep sequencing 
coverage (median 570x) using Illumina HiSeq 2000.  This assay will identify genetic 
alterations within the genes most commonly genetically altered in cancer, which should shed 
considerable light upon why patients respond to the combined therapy. Genes that are within 
all pathways potentially targeted by everolimus and bevacizumab, such as MTOR, TSC1, 
TSC2, FLT1 (VEGFR1), and KDR (VEGFR2), will be additionally scrutinized at the raw 
sequence level, since we would expect to see alterations of these genes in responders given 
preliminary data in other responders to rapalog therapy. 
 
Lastly, when additional tissues are available, additional studies, including gene-expression 
profiling, proteomics, and metabolomics will be performed. 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
Individual toxicities previously reported for everolimus and bevacizumab, as well as adverse 
events seen in prior early phase trials combining everolimus and bevacizumab have been 
described in detail in sections 3.3.6, 3.3.3, and 3.3.10, respectively. 
11.1 Severity assessment 


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The following definitions of Severity in accordance with Cancer Therapy Evaluation Program, 
Common Terminology Criteria for Adverse Events (CTCAE Version 4.03, Publish Date:  June 
14th, 2010 (Gompertz 1825)) to describe the maximum intensity of adverse events. If the 
event is serious (see section 17.2 for definition), the CTC grade reported and entered into the 
CRDB must be consistent with the description of CTC grade included in the narrative section 
of the serious adverse event report. 
 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
 
GRADE Clinical Description of Severity 
0 
No Change from Normal or Reference Range (This grade is not included 
in the Version 4.0 document but may be used in certain circumstances.) 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self care ADL 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
DEATH RELATED TO AE 
 
A Semi-colon indicates „or ‟ w ithin the description of the grade. A single dash (-) indicates a grade is not available. 
 
 
If required on SAE reporting forms, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  For 
purposes of consistency, these intensity grades are defined as follows: 
 
MILD 
does not interfere with patient‟s usual function 
MODERATE 
interferes to some extent with patient‟s usual function 
SEVERE 
interferes significantly with patient‟s usual function 
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious            
unless it met one of the criteria for serious adverse events, listed above. 
 
11.2 Management of specific toxicities 
 
11.2.1 Management of infections 


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Everolimus has immunosuppressive properties and may predispose patients to bacterial, 
fungal, viral or protozoal infections, including infections with opportunistic pathogens. 
Localized and systemic infections, including pneumonia, other bacterial infections, invasive 
fungal infections, such as aspergillosis or candidiasis and viral  infections  including 
reactivation of hepatitis B virus, have been described in patients taking Everolimus Some of 
these infections have been severe (e.g. leading to sepsis, respiratory or hepatic failure) and 
occasionally have had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with Everolimus 
Treat pre-existing infections prior to starting treatment with Everolimus. While taking 
Everolimus, be vigilant for symptoms and signs of infection; if a diagnosis of infection is 
made, institute appropriate treatment promptly and consider interruption or discontinuation of 
Everolimus. 
If a diagnosis of invasive systemic fungal infection is made, discontinue Everolimus and treat 
with appropriate antifungal therapy. 
 
11.2.2 Management of skin toxicity 
 
For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. 
Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with 
the following suggested supportive measures at the discretion of the investigator: oral 
minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, 
diphenhydramine, oral prednisolone (short course), topical corticosteroids, or pimecrolimus. 
 
11.2.3 Management of hypersensitivity reactions 
 
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, 
dyspnea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or 
without respiratory impairment) have been observed with everolimus. 
 
11.2.4 Renal failure events 
 
Cases of renal failure (including acute renal failure), some with fatal outcome, occurred in 
patients treated with everolimus. Renal function of patients should be monitored particularly 
where patients have additional risk factors that may further impair renal function. 
Elevations of serum creatinine, usually mild, and proteinuria have been reported in patients 
taking everolimus. Monitoring of renal function, including measurement of blood urea 
nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of 
everolimus therapy and periodically thereafter. 
 
 
11.2.5 Management of stomatitis/oral mucositis/mouth ulcers 
 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local 
supportive care. They should be appropriately graded using the functional grading given on 
the NCI-CTC for adverse events, version 4.0 (Gompertz 1825) (see section 11.1). 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth 
wash or salt water (0.9%) mouth wash several times a day until resolution. 


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2. For Grade 2 toxicity, in which case patients have pain but are able to maintain adequate 
oral alimentation, the suggested treatments are topical analgesic mouth treatments (i.e., 
local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral 
paste 0.1% (Kenalog in Orabase®). 
3. For Grade 3 toxicity in which case patients cannot maintain adequate oral alimentation), 
Everolimus should be dose reduced.  Everolimus should be discontinued if toxicity is a 
Grade 4. 
4. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. 
5. 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, 
thereby leading 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. 
 
11.2.6 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 and will be 
obtained prior to study treatment initiation as well as once every two cycles while on 
treatment. 
Grade 2 or 3 hypercholesterolemia (> 300 mg/dL or 7.75 mmol/L) or Grade 2 
hypertriglyceridemia (>2.5 x ULN) do not require dose modifications or interruption of 
treatment with everolimus, but should instead be treated with a 3-hydroxy-3-methyl-glutaryl 
(HMG)-CoA reductase inhibitor (e.g., atorvastatin, pravastatin) or appropriate lipid-lowering 
medication, in addition to diet. As per section 6.1, these interventions are also indicated for 
patients with grade 2 or 3 cholesterol / triglyceride levels at the time of pre-treatment 
screening. Lipid lowering treatment tor these patients must be initiated prior to beginning 
study treatment. Patients with Grade 3 hypertriglyceridemia should be dose reduced one 
level. 
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. Everolimus should be discontinued for development of Grade 
4 hyperlipidemia. 
Hyperglycemia has been reported in clinical trials. Fasting serum glucose will be assessed 
prior to the start of everolimus therapy and will be monitored while on treatment with fasting 
blood glucose checked every 2 cycles. Optimal glycemic control should be achieved before 
starting trial therapy and while on treatment using anti-hyperglycemic agents at the discretion 
of the individual investigator following the patient. See table 9.2 for everolimus dose 
modifications in the setting of treatment-related hyperglycemia. 


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11.2.7 Management of diarrhea 
Appearance of diarrhea attributed to everolimus toxicity may be treated with loperamide. 
 
11.2.8 Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a known side effect of rapamycin analogues including 
everolimus. Clinically significant pneumonitis is typically accompanied by non-specific 
symptoms including dyspnea, nonproductive cough, fatigue, and fever. Diagnosis is  
generally suspected in individuals receiving mTOR inhibitors who develop these symptoms  
or in asymptomatic individuals in whom a routine chest CT scan reveals a new ground glass 
or alveolar infiltrate. The frequency of symptomatic pulmonary toxicity (all grades) was 
approximately 13% in a phase III study of everolimus in patients with metastatic renal cell 
carcinoma (Motzer, Escudier et al. 2008). Severe (CTC grade 3) pneumonitis occurred in 4% 
of patients, and an occasional fatality was reported. The lung toxicity was partly or  
completely reversible in the majority of cases with interventions including drug interruption, 
discontinuation and the use of corticosteroids. If non-infectious pneumonitis develops, 
consultation with a pulmonologist is recommended. Management of non-infectious 
pneumonitis suspected to be associated with everolimus and dose modification instructions 
are provided in table 11.1 and table 9.2  respectively. 
 
Table 11.1 
Management of non-infectious pneumonitis 
 
Worst Grade 
Pneumonitis 
Required  Investigations 
Management of 
Pneumonitis 
Everolimus Dose 
Adjustment 
Grade 1 
CT scans with lung windows. 
Repeat at least every 3 cycles 
until return to within normal limits. 
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. * 
Consider 
corticosteroids if 
symptoms are 
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. everolimus dose 
cannot be escalated. 
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 
infecti ve 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. 
Grade 4 
CT scan with lung windows and 
required pulmonary function 
testing, if possible, including: 
spirometry, DLCO, and room air 
O2 saturation at rest. Repeat each 
subsequent Cycle until return to 
Consider 
corticosteroids if 
infecti ve origin is 
ruled out. Taper 
as medically 
indicated. 
Discontinue  treatment. 


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Worst Grade 
Pneumonitis 
Required  Investigations 
Management of 
Pneumonitis 
Everolimus Dose 
Adjustment 
baseline. Bronchoscopy with 
biopsy and/or BAL is 
recommended i f possible. 
* If a bronchoscopy is performed, then a biopsy and/or bronchoalveolar lavage is required. 
 
 
11.2.9 Monitoring and prophylactic treatment for hepatitis B reactivation 
Per MSKCC institutional policy for all patients undergoing anti-cancer therapy, all patients will 
be screened for hepatitis B prior to initiation of study treatment. HB Surface Antigen and HB 
core Antibody will be tested with HBV PCR performed reflexively for any abnormal results 
(see appendix). Patients with positive HB Surface Antigen or HBV PCR will be started on  
viral suppressive therapy with entecavir 0.5mg PO daily ≥ 1 week prior to the first dose of 
study drug. HBV DNA should be monitored periodically while on treatment. Treatment must 
continue throughout their treatment course with the study drugs and per MSKCC guidelines 
should be continued for at least six months after completion of treatment with everolimus 
and/or bevacizumab. 
11.2.10 Management of hepatitis B reactivation 
For  hepatitis  B  reactivation  definition  and  the  management  guidelines,  see  Table  11.2 
Guidelines for management of hepatitis B. 
 
 
Table 11.2 
Guidelines for management of hepatitis B 
 
HBV reactivation  (with or without clinical signs and symptoms)* 
For patients with 
baseline results: 
Positive HBV-DNA 
OR 
positi ve HBs Ag 
------------------------- 
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 anti vi ral 
AND 
Interrupt study drug administration until resolution: 
≤ grade 1 ALT (or baseline ALT, if > grade 1) and 
≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re -started 
at one dose lower, if available.  (see Table 9.1 – Dose reduction 
steps for everolim us) 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 anti vi ral 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 anti vi ral therapies at least 4 weeks after last dose 
of study drug. 
For patients with 
baseline results: 
Negative HBV- 
DNA and HBsAg 
Treat : Start first anti vi ral medication 
AND 
Interrupt study drug administration until resolution: 
≤ baseline HBV-DNA levels 


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* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 4.0 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 4.0 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). 
 
11.2.11 Guidelines for management of hepatitis C reactivation 
 
The following two categories of patients should be monitored every 4–8 weeks for HCV flare: 
• 
Patients with detectable HCV RNA-PCR test at screening. 
• 
Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including those that were treated and are considered „cured‟) 
For definitions of HCV flare and actions to be taken in the event of a flare, please refer to 
Table 11.3. 
 
Table 11.3 
Guidelines for the management of hepatitis C flare 
 
Baseline results 
HCV flare definition* 
HCV flare 
management 
Detectable HCV-RNA 
> 
2 
log10 
IU/mL 
increase in HCV-RNA 
AND 
ALT elevation > 5 x 
ULN or 3 x baseline 
level, 
whichever 
is 
higher. 
Discontinue 
E verolimus 
Knowledge 
of 
past 
hepatitis 
C infection 
with 
no 
detectable 
HCV -RNA 
New appearance of 
detectable HCV-RNA 
AND 
ALT elevation > 5 x 
ULN or 3 x baseline 
level, 
whichever 
is 
higher. 
Discontinue 
E verolimus 
* All flares of HCV are to be recorded as grade 3 (e.g.  CTCAE Version 3.0 - Investigations - Other: 
Viral Flare), unless considered life threatening by the investigator; in which case  they  should  be 
recorded as grade 4. Date of vi ral flare is the date on which both the clinical criteria described above 
AND 
[Positive HBs Ab 
(with no prior 
history of 
vaccination against 
HBV), OR positi ve 
HBc Ab] 
------------------------- 
reactivation is 
defined as: 
New appearance 
of measurable 
HBV-DNA 
If resolution occurs within ≤ 28 days study drug should be re -started 
at one dose lower, if available. (see Table 9.1 – Dose reduction steps 
for everolimus) If the patient is already recei vi ng the lowest dose of 
study drug according to the protocol, the patient should restart at the 
same dose after resolution. Anti vi ral 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. 


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were met. (e.g., for a patient whose HCV-RNA increased by 2 logs on 01 JAN 2011 and whose ALT 
reached > 5 x ULN on 22 JAN 2011, the date of viral flare is 22 JAN 2011). 
 
 
11.2.12 Management of gastrointestinal perforation 
 
Bevacizumab should be permanently discontinued in patients who develop gastrointestinal 
perforation. 
An adverse event of gastrointestinal perforation, irrespective of causal relationship, should be 
reported throughout the course of the study and during the 6 month follow-up period. 
11.2.13 
Management of surgical procedures/wound-healing complications 
Bevacizumab should not be initiated for at least 28 days following major surgery or until the 
surgical wound is fully healed.  In patients who experience wound-healing complications 
during bevacizumab treatment, bevacizumab should be withheld until the wound is fully 
healed.  Bevacizumab should be withheld for elective surgery. 
11.2.14 Management of hypertension 
Patients should be monitored for the development or worsening of hypertension via frequent 
blood pressure measurement.  Temporary suspension of bevacizumab is recommended in 
patients with evidence of severe hypertension that is not controlled with medication. 
Hypertension is to be treated with appropriate anti-hypertensive therapy. See Table 11-4 for 
management of hypertension. 
Table 11.4 
Management of Hypertension 
 
Worst Grade 
Hypertension 
Definition 
Action 
Grade 1 
Asymptomatic, transient (< 24 
hours) increase by >20 mm Hg 
diastolic or to > 140/90 mmHg if 
previously within normal limits 
Intervention is not indicated. 
Grade 2 
Symptomatic increase by > 20 
mmHg (diastolic) or to >140/90mm 
Hg if previously within normal limits; 
recurrent or persistent (> 24 hours) 
Monotherapy of anti-hypertensive may 
be indicated.  Once controlled and 
stable <150/100 mm Hg, patients may 
continue  bevacizumab treatment. 
Grade 3 
Requiring more than one anti- 
hypertensive or more intensive 
therapy than previously: 
Bevacizum ab should be withheld for 
persistent or symptomatic hypertension 
and should be permanently 
discontinued if hypertension is not 
controlled. 
Grade 4 
Life threatening consequences 
(e.g., hypertensive crisis) 
Occurrence of Grade 4 hypertension 
should lead to permanent 
discontinuation of bevacizumab.   All 
doses of anti-hypertensive medicines 
should be recorded at all visits. 
 
 
11.2.15 Management of Proteinuria 


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While receiving bevacizumab, patients will be monitored for the occurrence of significant 
proteinuria. All patients will have a dipstick urinalysis performed at the beginning of every 
other cycle, i.e. prior to every fourth bevacizumab dose.  For ≥2+ proteinuria on dipstick, 
reflective quantification of proteinuria will be performed by determination of the urine protein- 
creatinine ratio (UPCR). The UPCR has been found to correlate directly with the amount of 
protein excreted in a 24 hour urine collection (Ginsberg, Chang et al. 1983; Schwab, 
Christensen et al. 1987; Rodby, Rohde et al. 1995). Specifically, a UPCR of 1.0 is equivalent 
to 1.0 gram of protein in a 24 hour urine collection. For this purpose, at least 4 ml of a 
random urine sample will be collected in a sterile container (this does not have to be a 24- 
hour urine). Samples will be analyzed for random urine protein and creatinine levels 
[separate requests]. The lab will measure protein concentration (mg/dL) and creatinine 
concentration (mg/dL). The UPCR is derived as follows: protein concentration 
(mg/dL)/creatinine (mg/dL). 
Management in regards to further administration of bevacizumab will be determined as 
follows: 
• < 2+ proteinuria (dipstick): administer bevacizumab as planned. 
• ≥ 2+ proteinuria (dipstick): determination of urine protein-creatinine ratio (UPCR) 
• 
UPC ratio < 2.0 Continue bevacizumab. 
• 
UPC ratio ≥ 2.0 Hold bevacizumab until UPC ratio recovers to < 2.0 (recheck every 
other week). 
• 
If therapy is held for > 2 months due to proteinuria, discontinue bevacizumab. 
• 
nephrotic syndrome: Discontinue bevacizumab 
 
Table 11.5 
Management of proteinuria 
 
UPC ratio < 2.0 
Continue bevacizumab 
UPC ratio ≥ 2.0 
Hold bevacizumab until UPC ratio recovers to < 2.0 
(recheck every other week) 
nephrotic syndrome 
Discontinue bevacizumab 
 
11.2.16 Management of thrombosis/embolism 
 
All  toxicity  will  be  graded  according  to  the  CTCAEv4.0  guidelines.  For  management 
decisions in the setting o thromboembolic events, see table 11.5. 
 
 
Table 11.6 
Management of thrombosis / embolism 
 
E vent 
Action 
Arterial  thromboembolic 
event 
Discontinue bevacizumab permanently 
Grade 3 or 4 venous 
thrombosis 
Hold bevacizumab for 2 weeks.  Bevacizumab may be resumed after 
initiation of therapeutic-dose anticoagulant therapy as soon as all of 
the following criteria have been met: 
The patient must be on a stable dose of anticoagulant, and if on 
warfarin, the patient must have an INR within the target range 
(usually between 2 and 3) prior to restarting bevacizumab. 
The p atient must not ha ve h ad a G ra de 3 o r 4 he morrh agic e vent  


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E vent 
Action 
since entering the study. 
The patient must not have had any evi dence of tumor invading or 
abutting major blood vessels on any prior disease assessment. 
Blood samples should be taken prior to initiation of treatment for the 
following lab values:  INR, PTT, PT, D-dimers, anti-thrombin III. 
Symptomatic Grade 4 
thrombosis 
Discontinue patient from study 
 
 
11.2.17 Management of Hemorrhage 
All toxicity will be graded according to the CTCAEv4.0 guidelines.   Patients who develop ≥ 
Grade 3 hemorrhage should discontinue bevacizumab. 
 
 
11.2.18 Infusion Reactions 
Infusion reactions reported in prior clinical trials include hypertension, hypertensive crises 
associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 
hypersensitivity, chest pain, headaches, rigors, and diaphoresis. Reactions with the first dose 
of bevacizumab are uncommon (<3%) and severe reactions have been reported in 0.2% of 
patients. 
If a severe infusion reaction occurs, infusion should be stopped and appropriate medical 
therapy should be administered. Treatment can be continued with premedication for 
subsequent cycles at the investigator‟s discretion. 
 
11.8 
Laboratory Safety Assessments 
 
Blood: 
 
• 
Hematology, Coagulation, and Blood Chemistry samples will be drawn at the time 
points described in Sections 8.0 and 10.0.  Additional blood tests may be performed 
for the purposes of planning treatment administration, dose modification, or following 
adverse events. 
 
• 
Fasting blood glucose. The patient must be in a fasting state (at least 6 hours) at the 
time of blood sampling for this evaluation. 
 
• 
Serum pregnancy test for women of childbearing potential will be performed prior to 
administration of the first dose of study treatment (results must be available for 
eligibility determination). 
 
• 
Lipid panel: A serum lipid profile includes: total cholesterol, triglycerides, LDL, and 
HDL. The patient must be in a fasting state (at least 6 hours) at the time of blood 
sampling for this evaluation. 
 
Urine: 


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• 
Urinalysis will be performed periodically for detection of elevated urine protein 
excretion. Should such elevation be seen, 24 hour urine collection or urine collection 
for UPCR will be necessary, as outlined in sections 6.2 and 11.2.10, respectively. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The determination of antitumor efficacy will be based on objective tumor assessments made 
according to the RECIST1.1(Eisenhauer, Therasse et al. 2009) system of unidimensional 
evaluation and treatment decisions by the investigator will be based on these assessments. 
A minor modification will be adopted to accommodate standard practic e in use of spiral CT 
scan (i.e., reconstruction interval up to 8 mm).  In the event spiral CT scan is used to assess 
tumors, minimum lesion size qualifying as measurable should be twice the reconstruction 
interval used and at least 10 mm. 
 
The same method and technique should be used to characterize each identified and reported 
lesion at baseline, during the study treatment period, and during the follow-up period. 
Imaging-based evaluation over clinical examination is the required technique when both 
could be used to assess the antitumor effect of the treatment.  CT or MRI scan are the 
preferred methods for the tumor assessment. 
 
For patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI should be performed should also be based  
on tumor type, anatomic location of the disease and should be optimized to allow for 
comparison to prior studies if possible. 
 
Whenever possible, clinical evaluation of superficial lesions should not be used as the sole 
form of measurement.  However, when necessary, color photograph with metric caliber is 
acceptable.  Tumor evaluation by positron emission tomography (PET) scan or by ultrasound 
may not substitute for CT or MRI scans. 
 
Radiologic tumor assessments will be performed at screening, at the end of the dosing 
period of cycles as outlined in Section 10 and whenever disease progression is suspected. 
After the patient is withdrawn from study treatment, another tumor assessment will be 
performed if an assessment has not been performed within the prior 6 weeks.  12.1 
Calculated Endpoint Definitions 
 
12.1.1 Progression free survival (PFS) 
 
PFS will be defined as the duration of time from enrollment until death or progression of 
disease. Patients still progression free at the time of analysis will be considered censored. 
 
12.1.2 Objective response rate (ORR) 
 
• 
Overall confirmed objective response rate (ORR), defined as the proportion of 
patients with confirmed complete response (CR) or confirmed partial response (PR) 


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according to the RECIST1.1 criteria (Eisenhauer, Therasse et al. 2009), relative to the 
total population of patients who receive at least one dose of study drug.  Confirmed 
responses are those that persist on repeat imaging study  4 weeks after initial 
documentation of response. 
 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
 
13.2 Study treatment discontinuation 
 
If both medications have to be interrupted for more than 21 days (>4 weeks for hepatitis B 
reactivation), the patient will be discontinued from the study. 
The patient may discontinue study treatment for any of the following reasons: 
• 
Adverse event(s) as specified in sections 9.3 and 11.2 
• 
Subject withdrew consent 
• 
Lost to follow-up 
• 
Administrative problems 
• 
Disease progression 
• 
Protocol deviation 
• 
Discretion of the Investigator 
If a patient has discontinued the study treatment due to an unacceptable adverse drug 
reaction or an abnormal laboratory value, he/she should not have withdrawal of consent 
recorded as the reason for discontinuation. Instead, the reason for discontinuation must be 
recorded as due to adverse drug reaction or an abnormal laboratory value. 
 
14.1 
BIOSTATISTICS 
 
14.2 Study design / Primary endpoint 
 
The purpose of this study is to assess the efficacy of everolimus plus bevacizumab in 
patients with metastatic non-clear cell RCC. The primary endpoint is the percent of patients 
alive and progression-free after 6 months of therapy. 
 
This study is designed as a single-stage, phase II trial which requires a total of 34 patients. If 
22 or more patients are progression-free after 6 months from the first day of treatment, this 
regimen will be considered feasible and will merit further clinical study.  With 34 patients, this 
design discriminates between true response rates of ≤ 50% and ≥ 70% at a Type I error of 
6% and a Type II error of 19%.  Our null hypothesis of 50% was chosen based on phase II 
data in non-clear cell RCC from our center showing a PFS of 50% at 6 months with single 
agent sunitinib in the first-line setting(Molina, Feldman et al. 2010). While sunitinib is not part 
of this regimen, this is the only prospective data for targeted therapy in this group of kidney 
cancer subtypes available for comparison. 
 
Patients that come off study before 6 months before documented progression/death will be 
treated as events for the 6 month PFS endpoint.  In addition to counting the number of 
patients alive and progression-free at 6 months, a Kaplan-Meier curve will be calculated for 


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progression-free survival.  All patients will be used in the analysis.  Patients still progression 
free at the time of analysis will be considered censored.  Median progression-free survival 
(and 95% confidence interval) will be determined from that curve.  In addition to counting the 
number of patients alive and progression-free at 6 months, a Kaplan-Meier curve will be 
calculated for progression-free survival.  Patients still progression free at the time of analysis 
will be considered censored.  Median progression-free survival (and 95% confidence interval) 
will be determined from that curve. 
 
To date (11/26/2013), the study has enrolled 32 patients (5 chromophobe, 2 medullary, 7 
papillary, 11 unclassified and 7 unclassified with papillary features).  Preliminarily, 5/6 
patients with papillary and 3/6 patients with unclassified (papillary features) have met the 
study‟s primary endpoint of progression-free after 6 months of therapy.   Three out of six 
patients with papillary RCC achieved a partial response (PR) as best response.  Two out of 
six patients with unclassified with papillary features achieved a PR as best response (1 is 
unconfirmed).  Additionally, 4 patients (2 papillary and 2 unclassified with papillary features) 
have stable disease beyond 14 and 11 months, respectively. 
The preliminary efficacy 
results are extremely encouraging for this subgroup of patients who traditionally experience 
modest responses to targeted agents. 
Based on these extremely encouraging preliminary results and the lack of a standard of care 
for these rare kidney tumors, we will accrue a separate cohort of patients with non-clear cell 
RCC with papillary features. We expect to see a total of approximately 10 patients per year 
with non-clear cell RCC with papillary features. We anticipate this will take two years but will 
continue past this point if necessary to accrue all 20 patients.  The efficacy of treatment in 
this cohort will be analyzed descriptively.  They will be studied separately in secondary 
analyses and will have no effect of analysis of the study‟s main objective. 
14.3 Sample Size / Accrual Rate 
 
The total planned sample size is 54 patients. An estimated 10 patients with non-clear cell 
RCC with papillary features are seen at MSKCC per year. Considering this, estimated time to 
accrue an additional 20 patients is two years. Following completion of accrual, an additional 6 
months is estimated for follow-up. 
14.4 Analysis of secondary endpoints 
 
Secondary endpoints include objective response rate, the safety of the drug combination in 
this population and the assessment of expression of correlative biomarkers. 
14.4.1 Objective response rate (ORR) 
 
Response will be evaluated by use of the international criteria as defined by the Response 
Evaluation Criteria in Solid Tumors Committee (RECIST 1.1) (Eisenhauer, Therasse et al. 
2009). All responses will be confirmed ≥ 4 weeks after initial documentation of response. 
Response rates and 95% confidence interval will be estimated using exact binomial 
methods. 
 
14.4.2 Safety of the study drug combination in the study population 


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Toxicity will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 (Gompertz 1825), as outlined in section 11.5. Toxicities will be summarized by type and 
grade using frequencies and rates. 
14.4.3 Correlative biomarkers 
 
Expression levels of phospho-Akt, phospho-S6, HIF-1α, and PTEN in pretreatment patient 
tumor samples will be assessed with aim of correlating levels to treatment benefit. In 
evaluating the correlative endpoints to this study, Fisher‟s exact test will be employed to 
determine, whether the biomarkers are predictive for treatment response in the studied drug 
combination.  Logistic regression will be used to relate 2 or 3 biomarkers to response 
simultaneously. 
 
In evaluating the correlative markers for the combined everolimus and bevacizumab 
treatment, two-sided Fisher‟s exact test will be employed to determine whether the 
biomarkers are predictive for treatment response in the studied drug combination. A Kaplan- 
Meier curve will be calculated for progression-free survival related to specific biomarkers or 
combinations of biomarkers. 
 
Multivariate analyses with age, gender, tumor size, histological subtype, and grade will be 
performed.  Pearson correlation, Chi-square tests, Student‟s t test, univariable and 
multivariable Cox regression analysis, hazard ratios, Kaplan-Meier curves, and log-rank test 
will all be used to calculate significant association of biomarkers with clinical results and 
determine if the biomarkers are indeed predictive. 
 
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. 
15.3 
Randomization 
 
N/A – no randomization in this study. 


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16.1 
DAT A M ANAGEMENT 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 coordinate the activities of 
the protocol study team. 
 
The data collected for this study will be entered into a secure database.  Source documents 
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 m issing data 
and inconsistencies.  Accrual rates and extent and accuracy of evaluations and follow-up will 
be 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. 
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 DMS 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. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
 
The risks, benefits and objectives of the study will be reviewed with each participant prior to 
enrollment. Patients will be made aware of the voluntary nature of this trial, potential adverse 


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effects of the study treatment, alternative treatment options, and financial costs associated 
with treatment on this trial. Written informed consent will then be obtained prior to enrollment. 
Privacy and confidentiality will be maintained for all participants, and the study is designed 
with careful monitoring of toxicity through physician visits and laboratory assessment to 
assure patient safety. 
 
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 (IRB/PB). 
17.3 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant‟s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of Serious 
Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org.  All other 
reports should be sent to sae@mskcc.org. 


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The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s initials 
• 
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 
• 
The grade of the event 
• 
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 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
The PI‟s signature and the date it was signed are required on the completed report. 
 
 
 
17.2.1  SAE reporting to Novartis 
 
All SAEs, regardless of suspected causality, that occur within 30 days of the last intervention 
or the last dose/treatment with the investigational agent/product must be reported to Novartis. 
Any SAEs experienced after this period should only be reported to Novartis only  if the 
investigator suspects a causal relationship to the study treatment. The completed, signed 
form will be faxed (877-778-9739) within 24 hours to the Novartis Drug Safety and 
Epidemiology Department. Recurrent episodes, complications, or progression of the initial 
SAE must be reported as  follow-up to the original episode within 5 business days of the 
investigator receiving the follow-up information. An SAE occurring at a different time interval 
or otherwise considered completely unrelated to a previously reported event should  be 
reported separately as a new event. 
 
17.3 Pregnancy and assessments of fertility 
Pregnancy testing is required at screening and recommended monthly until the end of the 
trial. Serum pregnancy testing should be performed at screening and at the end of the study. 
Urine pregnancy testing should be performed at each visit (every 4 weeks). 


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There are no adequate data from  the use of everolimus in pregnant women. Studies  in 
animals have shown reproductive toxicity effects including embryo-toxicity and feto-toxicity. 
The potential risk for humans is unknown. Everolimus  should not be given  to  pregnant 
women unless  the potential benefit outweighs  the potential risk to the fetus. If a female 
becomes pregnant while on study treatment, the newborn will be followed for at least 12 
months. 
It is not known whether everolimus is excreted in breast milk. However, in animal studies 
everolimus and/or its metabolites readily passed into the milk of lactating rats. Women taking 
everolimus should therefore not breast-feed. 
 
 
17.3.1 Women of childbearing potential 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 8 weeks after 
stopping treatment. Highly effective contraception is defined as either: 
• 
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception] 
• 
Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least six weeks before taking study treatment. In case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment 
• 
Male partner sterilization (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate). [For female subjects on the study, the vasectomised 
male partner should be the sole partner for that subject]. 
• 
Use of a combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, implanted or other hormonal methods of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
• 
In case of use of oral contraception, women should have been stable on the oral agent 
before taking study treatment. 
 
17.3.2 Male Contraception 
Sexually active males must use a condom during intercourse while taking the drug and for 8 
weeks after stopping treatment and should not father a child in this period. 
A condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid. 
Female partners of male patients must also be advised to use one of the following 
contraception methods: Use of (1) oral, injected, implanted or other hormonal methods of 
contraception, or (2) intrauterine device (IUD) or intrauterine system (IUS), or (3) prior 
male/female sterilization. 
 
 
17.3.3 Fertility 
The potential for everolimus to cause infertility in male and female patients is unknown. 


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However, menstrual irregularities, secondary amenorrhea and associated luteinizing 
hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed. 
 
Based on non-clinical findings, male and female fertility may be compromised by treatment 
with everolimus. 
17.3.4 Pregnancy 
Preclinical data regarding reproductive toxicity is described in the most recent Investigator 
Brochure. The potential reproductive risk for humans is unknown. Women of childbearing 
potential should be advised to use highly effective contraception methods while they are 
receiving everolimus and up to 8 weeks after treatment has been stopped. 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. The newborn will be followed for at 
least 12 months. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment and any pregnancy outcome. 
Any SAE experienced during pregnancy must be reported on the SAE Report Form . 
 
17.4     Cost 
 
The patient will be responsible for all costs related to treatment and complications of 
treatment.  Costs to the patient (third party insurer) will include the cost of bevacizumab, 
hospitalizations, routine blood tests and diagnostic studies, office visits, baseline EKG and 
doctor‟s fees. However, the sponsor, Novartis International AG, will supply everolimus at no 
cost to the patient.  Patients will not be charged for the correlative studies included in this 
trial. 
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.) 


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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. 
 
19.0 
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434. 
 
 
20.0 
APPENDICES 
 
Appendix 1: MSKCC standard for screening and treatment of HBV 
Appendix 2: Package Insert Bevacizumab 
Appendix 3: Package Insert Everolimus