EVEREST: EVErolimus for Renal Cancer Ensuing Surgical Therapy, A Phase III Study
Phase: PHASE3
Conditions: Kidney Cancer
Sponsor: SWOG Cancer Research Network

 
 
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PRIVILEGED COMMUNICATION 
Activated April 1, 2011 
FOR INVESTIGATIONAL USE ONLY 
 
 
 
SWOG 
TITLE 
EVEREST:  EVErolimus for Renal Cancer Ensuing Surgical Therapy, A Phase III Study 
 
NCT #01120249 
 
STUDY CHAIRS: 
AGENTS: 
 
 
Christopher W. Ryan, M.D. (Medical Oncology) 
SWOG-held IND Agent: 
Oregon Health & Science University 
Everolimus (RAD001, Afinitor®, Zortress®)  
3303 SW Bond Avenue,  
CR14 
(NSC- 733504) (IND-75,093) 
Portland, OR 97239 
 
Phone: 503/494-8487 
 
FAX: 503/494-6197 
 
E-mail: ryanc@ohsu.edu  
 
 
 
Elisabeth I. Heath, M.D. (Medical Oncology) 
Ganesh S. Palapattu, M.D. (Urology) 
Wayne State University 
The Methodist Hospital 
Karmanos Cancer Institute 
6560 Fannin Street, Suite 2100 
4100 John R 
Houston, TX 77030 
 
4 HWCRC 
Phone: 713/441-8137 
Detroit, MI  48201 
FAX: 713/441-6463 
 
Phone: 313/576-8715 
E-mail: gpalapattu@tmhs.org  
FAX: 313/576-8767 
 
E-mail: heathe@karmanos.org  
 
 
 
Primo N. Lara, Jr., M.D. (Medical Oncology  
Philip C. Mack, Ph.D. (Translational Medicine) 
& Translational Medicine) 
UC Davis Cancer Center 
UC Davis Cancer Center 
Division of Hematology/Oncology 
4501 X Street 
4501 X Street 
Sacramento, CA 95817 
Sacramento, CA 95817 
Phone: 916/734-3771 
Phone: 916/734-8022 
FAX: 916/734-7946 
FAX: 916/734-2361 
E-mail:  pnlara@ucdavis.edu  
E-mail:  pcmack@ucdavis.edu  
 
 
BIOSTATISTICIANS: 
 
 
 
Cathy M. Tangen, Dr.P.H. (Biostatistics) 
 
Melissa Plets, M.S. 
SWOG Statistical Center 
 
Fred Hutchinson Cancer Research Center 
 
1100 Fairview Avenue North, M3-C102 
 
P.O. Box 19024 
 
Seattle, WA  98109-1024 
Phone:  206/667-4623 
FAX: 206/667-4408 
E-mail: ctangen@fredhutch.org  
E-mail: mplets@fredhutch.org  
 
ALLIANCE STUDY CHAIR: 
ECOG-ACRIN STUDY CHAIR: 
 
 
 
Maxwell V. Meng, M.D. 
Mark Stein, M.D. 
 
University of California at San Francisco –  
The Cancer Institute of New Jersey 
Mount Zion 
E-mail: mark.stein@rutgers.edu  
E-mail: mmeng@urology.ucsf.edu  
 

 
 
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PARTICIPANTS 
 
ALL NATIONAL CLINICAL TRIAL NETWORK (NCTN) MEMBERS – U.S. INSTITUTIONS ONLY 
 
SWOG/SWOG 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
 
NRG/NRG Oncology 
 
 
 

 
 
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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ................................................................................................................................ 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ........................ 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES ................................................................................................................................... 7 
1.1 
Primary Objective ............................................................................................................................. 7 
1.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
Translational Medicine Objectives ................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................................... 7 
3.0 
DRUG INFORMATION .................................................................................................................. 11 
3.1 
Everolimus (RAD001, Afinitor®, Zortress®) (NSC- 733504) (IND-75,093) ..................................... 11 
4.0 
STAGING CRITERIA ..................................................................................................................... 18 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................. 19 
5.1 
Disease Related Criteria ................................................................................................................ 20 
5.2 
Prior Therapy Criteria ..................................................................................................................... 20 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 21 
5.4 
Translational Medicine Criteria ...................................................................................................... 22 
5.5 
Regulatory Criteria ......................................................................................................................... 22 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 23 
a. 
Risk group based on pathologic stage (intermediate high-risk vs very high risk) (see Section 4.0),
 ....................................................................................................................................................... 23 
b. 
Histology (clear cell vs non-clear cell); (NOTE:  The tumor will be classified as clear cell if any 
component of clear cell histology is identified in the specimen.) ................................................... 23 
c. 
Performance status (0 vs 1). .......................................................................................................... 23 
7.0 
TREATMENT PLAN ....................................................................................................................... 23 
7.1 
Good Medical Practice ................................................................................................................... 23 
7.2 
Treatment Schedule ....................................................................................................................... 24 
7.3 
Concomitant Therapy ..................................................................................................................... 24 
7.4 
Intake Calendar .............................................................................................................................. 25 
7.5 
Unblinding Procedures ................................................................................................................... 25 
7.6 
Criteria for Removal from Protocol Treatment ............................................................................... 27 
7.7 
Discontinuation of Treatment ......................................................................................................... 27 
7.8 
Follow-Up Period ............................................................................................................................ 27 
8.0 
DOSE MODIFICATIONS ............................................................................................................... 27 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 27 
8.2 
General Dose Modification Considerations.................................................................................... 27 
8.3 
Everolimus Dose Levels................................................................................................................. 28 
8.4 
Everolimus Dose Modifications ...................................................................................................... 28 
8.5 
Infection Precaution ....................................................................................................................... 32 
8.6 
Management of Hepatitis Reactivation .......................................................................................... 32 
8.7 
Emergency Unblinding ................................................................................................................... 34 
8.8 
Dose Modification Contacts ........................................................................................................... 34 
8.9 
Adverse Event Reporting ............................................................................................................... 34 
9.0 
STUDY CALENDAR ...................................................................................................................... 36 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS................................................. 39 
10.1 
Recurrence ..................................................................................................................................... 39 
10.2 
Symptomatic deterioration ............................................................................................................. 39 
10.3 
Performance Status ....................................................................................................................... 40 
10.4 
Recurrence-Free Survival .............................................................................................................. 40 
10.5 
Time to Death ................................................................................................................................. 40 
11.0 
STATISTICAL CONSIDERATIONS ............................................................................................... 40 
11.1 
Accrual Goal ................................................................................................................................... 40 
11.2 
Analysis of Primary Endpoint ......................................................................................................... 41 
11.3 
Analysis of Secondary Endpoints .................................................................................................. 42 

 
 
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11.4 
Analysis of Translational Medicine Endpoints ............................................................................... 43 
11.5 
Pharmacokinetic Analysis of Blood Samples ................................................................................. 44 
11.6 
Data and Safety Monitoring Committee Oversight ........................................................................ 45 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 45 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 45 
13.1 
Registration Timing ........................................................................................................................ 45 
13.2 
Investigator/Site Requirements ...................................................................................................... 45 
13.3 
OPEN Registration Requirements ................................................................................................. 46 
13.4 
Registration Procedures................................................................................................................. 47 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 49 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................. 49 
14.1 
Data Submission Requirement ...................................................................................................... 49 
14.2 
Master Forms ................................................................................................................................. 49 
14.3 
Data Submission Procedures ........................................................................................................ 49 
14.4 
Data Submission Overview and Timepoints .................................................................................. 50 
15.0 
SPECIAL INSTRUCTIONS ............................................................................................................ 51 
15.1 
Tissue Specimen Banking ............................................................................................................. 51 
15.2 
Plasma, Buffy Coat, and Whole Blood Specimen Banking ............................................................ 52 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................... 55 
16.1 
Adverse Event Reporting Requirements........................................................................................ 55 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 60 
18.0 
APPENDIX ..................................................................................................................................... 63 
18.1 
New York Heart Association Classifications .................................................................................. 64 
18.2 
Emergency Unblinding Guidelines ................................................................................................. 65 
18.3 
Examples of Clinically Relevant Drug Interactions:  Substrates, Inducers and Inhibitors of the 
Isoenzyme CYP3A4 ....................................................................................................................... 67 
18.4 
Intake Calendar .............................................................................................................................. 70 
 

 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient 
enrollments: 
Submit study data directly to 
the Lead Cooperative Group 
unless otherwise specified in 
the protocol: 
 
CTSU Regulatory Office 
1818 Market Street, 
Suite 1100 
Philadelphia, PA19103 
 
Fax: 215-569-0206 
 
Email:   
CTSURegulatory@ctsu.coccg.org 
 
For more information, call the CTSU 
Help Desk at 888-823-5923 or the 
Regulatory Help Desk at 866-651-
CTSU. 
 
 
Please refer to the patient enrollment 
section of the protocol for instructions on 
using the Oncology Patient Enrollment 
Network (OPEN) which can be accessed 
at https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
 
 
 
Online Data Submission:  
Institutions participating through 
the CTSU are required to 
submit and amend their data 
electronically via Online Data 
Submission.  Access the 
SWOG Workbench using your 
CTSU User ID and password at 
the following url: 
 
https://crawb.crab.org/TXWB/ct
sulogon.aspx 
 
Exceptions: Data items that are 
not available for online 
submission (operative and 
pathology reports, patient 
completed forms, scan reports, 
etc.) may be submitted by fax at 
800-892-4007. 
 
Do not submit data forms to 
CTSU Data Operations. 
 
Do not copy the CTSU on data 
submission. 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to the CTSU 
members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access 
Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and password.  
For patient eligibility questions contact the SWOG Data Operations Center by phone or email: 
 
Phone:  206/652-2267 
E-mail:  guquestion@crab.org 
 
For treatment or toxicity related questions contact the Study PI of the Coordinating Group (Dr. Christopher Ryan 
at 503/494-8487).   
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help 
Desk by phone or e-mail: 
 
CTSU General Information Line:  888-823-5923 
E-mail:  ctsucontact@westat.com 
 
All calls and correspondence will be triaged to the appropriate CTSU representative. 
For detailed information on the regulatory and monitoring procedures for CTSU sites please review the CTSU 
Regulatory and Monitoring Procedures policy located on the CTSU members’ website: 
 
https://www.ctsu.org > education and resources tab > CTSU Operations Information >CTSU Regulatory and 
Monitoring Policy 
The CTSU website is located at https://www.ctsu.org 
 

 
 
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SCHEMA 
 
Nephrectomy 
 
 
 
 
 
 
Stratify:   
Pathologic Stage 
Histologic Subtype 
Performance Status 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
Everolimus (daily) 
Placebo (daily) 
For 9 cycles (54 weeks) 
for 9 cycles (54 weeks) 
 
 
 
 
 
 
 
 
 
 
Follow-Up 
(10 years) 
 
 
 
 
NOTE:  Procedure for optional unblinding of treatment at recurrence outlined in Section 7.5. 
 

 
 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
The primary objective of this study is to compare recurrence-free survival in renal 
carcinoma patients randomly assigned to 54 weeks of everolimus versus 54 weeks of 
placebo after nephrectomy or partial nephrectomy. 
 
1.2 
Secondary Objectives 
 
a. 
To compare overall survival in those patients randomized to everolimus versus 
those randomized to placebo. 
 
b. 
To compare qualitative and quantitative toxicity between the two study arms. 
 
1.3 
Translational Medicine Objectives 
 
a. 
To bank tissue and biologic specimens for future study of molecular biomarkers 
relevant to the AKT/mTOR and other pathways implicated in the pathogenesis of 
renal carcinoma and to investigate their potential predictive and prognostic value. 
 
b. 
To bank blood specimens for the future study of the relationship between steady 
state trough levels of everolimus and relevant side effects (lymphopenia, 
infection, hyperglycemia, hypercholesterolemia, hypertriglyceridemia) in patients 
treated on this study with everolimus. 
 
 
2.0 
BACKGROUND 
 
Nearly 58,000 patients are expected to be diagnosed with kidney cancer in the United States in 
2009.  (1)  Despite significant improvements made over the last several years in treatment of 
advanced kidney cancer, 13,000 patients are expected to die from their disease in 2009.  Many of 
these patients originally present with localized disease and are treated with surgical resection 
with curative intent. However, up to one-third of patients with fully resected, localized disease will 
develop either a local or distant recurrence; the majority of whom will succumb to distant 
metastases.  (2,3)  Despite this significant risk, current standard treatment after resection in these 
patients is surveillance.  Multiple studies investigating interferon or interleukin-2 in the adjuvant 
setting have failed to demonstrate any benefit over observation alone.  (4,5,6,7)  Studies 
investigating autologous tumor vaccines have shown equivocal results.  (8,9)  Such first-
generation adjuvant studies predated VEGF- and mTOR-directed therapies which have now been 
established in the treatment of advanced disease based on improved progression-free- and 
overall-survival.  (10,11,12,13,14,15) 
 
The Eastern Cooperative Oncology Group E2805 study (ASSURE) is a second-generation 
adjuvant study investigating the potential role of the multi-kinase inhibitors sorafenib and sunitinib 
as adjuvant therapy in the post-operative setting for patients with fully resected localized disease.  
ASSURE is a randomized Phase III study of one year of sunitinib versus one year of sorafenib 
versus one year of placebo in patients with intermediate to high-risk M0 renal carcinoma 
beginning within 12 weeks of nephrectomy.  (16)  This study completed accrual September 1, 
2010.  It is likely that results will not be available for several years after study closure. Until the 
results of ASSURE are known, surveillance will remain as standard treatment for such patients.  
Several additional industry-sponsored, international trials investigating the utility of adjuvant 
VEGF-R tyrosine kinase inhibitors are currently enrolling, including the SORCE trial (sorafenib), 
S-TRAC trial (sunitinib), NCT 00492258, NCT 00375674, and NCT 01235962. 
 
ASSURE was designed to study the adjuvant activity of sunitinib and sorafenib, the first two agents 
to receive FDA approval for advanced renal carcinoma in the post-immunotherapy era, both of 

 
 
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which are VEGF-R tyrosine kinase inhibitors. Inhibitors of mTOR have since emerged as treatment 
options for advanced renal carcinoma.  mTOR is a serine/threonine kinase that recognizes stress 
signals via the PI3K-AKT pathway and phosphorylates p70 ribosomal S6 kinase 1 (S6K1) and 
eukaryotic initiation factor 4E binding protein 1 (4EP1).  Its role in progression of renal carcinoma 
may be due to its downstream regulation of hypoxia-inducible factor 1-α.  (17)  Recent Phase III 
studies have established mTOR inhibition as a clinically relevant treatment strategy for advanced 
renal carcinoma. In a Phase II trial, temsirolimus, a pro-drug of rapamycin, was shown to 
improve progression-free and overall-survival in modified Memorial Sloan-Kettering Cancer 
Center (MSKCC) criteria poor-risk, advanced renal carcinoma patients, and received FDA 
approval for treatment of the disease.  (18,19)  Everolimus is an orally-administered derivative of 
rapamycin that was studied in a placebo-controlled Phase III study in patients with advanced 
renal carcinoma who had received prior therapy with sorafenib, sunitinib, or both.  In this study, 
everolimus improved progression-free survival compared with placebo (hazard ratio 0·30, 95% CI 
0·22–0·40, p<0·0001) and has been FDA-approved for the treatment of patients with advanced 
renal cell carcinoma after failure of treatment with sunitinib or sorafenib. (20) 
 
Everolimus 
 
Everolimus is an orally bioavailable macrolide derivative of rapamycin that targets the activity of 
mTOR kinase and demonstrates potent antiproliferative effects against a variety of tumor types in 
the pre-clinical setting.  (21)  Everolimus exerts its activity through high affinity interaction with an 
intracellular receptor protein, the immunophilin FKBP12.  The FKBP12/everolimus complex 
subsequently interacts with the mTOR protein kinase, inhibiting downstream signaling events 
involved in regulation of the G1 to S-phase transition.  The antitumor effect of everolimus may be 
due to direct inhibition of tumor cell growth and indirectly by inhibiting angiogenesis.  The 
observation of in vivo sensitivity of xenografts comprised of cells demonstrating resistance to 
everolimus in vitro attributes to the drugs potential to act on the vascular component of the 
supporting peritumoral stroma.  The antiangiogenic property of everolimus confirmed through 
experiments demonstrating the effect of everolimus in countering VEGF-induced proliferation of 
human umbilical endothelial cells (HUVEC) in vitro, VEGF-driven angiogenesis in a chamber 
implant murine model and neovascularization in a murine orthotopic melanoma model. 
 
Clinical Development 
 
Everolimus has been extensively investigated as an immunosuppressant in solid organ 
transplantation and is approved in renal and cardiac transplantation in many countries.  
Everolimus has been in development for patients with various hematologic and nonhematologic 
malignancies both as a single agent or in combination with other antitumor agents.  Diseases 
under study included renal cell carcinoma, breast cancer, carcinoid neuroendocrine tumors, 
pancreatic islet cell tumors (pNET), hematologic malignancies including chronic myelogenous 
leukemia (CML), non-Hodgkin’s and mantle cell lymphoma, hepatocellular, gastric, colorectal, 
gastrointestinal stromal tumors (GIST), prostate and others. 
 
Phase I studies of cancer patients with single-agent everolimus have been conducted with both 
weekly and daily regimens.  Dose-limiting toxicities included stomatitis, fatigue, hyperglycemia, 
and neutropenia.  (22,23) 
 
A Phase III, randomized, double blind, placebo controlled study in patients with mRCC who 
progressed on VEGF-R tyrosine kinase inhibitors demonstrated that everolimus administered 
daily at an oral dose of 10 mg prolonged median progression free survival from 1.87 months for 
patients receiving placebo to 4.9 months for everolimus treated patients (hazard ratio 0.33, 95% 
CI 0.25-0.43, p<0·0001).  (24,25) 
 
Everolimus 5 mg and 10 mg tablets were recently approved under the trade name Afinitor® for 
patients with advanced renal cell carcinoma (RCC) after failure of treatment with Sutent® 
(sunitinib) or Nexavar® (sorafenib) in the US, EU and several other countries and is undergoing 
registration in other regions worldwide. 
 

 
 
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The most common treatment-related adverse effects observed in the renal carcinoma study 
included stomatitis (40%), rash (40%), fatigue (20%), asthenia (18%), diarrhea (17%), anorexia 
(16%), and nausea (15%).  The most common laboratory abnormalities include anemia (91%), 
hypercholesterolemia (76%), hypertriglyceridemia (71%), hyperglycemia (50%), increased 
creatinine (46%), and lymphopenia. (42%).  (26) 
 
Study Rationale 
 
Given that mTOR inhibition has been shown to improve progression-free survival in two different 
patient populations of advanced renal carcinoma, it is warranted to study an mTOR inhibitor in the 
adjuvant setting.  Everolimus has the advantage of oral dosing, making it potentially more suitable 
for adjuvant administration, and has been chosen for this study.  The dosing will be 10 mg orally 
once daily which is the dosing schedule used in the Phase III trial and was the maximum daily 
dose evaluated in Phase I cancer trials.  (27,28,29)  The control arm will be placebo with a 
randomized double-blind design, justified by the fact that surveillance is the current standard 
treatment in this disease setting.  We hypothesize that one year of adjuvant treatment with 
everolimus will improve recurrence-free survival without addition of excessive toxicity. 
 
Accrual to the ASSURE trial was quicker than anticipated with a projected accrual rate of 480 
patients per year.  However, a high treatment discontinuation rate was noted with approximately 
25% of patients on the active arms discontinuing treatment within three months due to adverse 
events or patient refusal.  ASSURE was amended to lower the starting doses of sorafenib and 
sunitinib in an attempt to ameliorate these effects and to increase the sample size to account for 
the high dropout rate.  Given that everolimus has a different side effect profile than sunitinib or 
sorafenib, it is quite possible that this agent may be more tolerable in the adjuvant setting and 
result in better patient adherence.  As an example, hand foot syndrome is not a common side 
effect of mTOR inhibitor therapy, and this particular toxicity has been cited as one of the potential 
early-onset VEGF-TKI toxicities that have influenced the ASSURE dropout rate.  (30) 
 
ASSURE employs the UCLA Integrated Staging System (UISS) in determining risk grouping.  
(31)  Intermediate-risk, high-risk, and node-positive patients were eligible for ASSURE, based on 
an analysis of the UCLA database that demonstrated a five year recurrence free rate of 61.8% in 
the intermediate risk group, 41.9% in the high risk group, and 36% in the node-positive group.  
(32)  Although it was expected that 69% of accrued subjects would be intermediate risk and 31% 
would have high-risk or node positive disease (“very high-risk”), actual accrual numbers reveal 
that a full 50% of accrued patients are very-high risk.  (33)  We therefore expect a significant 
proportion of very-high risk patients to be enrolled in this trial, a population in whom mTOR 
inhibition may theoretically be most relevant given its proven effectiveness in metastatic poor 
prognosis patients.  (34)  If that proportion of very-high risk patients is not met, closure of lower 
risk strata will occur to ensure adequate representation.  Similarly, given the potential particular 
activity of mTOR inhibition in non-clear cell histology renal carcinoma, accrual of non-clear cell 
subjects will be ensured by closure of the clear-cell strata if adequate representation is not 
achieved.  (35) 
 
Translational Medicine 
 
Predictive and Prognostic Value of AKT/mTOR Pathway Status in Intermediate and High-Risk, 
Localized Renal Carcinoma 
 
In order to investigate molecular biomarkers relevant to AKT/mTOR pathway inhibition in this trial, 
relevant translational studies are planned.  The overall hypothesis is that patients with RCC 
tumors characterized by AKT/mTOR pathway activation will benefit from mTOR-targeted therapy. 
In light of the paucity of information regarding the role of AKT/mTOR activation in post-
nephrectomy tumor recurrence and survival, it is critical to distinguish between the prognostic 
and/or predictive roles of these biomarkers.  In the context of this Phase III trial, the following 
aims are proposed: 1) To define the status (activation, expression and functional) of factors 
involved in AKT/mTOR signaling in RCC tumor specimens, including AKT, mTOR, S6K, 4EBP1, 
HIFα, vHL, PTEN and other pathway-specific factors.  2) To perform exploratory microarray 
analysis in tumor tissue to identify genes and pathways prognostic for recurrence and/or 
predictive of response to everolimus.  Pathways to be analyzed will include but not be limited to 
PI3K-AKT-mTOR, HIF-1α protein translation and VEGFR-PDGFR (using Ingenuity Pathway 

 
 
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Analysis).  Additionally, levels of tumor-associated plasma proteins from serial draws will be 
examined using multiplex analysis.  3)  To correlate molecular biomarkers with patient outcome, 
including recurrence-free survival and overall survival, and to identify specific cohorts of patients, 
categorized by molecular phenotype, who benefit from everolimus therapy. 
 
The following specimens will be collected for the above studies (further described in Section 
15.0): 1) Tissue specimen: a paraffin embedded nephrectomy block will be collected from all 
consenting patients; 2) blood specimens: (plasma and buffy coats) for correlative studies will be 
collected after registration, but prior to treatment; at the beginning of Cycles 2 and 3; at the end of 
therapy (54 weeks); and at the time of recurrence. 
 
Pharmacodynamic Evaluation of Everolimus in Adjuvant Renal Carcinoma Subjects 
 
Everolimus was originally developed for its immunosuppressant properties in the prevention of 
rejection after solid-organ transplantation.  Chronic daily dosing of an mTOR inhibitor has not 
been studied in an adjuvant cancer population, and potential adverse effects of longer-term 
administration of everolimus need to be carefully assessed.  While this trial will evaluate one year 
of adjuvant therapy, it is possible that longer dosing duration may eventually prove advantageous, 
and understanding and predicting for chronic toxicity is important in this population.  We will 
therefore study adverse effects of everolimus in this study population and determine a 
relationship with steady-state trough levels of the drug. 
 
The published literature on steady-state pharmacokinetics and chronic toxicity has largely been in 
the post-transplant setting in which everolimus has been co-administered with other 
immunosuppressant drugs as part of triple-therapy rejection prophylaxis. (36,37) The applicability 
of this toxicity data to the adjuvant renal carcinoma population is clouded by the potential 
contribution of co-administered immunosuppressant drugs and other factors peculiar to post-
transplant setting.  Since the adjuvant renal carcinoma setting represents a population with 
curative potential, mTOR inhibitor side effects with potential long-term implications are of 
concern, including hyperlipidemia and immunosuppression, which may be a particular issue with 
the daily dosing regimen studied in cancer.  (38) 
 
In renal transplantation patients, steady-state minimum concentrations were well correlated with 
AUC (correlation coefficient [r value] = 0.88).  (39)  A relationship was seen between AUC and 
thrombocytopenia (p=0.03), and there was a positive trend between AUC and both 
hypercholesterolemia and hypertriglyceridemia.  These results suggest that monitoring Cmin may 
serve as a good marker for overall everolimus exposure.  (40)  In the post-transplantation setting, 
trough levels are recommended to be in the desired range of 3 to 8 ng/mL to optimize efficacy 
and decrease the incidence of adverse reactions, although it has been suggested that everolimus 
use with levels of up to 15 ng/mL is manageable.  (41,42)  In Phase I studies in advanced cancer 
patients using 10 mg daily dosing, trough levels exceeded the recommended range for the 
transplant population.  (43,44) 
 
In order to investigate the relationship between steady-state trough concentrations of everolimus 
in adjuvant renal cancer patients and drug toxicity, we will collect specimens to study the 
incidence of lymphopenia, infection, thrombocytopenia, hyperglycemia, hypercholesterolemia, 
hypertriglyceridemia, stomatitis, creatinine elevation, and non-infectious pneumonitis as 
pharmacodynamic markers of everolimus exposure.  Blood sampling for pre-dose trough levels of 
everolimus will be obtained after registration, but prior to treatment; at the beginning of Cycles 2 
and 3; and at the time the patient is removed from protocol treatment.  Everolimus whole-blood 
concentrations 
will 
be 
determined 
via 
high-performance 
liquid 
chromatography/mass 
spectroscopy assay.  Relationships between everolimus steady-state Cmin and the incidence of 
specific toxicities will be explored. 
 
Trough levels of everolimus in post-nephrectomy renal carcinoma patients will correlate with 
toxicity and yield an upper threshold level that can be used in developing a therapeutic range for 
everolimus in the adjuvant population. 

 
 
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Inclusion of Women and Minorities: 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below.  Both men and women of all races and ethnic groups are 
eligible for this study. 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
55 
89 
144 
Not Hispanic or Latino 
436 
957 
1393 
Total Ethnic 
491 
1046 
1537 
Racial Category 
American Indian or Alaskan Native 
1 
4 
5 
Asian 
10 
42 
52 
Black or African American 
29 
42 
71 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
451 
958 
1409 
Racial Category: Total of all Subjects 
491 
1046 
1537 
 
 
3.0 
DRUG INFORMATION 
 
nvestigator's Brochure 
 
For information regarding Investigator’s Brochures, please refer to SWOG Policy 15. 
 
For this study, everolimus is investigational and is being provided under an IND held by SWOG.  
For IND’s filed by SWOG, the protocol serves as the Investigator Brochure for the performance of 
the protocol.  In such instances submission of the protocol to the IRB should suffice for providing 
the IRB with information about the drug.  However, in cases where the IRB insists on having the 
official Investigator Brochure from the company, further information may be requested by 
contacting the SWOG Operations Office at 210/614-8808. 
 
3.1 
Everolimus (RAD001, Afinitor®, Zortress®) (NSC- 733504) (IND-75,093) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Everolimus binds to the cytosolic immunophyllin FKBP12; 
both agents inhibit growth factor-driven cell proliferation, including that of T-cells 
and vascular smooth muscle cells. The everolimus and FKBP12 complex 
selectively inhibits mTOR (mammalian target of rapamycin), an intracellular 
protein kinase implicated in the control of cellular proliferation of neoplastic cells, 
specifically in the progression of cells from G1 to S phase.  Everolimus also 
reduces angiogenesis by inhibiting VEGF and HIF-1 expression. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Everolimus levels peak in 1-3 hours after oral administration. 
There is rapid but moderate absorption.   
 
2. 
Distribution: Everolimus is about 74% protein bound in healthy subjects 
and patients with moderate hepatic impairment.   

 
 
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3. 
Metabolism: Everolimus is extensively metabolized by CYP3A4 and 
forms 6 weak metabolites.  It is also a P-glycoprotein substrate.    
 
4. 
Elimination: Everolimus is extensively eliminated via the bile. The 
elimination half-life of everolimus is about 30 hours and is prolonged in 
patients with hepatic impairment.  Everolimus is primary excreted 
through the feces.   
 
c. 
ADVERSE EFFECTS  
 
1. 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears 
in a separate column and is identified with bold and italicized text. This 
subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/doc
s/aeguidelines.pdf for further clarification. Frequency is provided based 
on 3033 patients. Below is the CAEPR for Everolimus (RAD-001). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER. If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
Version 2.4, July 10, 20171 
 
 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 4.0 Term) 
[n= 3033] 
 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM 
DISORDERS 
 
Anemia 
 
 
Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain  
 
 
Constipation 
 
 
Diarrhea2 
 
 
Diarrhea2 (Gr 2) 
Mucositis oral3 
 
 
Mucositis oral3 (Gr 2) 
 
Nausea 
 
Nausea (Gr 2) 
 
Vomiting 
 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Edema limbs 
 
Edema limbs (Gr 2) 
Fatigue 
 
 
Fatigue (Gr 2) 
 
Fever 
 
Fever (Gr 2) 
 
INFECTIONS AND INFESTATIONS 
 
 
Infection4 
 
Infection4 (Gr 2) 

 
 
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 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 4.0 Term) 
[n= 3033] 
 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS 
 
 
 
Wound 
complication5 
 
INVESTIGATIONS 
 
 
Alanine 
aminotransferas
e increased 
 
Alanine 
aminotransferase 
increased (Gr 2) 
 
Alkaline 
phosphatase 
increased 
 
Alkaline phosphatase 
increased (Gr 2) 
 
Aspartate 
aminotransferas
e increased 
 
Aspartate 
aminotransferase 
increased (Gr 2) 
 
Cholesterol high  
Cholesterol high (Gr 2) 
 
Creatinine 
increased 
 
Creatinine increased 
(Gr 2) 
 
Lymphocyte 
count decreased 
 
Lymphocyte count 
decreased (Gr 2) 
 
Neutrophil count 
decreased 
 
Neutrophil count 
decreased (Gr 2) 
 
Platelet count 
decreased 
 
Platelet count 
decreased (Gr 2) 
 
Weight loss 
 
 
 
White blood cell 
decreased 
 
White blood cell 
decreased  
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
 
Hyperglycemia6  
Hyperglycemia6 (Gr 2) 
 
Hypertriglyceride
mia 
 
Hypertriglyceridemia 
(Gr 2) 
 
Hypophosphate
mia 
 
Hypophosphatemia (Gr 
2) 
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
Back pain 
 
 
 
Pain in extremity  
 
NERVOUS SYSTEM DISORDERS 
 
 
Dysgeusia 
 
 
 
Headache 
 
Headache (Gr 2) 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney 
injury 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Cough 
 
Cough (Gr 2) 

 
 
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 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 4.0 Term) 
[n= 3033] 
 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
 
Dyspnea 
 
Dyspnea (Gr 2) 
 
Epistaxis 
 
Epistaxis (Gr 2) 
 
Pneumonitis7 
 
 
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS 
 
 
Dry skin 
 
 
 
Pruritus 
 
 
Rash maculo-
papular 
 
 
Rash maculo-papular 
(Gr 2) 
 
 
Skin and 
subcutaneous 
tissue disorders 
- Other 
(angioedema)8 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, 
and steatorrhea. 
3 Includes 
stomatitis, 
aphthous 
stomatitis, 
gingival 
pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth 
ulceration, tongue ulceration, and mucosal inflammation. 
4 Infection includes all 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
5 Everolimus delays wound healing and increases the occurrence of 
wound-related complications like wound dehiscence, wound infection, 
incisional hernia, lymphocele, and seroma. 
6 Hyperglycemia may result in either exacerbation of or development of 
new onset diabetes mellitus. 
7 Includes pneumonitis, interstitial lung disease, lung infiltration, 
pulmonary 
alveolar 
hemorrhage, 
pulmonary 
toxicity, 
alveolitis, 
pulmonary fibrosis, and restrictive pulmonary disease. 
8 Patients taking concomitant ACE inhibitor therapy may be at increased 
risk for angioedema. 
9 Includes agitation, anxiety, panic attack, aggression, abnormal 
behavior, and obsessive compulsive disorder. 
 
Adverse events reported on Everolimus (RAD-001) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that Everolimus (RAD-001) caused the 
adverse event: 

 
 
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BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and 
lymphatic system disorders - Other (thrombotic microangiopathy) 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other 
(myocardial abnormality); Chest pain - cardiac; Heart failure; Left 
ventricular systolic dysfunction; Myocardial infarction; Sinus bradycardia; 
Sinus tachycardia; Supraventricular tachycardia 
ENDOCRINE DISORDERS - Endocrine disorders - Other (increased 
blood follicle stimulating hormone [FSH] levels); Endocrine disorders - 
Other (increased blood luteinizing hormone [LH] levels); Endocrine 
disorders - Other (low testosterone); Hypothyroidism 
EYE DISORDERS - Blurred vision; Conjunctivitis; Keratitis 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; 
Dyspepsia; Dysphagia; Flatulence; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (Dieulafoy's lesion); Hemorrhoids; 
Intra-abdominal hemorrhage; Oral pain; Pancreatitis; Periodontal 
disease; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Chills; Edema face; Edema trunk; Flu like symptoms; Irritability; Non-
cardiac chest pain; Pain 
HEPATOBILIARY 
DISORDERS 
- 
Hepatic 
failure; 
Hepatobiliary 
disorders - Other (hepatomegaly) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; 
Blood bilirubin increased; CPK increased; GGT increased; INR 
increased; Investigations - Other (bicarbonate decreased); Investigations 
- Other (increased lactate dehydrogenase); Investigations - Other (low 
density lipoprotein raised); Investigations - Other (thrombocythemia) 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Glucose 
intolerance; 
Hypercalcemia; 
Hyperkalemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypokalemia; 
Hypomagnesemia; 
Hyponatremia; 
Metabolism and nutrition disorders - Other (high ammonia); Metabolism 
and nutrition disorders - Other (hyperlipidemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Bone pain; Chest wall pain; Generalized muscle weakness; Muscle 
weakness lower limb; Musculoskeletal and connective tissue disorder - 
Other (muscle spasms); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (ovarian cysts) 
NERVOUS SYSTEM DISORDERS - Dizziness; Encephalopathy; 
Hydrocephalus; Lethargy; Paresthesia 
PSYCHIATRIC DISORDERS - Agitation; Anxiety9; Delirium; Depression; 
Insomnia; Mania 
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Urinary 
frequency 
REPRODUCTIVE 
SYSTEM 
AND 
BREAST 
DISORDERS 
- 
Dysmenorrhea; Genital edema; Irregular menstruation; Menorrhagia; 
Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchopulmonary 
hemorrhage; 
Pharyngolaryngeal 
pain; 
Pleural 
effusion; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (rales); Respiratory, thoracic and mediastinal disorders 
- Other (rhinorrhea); Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Palmar-
plantar erythrodysesthesia syndrome; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (nail disorder); Skin and 
subcutaneous tissue disorders - Other (skin lesion); Skin ulceration 

 
 
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VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; 
Phlebitis; Thromboembolic event; Vascular disorders - Other (acute 
bowel ischemia); Vascular disorders - Other (hemorrhage) 
 
Note: Everolimus (RAD-001) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
2. 
Pregnancy and Lactation: Pregnancy category D.  It is not known if 
everolimus is excreted in human milk. 
 
Drug Interactions: Everolimus is a substrate of cytochrome P450 3A4 
(CYP3A4) and also a substrate and moderate inhibitor of the multidrug 
efflux pump P-glycoprotein (PgP).  In vitro, everolimus is a competitive 
inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Due to the 
extensive number of everolimus drug interactions, a complete patient 
medication list, including everolimus, should be screened prior to 
initiation of everolimus (as indicated in Section 7.3 and Appendix 18.3). 
 
Patients taking concomitant angiotensin converting enzyme (ACE) 
inhibitor therapy may be at increased risk for angioedema (e.g. swelling 
of the airways or tongue, with or without respiratory impairment). 
 
3. 
Hepatic Impairment: Dosage adjustment of everolimus is recommended 
in moderate hepatic impairment (Child-Pugh class B). Contact the Study 
Chair for guidance. Use of everolimus is not recommended in severe 
hepatic impairment (Child-Pugh class C).  
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Treatment Plan (see Section 7.2) 
 
2. 
Everolimus (or matching placebo) should be administered orally, once 
daily preferably in the morning with a glass of water and no more than a 
light fat-free meal. Tablets should be swallowed whole with a glass of 
water. Grapefruit or citrus juices should be avoided. The tablets must not 
be chewed or crushed. If unable to swallow whole tablet, may disperse 
tablet completely in 30 mL water and drink immediately; rinse container 
with additional 30 mL water and swallow.  
 
e. 
STORAGE & STABILITY 
 
The intact blister packs should be stored at controlled room temperature (15°-
30°C) and protected from light. Current stability data permit shelf life of 24 
months for 5 mg tablet variant based on solid dispersion dried by paddle dryer 
and 36 months for 5 mg tablet variant based on solid dispersion dried by 
evaporation/drying oven if stored below 30°C in the original double sided 
aluminum blister and protected from light and moisture. 
 
f. 
HOW SUPPLIED  
 
1. 
Everolimus or matching placebo will be supplied as tablets blister-packed 
under aluminum foil in units of 10 tablets. Blisters should be opened only 
immediately prior to ingestion as the drug is both hygroscopic and light-
sensitive. 
 

 
 
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Everolimus or matching placebo 5 mg tablets are white to slightly yellow, 
elongated tablets with a beveled edge and no score, engraved with “5” 
on one side and “NVR” on the other. 
 
Everolimus is commercially available, however it is considered 
investigational for this study. Everolimus 5 mg tablets and placebo to 
match everolimus 5 mg tablets will be supplied by Novartis 
Pharmaceuticals Corporation and will be distributed by the Department 
of Veterans Affairs Cooperative Studies Program Clinical Research 
Pharmacy Coordinating Center (PCC). Each participating Institution must 
have a Pharmacy ID Number, in addition to their Institution Number, 
before randomization of subjects can begin. SWOG institutions already 
have a pharmacy associated with them, so they do not need to report a 
Pharmacy ID number since that information is already linked in the 
SWOG database. However, Institutions registering via CTSU must be 
assigned a pharmacy ID number by the PCC. With the initial and each 
subsequent randomization, the Institution registering via CTSU will be 
required to provide their Institution’s Pharmacy ID Number. No 
randomizations can be completed without a Pharmacy ID Number. For 
CTSU Participating Institutions, each Institution must call the PCC at 
(505) 248-3203 to register their Institution with the PCC and receive a 
Pharmacy ID Number. This registration by CTSU Participating 
Institutions with the PCC must be completed at least 1 working day 
prior to the randomization of the first subject at the site or 
randomization of the first subject will have to be postponed. When calling 
the PCC, the caller will be asked which study they are calling in regards 
to. To facilitate the caller being transferred to the correct PCC staff, the 
caller should indicate the “SWOG protocol “S0931”, “EVEREST”, or 
“P261” (the PCC internal number for the study). To register an Institution, 
the PCC will require: 
 
• 
the name of the receiving individual, 
• 
complete street address, and phone number, 
• 
e-mail address of the receiving individual. 
 
Everolimus or matching placebo will be packaged by the PCC and 
supplied to the Institutions in kits of 10 blister cards, with each kit 
containing sufficient drug for one cycle of treatment. No supply of 
unassigned everolimus or matching placebo will be maintained at the 
institutions. Rather everolimus or matching placebo will be supplied to 
the site in a “just in time” manner. Upon notification of a 
randomization by the SWOG Statistical Center, the PCC will ship the 
first patient-specific kit to an Institution to arrive within four 
working days. Each kit will be labeled specifically for an individual 
subject with the subject’s SWOG Patient Number. 
 
Subsequent patient-specific kits will automatically be shipped to the 
Institution approximately mid-cycle of Cycles 1-8. The blister card and 
kits labels will be permanently attached. The site will write down the kit 
numbers on the Drug Accountability Record Form when the kit is 
dispensed.  
 
If a subject requires a replacement kit (Emergency Kit) for lost (etc.) 
medication, an Emergency Kit should be supplied by calling the PCC at 
505/248-3203. 
 
Prior to dispensing the next kit of study medication, or at the study visit at 
the end of everolimus or placebo treatment, the old blister cards and any 

 
 
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unused tablets are to be collected from the subjects and quantity 
remaining logged on to the Drug Accountability Records. Any unused, 
partially used, or expired study drug remaining when a subject goes off 
treatment should be destroyed on-site in accordance with local 
institutional policy. In the event that a site does not have documented 
destruction procedures in place, call PCC at (505/248-3203 for 
instructions on how to return leftover study drug.  
 
2. 
Drug Handling and Accountability  
 
a. 
Drug accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, dispensing, and destruction of all study drugs 
received from the distributor using the NCI Oral Drug 
Accountability Record Form (NCI Oral DARF), available at 
http://ctep.cancer.gov. A separate record must be maintained for 
each patient on this protocol.  
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI Oral 
DARF.  
 
3. 
Drug Return and/or Disposition Instruction  
 
a. 
Drug Returns: All unused drug, unopened and unused blister 
cards remaining when a subject goes off treatment, and expired 
blister cards should be destroyed on-site in accordance with 
institutional policy. Partially used blister cards with remaining 
tablets 
should 
be 
documented 
in 
the 
patient-specific 
accountability record (i.e., logged in as "# of tablets returned") 
and destroyed on-site in accordance with institutional policy. 
 
b. 
Drug Transfers: Blister cards MAY NOT be transferred from one 
patient to another patient or from one protocol to another 
protocol. All other transfers (e.g. a patient moves from one 
participating institution to another participating institution) must 
be approved in advance by calling the PCC at (505) 248-3203. 
 
Contact Information: Questions about drug orders, transfers, returns or 
accountability should be addressed to the PCC at (505) 248-3203. 
 
4.0 
STAGING CRITERIA 
 
DEFINITION OF TNM (AJCC Seventh Edition, 2010) 
 
Primary Tumor (T) 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
T1 
Tumor 7 cm or less in greatest dimension, limited to the kidney 
T1a 
Tumor 4 cm or less in greatest dimension, limited to the kidney 
T1b 
Tumor more than 4 cm but not more than 7 cm in greatest dimension, limited to 
the kidney 
T2 
Tumor more than 7 cm in greatest dimension, limited to the kidney 
T2a 
Tumor more than 7 cm but less than or equal to 10 cm in greatest dimension, 
limited to the kidney 
T2b 
Tumor more than 10 cm, limited to the kidney 

 
 
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T3 
Tumor extends into major veins or perinephric tissues, but not into the ipsilateral 
adrenal gland and not beyond Gerota's Fascia 
T3a 
Tumor grossly extends into the renal vein or its segmental (muscle containing) 
branches, or tumor invades perirenal and/or renal sinus fat but not beyond 
Gerota's Fascia 
T3b 
Tumor grossly extends into the vena cava below the diaphragm 
T3c 
Tumor grossly extends into the vena cava above the diaphragm or invades the 
wall of the vena cava 
T4 
Tumor invades beyond Gerota's Fascia (including contiguous extension into the 
ipsilateral adrenal gland). NOTE:  Non-contiguous adrenal lesion is considered 
M1 disease and not eligible for protocol participation. 
 
Regional Lymph Nodes (N) 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in regional lymph node(s) 
 
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
 
HISTOLOGIC GRADE (G) 
 
GX 
Grade cannot be assessed 
G1 
Well differentiated 
G2 
Moderately differentiated 
G3 
Poorly differentiated 
G4 
Undifferentiated 
 
PATHOLOGIC STAGE 
 
Intermediate High-Risk Group 
 
pT1b  
G3-4, N0 (or pNX where clinically N0), M0 
pT2a-b 
G1-2, N0 (or pNX where clinically N0), M0 
pT2 a-b 
G3-4, N0 (or pNX where clinically N0), M0 
pT3a 
G1-2, N0 (or pNX where clinically N0), M0 
 
Microvascular invasion of the renal vein of pT1a-pT3a (as long as pT3a is Grade 1-2) N0 (or pNX 
where clinically N0) M0 
 
Very High Risk Group 
 
pT3a 
G3-4, N0 (or pNX where clinically N0), M0 
pT3b-c 
G any, N0 (or pNX where clinically N0), M0 
pT4 
G any, N0 (or pNX where clinically N0), M0 
pT any  
G any, N+ (fully resected), M0 
 
Microvascular invasion of the renal vein with above other characteristics 
 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S0931 Prestudy Form and submit to the Data 

 
 
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Operations Center in Seattle (see Section 14.0).  Any potential eligibility issues should be addressed to 
the Data Operations Center in Seattle at guquestion@crab.org or 206/652-2267 prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 2 weeks later would be considered Day 14.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 14, 28, 42, or 84 falls on 
a weekend or holiday, the limit may be extended to the next working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have histologically or cytologically confirmed renal cell carcinoma 
(clear cell or non-clear cell allowed, but collecting duct or medullary carcinomas 
excluded). Patients must be considered pathologically either Intermediate High 
Risk or Very High Risk as defined in Section 4.0.  Patients must not have a 
history of distant metastases.  Patients with microvascular invasion of the renal 
vein of any grade or stage (as long as M0) are also eligible. 
 
b. 
Patients must have undergone a full surgical resection (radical nephrectomy or 
partial nephrectomy), including removal of all clinically positive nodes.  Surgical 
margins must be negative.  Patients with positive renal vein margins are eligible 
unless there is invasion of the renal vein wall at the margin (provided no other 
margins are positive).  Patients must plan to start study drug within 84 days after 
the date of full surgical resection. Patients must have recovered from any 
surgical related complications. 
 
c. 
Patients with bilateral renal tumors are eligible provided both tumors have 
undergone full surgical resection and at least one of the tumors meets all 
eligibility criteria in Sections 5.1a-b.  Patients must plan to start study drug within 
84 days after the date of the resection of the first tumor. 
 
d. 
Patients must not have any evidence of residual or metastatic renal cell cancer 
on CT scan of the chest, abdomen, and pelvis, all with oral and IV contrast after 
nephrectomy and within a maximum of 28 days prior to registration. An MRI scan 
of the abdomen/pelvis with gadolinium and a non-contrast CT of the chest is an 
acceptable imaging alternative.  Non-contrast CT of the chest/abdomen/pelvis 
should only be performed if, in the opinion of the investigator, it is in the best 
medical interest of the patient to not receive IV contrast of any form.  NOTE:  
PET/CT is not an acceptable imaging alternative. Patients who display 
subcentimeter pulmonary nodules (by CT scan) that are non-specific and 
considered unlikely to represent metastatic disease by the treating investigator 
will be considered eligible. 
 
5.2 
Prior Therapy Criteria 
 
a. 
Patients must not have received any prior anti-cancer therapy (except for radical 
or partial nephrectomy noted above) for renal cell carcinoma, including systemic 
therapy in the adjuvant or neoadjuvant setting, immunotherapy, investigational 
therapy, surgical metastaticity, or radiation therapy. 
 
b. 
Patients must not be planning to receive other anti-cancer agents including 
investigational agents while on protocol treatment. 
 
c. 
Patients must not be receiving chronic, systemic treatment with corticosteroids or 
other immunosuppressive agent.  Topical or inhaled corticosteroids are allowed. 
 
d. 
Patients must not have received immunization with an attenuated live vaccine 
within seven days prior to registration nor have plans to receive such vaccination 
while on protocol treatment. 

 
 
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e. 
Patients must not be taking, nor plan to take while on protocol treatment, strong 
CYP3A4 inhibitors, (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, 
fluvoxamine, nefazodone, nelfinavir, ritonavir) and/or strong CYP3A4 inducers 
(e.g. phenytoin, rifampin, rifabutin) within 14 days prior to randomization.  
(Moderate inhibitors or inducers of isoenzyme CYP3A4 should be avoided, but if 
necessary can be used with caution.  See Section 7.1c.) 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have a complete physical examination and medical history within 
28 days prior to registration. 
 
b. 
Patients must not have any Grade III/IV cardiac disease as defined by the New 
York Heart Association Criteria (i.e., patients with cardiac disease resulting in 
marked limitation of physical activity or resulting in inability to carry on any 
physical activity without discomfort), unstable angina pectoris, myocardial 
infarction within 6 months, or serious uncontrolled cardiac arrhythmia.  See 
Appendix 18.1. 
 
c. 
Patients must not have any known uncontrolled underlying pulmonary disease 
(e.g. FEV1 or DLCO 50% or less of predicted OR O2 saturation 88% or less at 
rest on room air). 
 
d. 
Patients must not have any known hypersensitivity to everolimus or other 
rapamycins (sirolimus, temsirolimus) or to its excipients. 
 
e. 
Patients must have absolute neutrophil count (ANC) ≥ 1,500/mcL, platelet count ≥ 
100,000/mcL and hemoglobin ≥ 9.0 g/dl obtained within 28 days prior to 
registration. 
 
f. 
Patients must have serum creatinine ≤ 2.0 x upper limit of normal (ULN) or 
calculated creatinine clearance (CrCl) ≥ 30mL/min obtained within 28 days prior 
to registration. 
 
Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
72 x creatinine (mg/dl) 
 
g. 
Patients must have bilirubin ≤ 1.5 x ULN, and SGOT and SGPT ≤ 2.5 x ULN 
obtained within 28 days prior to registration. 
 
h. 
Patients must NOT have liver disease such as cirrhosis or severe hepatic 
impairment (Child-Pugh Class C).  NOTE:  A detailed assessment of Hepatitis 
B/C medical history and risk factors must be done at screening for all patients.  
HBV and HCV testing are required at screening for all patients with a positive 
medical history based on risk factors and/or confirmation of prior HBV/HCV 
infection.  (See Section 9.0 for testing information and Section 8.6 for 
management of patients with positive testing.) 
 
i. 
Patients must not have a known history of HIV seropositivity. 
 
j. 
Patients must not have uncontrolled hyperlipidemia (fasting serum cholesterol 
>300 mg/dL AND fasting triglycerides > 2.5 x ULN) obtained within 28 days prior 
to registration.  Optimal lipid control must be achieved before registration and 
monitored during protocol treatment (see Section 8.4b). 
 
k. 
Patients must not have uncontrolled diabetes mellitus (defined by fasting serum 
glucose > 1.5 x ULN) obtained within 28 days prior to registration.  Optimal 

 
 
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glucose control must be achieved before registration and monitored during 
protocol treatment (see Section 8.4b). 
 
l. 
Patients must be able to take oral medications.  Patient may not have any 
impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of everolimus (e.g. ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel 
resection). 
 
m. 
Patients must have a Zubrod Performance Status of 0 or 1 (see Section 10.3). 
 
n. 
All patients must be 18 years of age or older. 
 
o. 
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease-free for 5 
years. 
 
p. 
Patients must not be pregnant or nursing due to animal studies that have shown 
reproductive toxicity effects.  Women/men of reproductive potential must have 
agreed to use an effective contraceptive method during protocol treatment and 
up to 8 weeks after ending protocol treatment.  A woman is considered to be of 
"reproductive potential" if she has had menses at any time in the preceding 12 
consecutive months.  In addition to routine contraceptive methods, "effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.  However, if at 
any point a previously celibate patient chooses to become heterosexually active 
during the time period for use of contraceptive measures outlined in the protocol, 
he/she is responsible for beginning contraceptive measures. 
 
5.4 
Translational Medicine Criteria 
 
a. 
Patients must be offered the opportunity to participate in specimen banking for 
future use to include the translational medicine studies outlined in Section 15.0. 
 
5.5 
Regulatory Criteria 
 
a. 
All patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and 
federal guidelines. 
 
b. 
As part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered into the data base. 
 

 
 
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6.0 
STRATIFICATION FACTORS 
 
Patients will be randomized using a dynamic balancing algorithm (45) with stratification based on: 
 
a. 
Risk group based on pathologic stage (intermediate high-risk vs very high risk) 
(see Section 4.0), 
 
b. 
Histology (clear cell vs non-clear cell); (NOTE:  The tumor will be classified as 
clear cell if any component of clear cell histology is identified in the specimen.) 
 
c. 
Performance status (0 vs 1). 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification related questions, please contact Dr. Christopher Ryan at 
503/494-8487 or Dr. Elisabeth Heath at 313/576-8715.  For dosing principles or questions, please 
consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org 
(then click on "Policies and Manuals" under the "Visitors" menu and choose Policy #38). 
 
7.1 
Good Medical Practice 
 
The following tests (and/or assessments) are recommended within 28 days prior to 
registration in accordance with Good Medical Practice.  Results of these tests do not 
determine eligibility and minor deviations from normal limits would be acceptable if they 
do not affect patient safety in the clinical judgment of the treating physician.  If there are 
significant deviations in these tests/assessments that could impact on patient safety, it is 
highly recommended that the registering investigator discuss the patient with the Study 
Chair prior to registering. 
 
a. 
Patients should not have an uncontrolled intercurrent illness including, but not 
limited 
to 
active 
bleeding 
diathesis, 
uncontrolled 
infection/disorders, 
nonmalignant medical illnesses that are uncontrolled or whose control may be 
jeopardized by the treatment with the study therapy, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
b. 
Testing for hepatitis B viral load and serologic markers: HBV-DNA, HBsAg, HBs 
Ab, and HBc Ab should be performed at screening for all patients with the 
following risk factors (see Section 7.3 and 8.6): 
 
• 
Patients who currently live in (or have lived in) Asia, Africa, Central and 
South America, Eastern Europe, Spain, Portugal, and Greece. 
• 
known or suspected past hepatitis B infection, 
• 
blood transfusion(s) prior to 1990, 
• 
current or prior IV drug users, 
• 
current or prior dialysis, 
• 
current or prior high-risk sexual activity, 
• 
body piercing (other than ear piercing) or tattoos, 
• 
mother known to have hepatitis B 
• 
history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right 
upper quadrant pain. 
• 
Additional patients at the discretion of the investigator 
• 
household contact with hepatitis B infected patient(s), 
 
Testing for hepatitis C should be performed using quantitative RNA-PCR at 
screening for patients with the following risk factors (see Section 8.6): 
 

 
 
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• 
known or suspected past hepatitis C infection (including patients with past 
interferon ‘curative’ treatment), 
• 
blood transfusions prior to 1990, 
• 
current or prior IV drug users, 
• 
current or prior dialysis, 
• 
household contact of hepatitis C infected patient(s), 
• 
current or prior high-risk sexual activity, 
• 
body piercing other than ear piercing or tattoos, 
• 
Additional patients at the discretion of the investigators 
 
c. 
Coadministration of moderate CYP3A4 inhibitors (such as erythromycin, 
fluconazole, calcium channel blockers, benzodiazepines) and inducers (such as 
bamazepine, phenobarbital) should be avoided if possible, or used subject to 
caution. Coadministration with substrates, inducers, or inhibitors of P-
glycoprotein should be avoided if possible, or used subject to caution.  See 
Appendix 18.3.  Grapefruit and grapefruit juice affect cytochrome P450 and P-
glycoprotein activity and should be avoided. 
 
d. 
Alkaline phosphatase obtained. 
 
7.2 
Treatment Schedule 
 
All patients will be randomized to receive either everolimus or placebo daily for nine, six 
week cycles. 
 
AGENT 
DOSE 
ROUTE 
DAYS 
DURATION 
 
Everolimus or 
10 mg 
Oral 
Every Day 
378 days 
Matched Placebo 
(two 5 mg 
 
 
(54 weeks) 
 
Tablets) 
 
* Everolimus (or matched placebo) tablets are supplied as 5 mg tablets.  
 
Everolimus must be administered orally, once daily preferably in the morning with a glass 
of water and no more than a light fat-free meal. Tablets must be swallowed whole with a 
glass of water. The tablets must not be chewed or crushed, and grapefruit or citrus juices 
should be avoided.   
 
A cycle of treatment is six weeks.  Assessment for the primary endpoint (recurrence) 
must occur after every three cycles (18 weeks) for 54 weeks, then every six months for 
two years, and then annually thereafter until recurrence, death, or 10 years after 
registration, whichever comes first (regardless whether patient is still on active protocol 
treatment).  Recurrence assessments consist of physical exams and CT scans. 
 
Radiographic assessment for pneumonitis must be undertaken as per Section 8.4c. 
 
7.3 
Concomitant Therapy 
 
All medications taken other than study drugs and significant non-drug therapies (including 
physical therapy and blood transfusions) must be recorded. If concomitant therapy must 
be added or changed, the reason and name of the drug/therapy must be documented in 
the "comments" section of the S0931 Treatment Form. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the 
care of the patient are allowed, including drugs given prophylactically (e.g. antiemetics ± 
steroids), with the following exceptions: 
 
 

 
 
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• 
No other investigational therapy must be given to patients. 
• 
No chronic treatment with systemic steroids or another immunosuppressive agent.  
Topical or inhaled corticosteroids are allowed. 
• 
No anticancer agents other than the study medications administered as part of this 
study protocol must be given to patients. If such agents are required for a patient 
then the patient must be withdrawn from protocol treatment.  
• 
Growth factors (e.g. G-CSF, G-GM-CSF, erythropoietin, platelets growth factors etc.) 
are not to be administered prophylactically but may be prescribed by the treating 
physician for rescue from severe hematologic events.  
• 
Live vaccines must not be administered to patient due to immunosuppressant 
potential of everolimus.    
• 
Drugs known to be strong inhibitors or inducers of the isoenzyme CYP3A4 must not 
be administered as systemic therapy (see Section 5.2e).  Drugs or substances known 
to be moderate inhibitors or inducers of CYP3A (see Appendix 18.3) should be 
avoided if possible or used subject to caution as these can alter everolimus 
metabolism.  Co-administration with strong or moderate inhibitors of P-glycoprotein 
(PgP) (see Appendix 18.3) should be avoided if possible, or used subject to caution 
Seville orange, star fruit, grapefruit and their juices affect P450 and PgP activity.  
Concomitant use should be avoided. 
• 
It is highly recommended that patients positive HBV-DNA or HBsAg are treated 
prophylactically with an antiviral for 1-2 weeks prior to receiving study drug (see 
Section 8.5).  
• 
The antiviral treatment should continue throughout the entire study period and for at 
least 4 weeks after the last dose of study drug.  
• 
Patients on antiviral prophylaxis treatment or positive HBV antibodies should be 
tested for HBV-DNA according to study visit schedule (See Section 8.6 and 9.0). 
 
7.4 
Intake Calendar  
 
Everolimus drug compliance will be recorded on a treatment Intake Calendar (see 
Appendix 18.4).  Institutional CRAs will review and ascertain patient adherence with 
protocol therapy at the end of treatment for each cycle.  Calendar should be kept in the 
patient's clinic chart.  Sites utilizing the CIRB must use the Intake Calendar provided.  
Sites not utilizing the CIRB may use institutional pill diaries or other source 
documentation in place of Intake Calendar at the discretion of the treating physician. 
 
7.5 
Unblinding Procedures 
 
The procedures for emergency unblinding are outlined in Appendix 18.2.  Patients who 
have recurrence of disease as defined in Section 10.1 have the option to be unblinded in 
planned fashion, as described in this section.  Emergency unblinding will be done for 
anything other than recurrence as defined in Section 10.1.  Patients who undergo 
optional treatment unblinding and are found to have been randomized to “placebo” will 
not receive investigationally-supplied everolimus.  Novartis Pharmaceutical Corporation 
will NOT provide investigational supplies of everolimus once a patient has been 
unblinded. 
 
a. 
Criteria for Planned Unblinding: 
 
The planned unblinding procedure applies to patients who experience recurrence 
as defined in Section 10.1.  It is vital to properly apply the protocol specified 
definition of recurrence.  If any questions arise with regard to recurrence for a 
patient, please contact the GU Data Coordinator in Seattle by e-mail at 
guquestion@crab.org or by telephone at 206/652-2267, 6:30 a.m. to 4:00 p.m. 
Pacific Time, Monday through Friday, excluding holidays. 
 
 
Prior to requesting a planned unblinding, the following forms must be submitted 
and processed by the SWOG Data Operations Office: 

 
 
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Off Treatment Notice 
S0931 Recurrence Assessment Form 
Radiology report(s) supporting recurrence (see Section 10.1) 
Pathology report(s) supporting recurrence (see Section 10.1) 
 
Please submit all required forms to the SWOG Data Operations Center 
(guquestion@crab.org) with the subject line “S0931 Patient #XXXXXX, 
Requesting Planned Unblinding”.  Please allow a minimum of 2 working days for 
review of forms.   
 
Dr. Ryan (or Heath) will provide a written confirmation to the site that the patient 
has an adequately documented recurrence.  This documentation should be 
placed in the patient’s chart. 
 
b. 
Planned Unblinding Procedures 
 
You may unblind patients at time of disease recurrence from Member, Affiliate, 
and CCOP institutions to a Therapeutics study using the SWOG planned 
unblinding program.  To access the planned unblinding program go to the SWOG 
Web site (http://swog.org) and click on the Logon link to go to the SWOG 
Members Area logon page (https://swog.org/members/logon.asp).  This Web 
program is available at any time except for periods listed under Down Times.  
Log on as an Individual User using your SWOG Roster ID Number and individual 
web user password.  Help for the logon process may be found at 
https://swog.org/members/logonhelp.asp.  After you have logged on, click on the 
Workbenches link, then the CRA Workbench link, and then the Planned 
Unblinding link.  Go to the Entry Page for the Planned Unblinding program.  The 
CRA must have the SWOG ID number, initials, and investigator number available 
for the unblinding. 
 
To unblind a patient at disease recurrence, you must meet the following criteria 
(in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number. 
 
2. 
You are associated as an investigator or CRA/RN to the institution where 
a planned unblinding is occurring. 
 
3. 
You are granted permission to use the Planned Unblinding program at 
that institution. 
 
For assistance with points 1 and 2 call the SWOG Operations Office at 210/614-8808.  
For point 3 you must contact your Web User Administrator.  Each SWOG institution has 
one or more Web User Administrators who may set up Web Users at their institution and 
assign permissions and passwords to these users. 
 
Non-SWOG sites may unblind patients at time of disease recurrence using the following 
url:  https://crawb.crab.org/TXWB/ctsulogon.aspx. 
 
If the Web Planned Unblinding program is not used, the planned unblinding must be done 
by phone. 
 
Member, Affiliate and CCOP Institutions 
 
Planned unblinding by phone of patients from Member, Affiliate and CCOP institutions 
must be done through the SWOG Data Operations Center in Seattle by telephoning 

 
 
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206/652-2267, 6:30 a.m. to 4:00 p.m. Pacific Time, Monday through Friday, excluding 
holidays. 
 
NOTE:  When unblinding S0931 patients in the SWOG Planned Unblinding Program 
leave “Bottle ID” field blank. 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
Recurrence of disease or symptomatic deterioration (as defined in Section 10.0).  
If the patient has documented recurrence as defined in Section 10.1, unblinding 
of study treatment as outlined in Section 7.5 may be requested. 
 
b. 
Unacceptable toxicity defined as any toxicity requiring discontinuation of study 
drug per Section 8.0. If a patient is removed from protocol treatment due to 
toxicity, he/she must continue to be followed for recurrence according to the 
same schedule as detailed in Sections 7.2 and 9.0 (every 4 months [18 weeks] 
during Year 1 (regardless whether patient is still on active protocol treatment), 
then every six months for Years 2 and 3, and then annually thereafter until 
recurrence, death, or 10 years after registration, whichever comes first.  
Recurrence assessments consist of physical exams and CT scans) 
 
c. 
Delay in protocol treatment > 21 days due to pneumonitis or > 28 days due to 
any other reason.  If a patient is removed from protocol treatment due to toxicity, 
the must continue to be followed for recurrence according to the same schedule 
as detailed in Sections 7.2 and 9.0 (every 4 months [18 weeks] during Year 1 
(regardless whether patient is still on active protocol treatment), then every six 
months for two years, and then annually thereafter until recurrence, death, or 10 
years after registration, whichever comes first.  Recurrence assessments consist 
of physical exams and CT scans) 
 
d. 
Completion of nine cycles of protocol treatment. 
 
e. 
The patient may withdraw from the study at any time for any reason. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the study forms. 
 
7.8 
Follow-Up Period 
 
All patients will be followed for a maximum of 10 years after registration or until death 
(whichever occurs first) for recurrence and survival. 
 
 
8.0 
DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.0. 
 
8.2 
General Dose Modification Considerations  
 
a. 
Missed doses are to be omitted rather than made up. 
 
b. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction. 
 

 
 
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c. 
Reductions are based on the dose given in the preceding cycle and are based on 
toxicities observed since the prior toxicity evaluation. 
 
d. 
Once dose is reduced, patients will continue at new dose.  No dose re-
escalations are allowed. 
 
e. 
If protocol treatment is held > 21 days for pneumonitis or > 28 days due to any 
other reason, patient should be removed from protocol treatment. 
 
8.3 
Everolimus Dose Levels 
 
Dose Levels 
Dose 
 
 
Full 
10 mg daily (two 5 mg tablets) 
 
-1 Level 
5 mg daily 
 
-2 Level 
5 mg every other day 
 
-3 Level 
Discontinue study drug 
 
 
8.4 
Everolimus Dose Modifications  
 
NOTE: NO DOSE ESCALATION OR RE-ESCALATION IS ALLOWED. 
 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except pneumonitis – see 
8.4.c) 
(except hyperlipidemia – see 
8.4.b)* 
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 Grade ≤ 1. Then reintroduce everolimus at one 
lower dose level. 
 
Grade 3 
(except pneumonitis – see 
8.4.c) 
(except hyperlipidemia – see 
8.4.b)* 
Interrupt everolimus until recovery to Grade ≤ 1. Then 
reintroduce everolimus at one 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 same dose. 
If thrombocytopenia again returns to Grade 2, interrupt 
everolimus until recovery to Grade ≤1. Then reintroduce 
everolimus at one lower dose level. 
 
Grade 3 Thrombocytopenia 
(platelets < 50, ≥ 25x109/L) 
Interrupt everolimus until recovery to Grade ≤ 1 (platelets ≥ 
75 x109/L).  Then resume everolimus at one lower dose 
level.  If Grade 3 thrombocytopenia recurs, discontinue 
everolimus. 
 
Grade 4 Thrombocytopenia 
(platelets < 25 x109/L) 
Discontinue everolimus. 

 
 
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Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 3 Neutropenia 
(neutrophils < 1, ≥ 0.5 
x109/L) 
Interrupt everolimus until recovery to Grade ≤1 ( 
neutrophils ≥ 1.5 x 109/L). Then resume everolimus at the 
same dose.  If ANC again returns to Grade 3, hold 
everolimus until the ANC ≥ 1.5 x 109/L.  Then resume 
everolimus at one lower dose level.  Discontinue patient 
from study therapy for a third episode of Grade 3 
neutropenia. 
 
Grade 4 Neutropenia 
(neutrophils < 0.5 x109/L) 
Interrupt everolimus until recovery to Grade ≤ 1 
(neutrophils ≥ 1.5 x 109/L). Then resume everolimus at one 
lower dose level. If Grade 3 or Grade 4 neutropenia occurs 
despite this dose reduction, discontinue everolimus. 
Grade 3 febrile neutropenia 
(not life-threatening) 
Interrupt everolimus until resolution of fever and 
neutropenia to Grade ≤ 1. Hold further everolimus until the 
ANC ≥ 1,500/mm3 and fever has resolved. Then resume 
everolimus at one lower dose level. If febrile neutropenia 
recurs, discontinue everolimus. 
Grade 4 febrile neutropenia 
(life-threatening) 
Discontinue everolimus. 
* Grade 2-3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be 
managed using medical therapies (see Section 8.4b). 
 
If a patient requires a dose delay of > 21 days for pneumonitis or > 28 days for any other 
reason from the intended day of the next scheduled dose, then the patient must be 
removed from the protocol treatment. 
 
a. 
Hematological Toxicity  
 
No dose adjustments are recommended for anemia.  The treating physician may 
hold everolimus for anemia if it is felt to be in the best interest of the patient.  
Aranesp (darbepoetin alfa) and Procrit (epoetin alfa) are not indicated for 
anemia.  If patient does not recover after 28 days of holding drug then the patient 
must be removed from treatment. 
 
Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelet growth factors, 
etc.) are not to be administered prophylactically but may be prescribed by the 
treating physician for rescue from severe hematologic events. 
 
b. 
Hyperlipidemia and Hyperglycemia 
 
Treatment of hyperlipidemia should take into account the pre-treatment status 
and dietary habits. Blood tests to monitor hyperlipidemia must be taken in the 
fasting state. Grade 2 or greater hypercholesterolemia (> 300 mg/dL or 7.75 
mmol/L) or Grade 2 or greater hypertriglyceridemia (> 300 mg/dL - 500 mg/dL; 
>3.42 mmol/L- 5.7 mmol/L) should 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. Patients should be monitored 
clinically and through serum biochemistry for the development of rhabdomyolysis 
and other adverse events as required in the product label/data sheets for HMG-
CoA reductase inhibitors. 
 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity 
manifested by rhabdomyolysis, markedly elevated creatine phosphokinase (CPK) 
levels and myoglobinuria, acute renal failure and sometimes death. The risk 

 
 
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versus benefit of using this therapy should be determined for individual patients 
based on their risk of cardiovascular complications of hyperlipidemia. 
 
Grade 3 hyperglycemia has been observed in patients receiving everolimus 
therapy. The fasting state of patients should be verified when interpreting results.  
It is suggested that optimal glucose control should be achieved before starting a 
patient on everolimus and should be monitored during everolimus therapy. 
 
c. 
Pneumonitis 
 
Pneumonitis is a recognized adverse effect of rapamycins (sirolimus, 
temsirolimus, and everolimus). Numerous case reports in the literature suggest 
that rapamycin-associated pneumonitis is relatively unaggressive, limited in 
extent, and reversible upon drug discontinuation. The term ‘pneumonitis’ is used 
here to describe non-infectious, non-malignant infiltration in the lungs which is 
evident radiologically. More precise diagnosis should follow histocytological 
examination following lung biopsy, generally during bronchoscopy which may or 
may not be symptomatic. 
 
Both asymptomatic and symptomatic non-infectious pneumonitis have been 
noted in patients receiving everolimus. A diagnosis of non-infectious pneumonitis 
should be considered in patients presenting with non-specific respiratory signs 
and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and in 
whom infectious, neoplastic and other non medical causes have been excluded 
by means of appropriate investigations. Patients should be advised to report 
promptly any new or worsening respiratory symptoms.  
 
In order to monitor for asymptomatic non-infectious pneumonitis, the regularly 
scheduled chest CTs for disease surveillance should be assessed for evidence 
of pneumonitis during protocol treatment.  Additional chest CT scans may be 
performed, when clinically necessary.  If non-infectious pneumonitis develops, a 
consultation with a pulmonologist should be considered.  
 
Management of Non-Infectious Pneumonitis 
 
Worst Grade 
Pneumonitis 
Required 
Investigations 
Management of 
Pneumonitis  
Everolimus Dose 
Adjustment 
 
Grade 1 
CT scans with lung 
windows and 
pulmonary function 
testing including: 
spirometry, DLCO, 
and room air O2 
saturation at rest. 
Repeat chest x-ray/CT 
scan every 2 Cycles 
until return to baseline. 
No specific 
therapy is 
required 
Administer same 
dose of 
everolimus. 
Grade 2 
CT scan with lung 
windows and 
pulmonary function 
testing including: 
spirometry, DLCO, and 
room air O2 saturation 
at rest. Repeat each 
subsequent Cycle until 
return to baseline. 
Consider bronchoscopy 
Symptomatic 
only. Prescribe 
corticosteroids 
if cough is 
troublesome. 
Reduce 
everolimus one 
dose level until 
recovery to ≤ 
Grade 1. 
Everolimus may 
also be 
interrupted if 
symptoms are 
troublesome. 

 
 
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Worst Grade 
Pneumonitis 
Required 
Investigations 
Management of 
Pneumonitis  
Everolimus Dose 
Adjustment 
 
*  
Patients will be 
removed from 
protocol 
treatment if they 
fail to recover to 
≤ Grade 1 within 
21 days. 
Grade 3 
CT scan with lung 
windows and 
pulmonary function 
testing including: 
spirometry, DLCO, and 
room air O2 saturation 
at rest. Repeat each 
subsequent Cycle until 
return to baseline. 
Bronchoscopy is 
recommended * 
Prescribe 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Hold treatment 
until recovery to 
≤ Grade 1. May 
restart protocol 
at one lower 
dose level. 
Patients will be 
removed from 
protocol 
treatment if they 
fail to recover to 
≤ Grade 1 within 
21 days.  
 
Grade 4 
CT scan with lung 
windows and required 
pulmonary function 
testing includes: 
spirometry, DLCO, and 
room air O2 saturation 
at rest. Repeat each 
subsequent Cycle until 
return to baseline. 
Bronchoscopy is 
recommended *. 
 
Prescribe 
corticosteroids 
if infective 
origin is ruled 
out. Taper as 
medically 
indicated. 
Discontinue 
treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 
 
d. 
Oral Mucositis 
 
In addition to the dose modifications for non-hematological toxicity outlined in 
Section 8.4, oral mucositis due to everolimus should be treated using local 
supportive care. Follow the paradigm below for treatment of oral mucositis: 
 
1. 
For mild toxicity (Grade 1), use conservative measures such as non-
alcoholic mouth wash or salt water (0.9%) mouth wash several times a 
day until resolution. 
 
2. 
For more severe toxicity (Grade 2 in which case patients have pain but 
are able to maintain adequate oral alimentation, or Grade 3 in which case 
patients cannot maintain adequate oral alimentation), the suggested 
treatments are topical analgesic mouth treatments (i.e., local anesthetics 
such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, 
menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
 

 
 
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3. 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may 
tend to worsen mouth ulcers. It is preferable to avoid these agents. 
 
4. 
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. 
 
e. 
Nausea 
 
Routine premedication for nausea is not necessary, but symptomatic patients 
should be treated with standard antinausea/antiemetic therapy as necessary. 
 
If the patient vomits after taking the tablets, the dose is replaced only if the 
tablets can actually be seen and counted. 
 
f. 
Diarrhea 
 
Diarrhea has been seen with everolimus. In general, diarrhea has been transient, 
usually not of sufficient severity to hinder administration of everolimus and 
responsive to loperamide. The recommended dose of loperamide is 4 mg at first 
onset, followed by 2 mg PO q 2-4 hours until diarrhea free for 12 hours. 
 
8.5 
Infection Precaution 
 
Everolimus has immunosuppressive properties and may predispose patients to 
infections, especially those with opportunistic pathogens. Localized and systemic 
infections, including pneumonia, other bacterial infections and invasive fungal infections, 
such as aspergillosis, candidiasis, or pneumocystis jirovecii pneumonia (PJP) 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, be vigilant for 
symptoms and signs of infection, and institute appropriate treatment promptly. 
 
8.6 
Management of Hepatitis Reactivation 
 
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals 
during anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) 
reactivation and associated HBV morbidity and mortality.  (Loomba et al. 2008) 
Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 1 provides details of monitoring and prophylactic therapy according to the baseline 
results of viral load and serologic markers testing. 
 
Table 1 Action to be taken for positive baseline hepatitis B results 
 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
and no 
prior HBV 
+ or - 
- 
or + with 
prior HBV 

 
 
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Test 
Result 
Result 
Result 
Result 
Result 
vaccination 
vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment 
should be started 1-2 
weeks prior to first dose 
of study drug 
Monitor HBV-DNA 
approximately every 4-6 
weeks 
No prophylaxis 
Monitor HBV-DNA 
approximately every 4-
6 weeks 
 
No specific 
action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study 
drug.   
 
For hepatitis B reactivation, definition and management guidelines, see Table 2 
Guidelines for management of hepatitis B.   
 
Table 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 
positive HBsAg 
------------------------------- 
reactivation is defined 
as:   
[Increase of 1 log in 
HBV-DNA relative to 
baseline HBV-DNA 
value OR new 
appearance of 
measurable HBV-DNA] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral  
AND 
Interrupt study drug administration until resolution:  
 ≤ Grade 1 ALT (or baseline ALT, if > Grade 1) and 
 ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be 
re-started at one dose lower, if available. If the patient is 
already receiving the lowest dose of study drug according 
to the protocol, the patient should restart at the same dose 
after resolution. Both antiviral therapies should continue at 
least 4 weeks after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue 
study drug but continue both antiviral therapies at least 4 
weeks after last dose of study drug. 
For patients with 
baseline results:  
Negative HBV-DNA and 
HBsAg  
AND  
[Positive HBs Ab (with 
no prior history of 
vaccination against 
HBV), OR positive HBc 
Ab]  
------------------------------- 
Treat: Start first antiviral medication  
AND 
Interrupt study drug administration until resolution:  
  ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be 
re-started at one dose lower, if available. If the patient is 
already receiving the lowest dose of study drug according 
to the protocol, the patient should restart at the same dose 
after resolution. Antiviral therapy should continue at least 4 
weeks after last dose of study drug.  

 
 
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HBV reactivation (with or without clinical signs and symptoms)* 
reactivation is defined 
as: 
New appearance of 
measurable HBV-DNA 
If resolution occurs > 28 days Patients should discontinue 
study drug but continue antiviral therapy at least 4 weeks 
after last dose of study drug. 
* All reactivations of hepatitis B are to be recorded as Grade 3 (CTCAE v 4.0 Infections 
and Infestations:  Hepatitis Viral), unless considered life threatening by the investigator; 
in which case they should be recorded as Grade 4 (CTCAE 4.0 Infections and 
Infestations:  Hepatitis Viral). 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). 
 
Monitoring for Hepatitis C 
The following two categories of patients should be monitored every 4-6 weeks for HCV 
reactivation: 
• 
Patients with detectable HCV RNA-PCR test at baseline. 
• 
Patients known to have a history of HCV infection, despite a negative viral load test 
at baseline (including those that were treated and are considered ‘cured’) 
For definition of hepatitis C reactivation and the management guidelines, see Table 3 
Guidelines for management of hepatitis C. 
 
Table 3 Guidelines for management of hepatitis C 
 
HCV reactivation* 
For patients with baseline results:  
Detectable HCV-RNA,  
 
reactivation is defined as: 
ALT elevation x 5 ULN  
Discontinue study drug  
 
 
For patients with baseline results: 
Knowledge 
of 
past 
hepatitis 
C 
infection with no detectable HCV-
RNA,   
 
reactivation is defined as: 
New appearance of detectable HCV-
RNA  
Discontinue study drug 
 
* All reactivations of hepatitis C are to be recorded as Grade 3 (CTCAE 4.0 Infections 
and Infestations:  Hepatitis Viral), unless considered life threatening by the investigator; 
in which case they should be recorded as Grade 4 (CTCAE 4.0 Infections and 
Infestations:  Hepatitis Viral). 
 
8.7 
Emergency Unblinding 
 
For emergency unblinding guidelines see Section 18.2. 
 
8.8 
Dose Modification Contacts 
 
For treatment or dose modification related questions, please contact Dr. Christopher 
Ryan at 503/494-8487 or Dr. Elisabeth Heath at 313/576-8715. 
 
8.9 
Adverse Event Reporting 

 
 
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Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair, the NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

 
 
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9.0 
STUDY CALENDAR 
 
√ 
Cycle 1 
Cycle 2 
Cycle 3  § 
Off Treat  
F/U Prior to  
Recurrence  
Recurrence  
Off Treat 
 F/U After  
Recurrence 
REQUIRED  
STUDIES 
PRE 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
  
STUDY 
1 
2 
3 
4 
5 
6 
   7   ------->12 
   13  ------->18 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and  
Physical Exam   
X* 
XЯ 
 
 
X 
 
 
X 
  
X 
 
X 
X 
X 
Hepatitis B/C  
Screening † 
X 
 
 
 
 
 
 
 
  
 
 
 
 
 
Weight and  
Performance Status   
X 
XЯ 
 
 
 
 
 
X 
 
X 
 
 
 
 
Recurrence  
Assessment  ¶  Җ  
 
 
 
 
 
 
 
 
  
 
X 
X¶ 
X 
 
Toxicity Notation Ω  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Review   
Intake Calendar 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WBC/Differential 
/Platelets   
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Hemoglobin 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Bilirubin   
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
SGOT and SGPT    
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Serum Creatinine or 
Calculated Creatinine 
Clearance    
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Alkaline Phosphatase  
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Fasting Glucose, 
Cholesterol and 
Triglycerides 
X 
 
 
 
 
 
 
X 
  
X 
 
 
 
 
HBV DNA or  
HCV RNA-PCR   Δ  
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Study Calendar continued on next page.  Click here for footnotes. 

 
 
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√ 
Cycle 1 
Cycle 2 
Cycle 3  § 
Off Treat  
F/U Prior to  
Recurrence 
Recurrence 
Off Treat 
 F/U After  
Recurrence 
REQUIRED  
STUDIES 
PRE 
STUDY 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
WK 
 
1 
2 
3 
4 
5 
6 
   7   ------->12 
   13  ------->18 
SPECIMEN 
SUBMISSION ¥   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived  
Tumor Specimen            
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buffy Coat and  
Plasma Specimens 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Whole Blood for  
Trough Levels 
X 
 
 
 
 
 
 
X 
  
X 
 
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS 
AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scan of 
Chest/Abdomen/Pelvis   
£  Җ  
X 
 
 
 
 
 
 
 
  
 
X £ Җ 
X 
X 
 
Bone Scan  Ħ 
XĦ 
 
 
 
 
 
 
 
  
 
 
XĦ 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
(see Section 7.0 for 
details) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Everolimus/Placebo 
 
   X ---------------------------------------------------------------------------------------->X 
  
  
  
Click here for footnotes. 

 
 
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FOOTNOTES: 
 
NOTE:  Forms are found in Section 18.0.  Forms submission guidelines may be found in Section 14.0. 
* 
Physical exam and medical history must be completed within 28 day prior to registration (see Section 5.3a). 
Δ   Only for patients with positive HBV or HCV studies at baseline (see Section 8.6). 
†   An assessment of Hepatitis B/C medical history and risk factors must be done at screening (see Section 5.3h).  Patients with risk factors 
 
for Hepatitis B should undergo HBV DNA, HBsAg, HBsAb, and HBcAb  testing (see Sections 7.1, 7.3 and 8.6).  Patients with risk factors for  
 
Hepatitis C infection should undergo HCV RNA-PCR testing (see Sections 7.1 and 8.6) 
§ 
Protocol treatment will continue at the same intervals indicated for Cycle 3 for a maximum of 9 cycles (54 weeks) or until the patient has met  
 
any of the criteria listed in Section 7.6.     
√  After recurrence, follow-up will occur (with lab tests and scans performed at the discretion of the treating physician) every 6 months for the 
 
first two years and then yearly thereafter until 10 years after registration. 
£  CT scans of the chest must also be assessed for radiographic evidence of pneumonitis (see Section 8.4c). 
Җ Scan (CT scan of the chest, abdomen and pelvis with IV and oral contrast; CT scan of chest without contrast and MRI of abd/pelvis with  
 
gadolinium) and recurrence assessment must be performed every 4 months (18 weeks) during Year 1 (regardless of early protocol treatment  
 
discontinuation), every 6 months for Years 2 and 3, and yearly thereafter until recurrence, death, or 10 years after registration whichever comes 
 
first.  
 
The surveillance imaging therapy intervals prescribed here are considered standard of care by expert consensus (SWOG Genitourinary Committee)  
 
based on the high risk of cancer recurrence in the patients enrolled in this study. Non-contrast CT of the chest/abdomen/pelvis should only be used  
 
for surveillance imaging if, in the opinion if the investigator, it is in the best medical interest of the patient to not receive IV contrast of any form.   
 
NOTE:  PET/CT is not an acceptable imaging alternative. 
¥   See Section 15.0.  If patient has consented to banking for the translational medicine component, it is very important to obtain whole blood  
 
for trough levels and buffy coat and plasma specimens from any patient that is being removed from protocol treatment, regardless of the 
 
time point.  DO NOT COLLECT SPECIMENS AT EACH VISIT DURING FOLLOW-UP. Additionally, specimens for buffy coat and plasma  
 
specimens should be collected at disease recurrence. Specimens must be drawn prior to daily dose of study drug. 
Ω Once everolimus treatment has been initiated, weekly toxicity assessments are required during the first cycle.  Toxicity assessments during 
 
the first cycle may be performed via a phone call during weeks when a physical exam is not required. 
Ħ  Bone scan recommended if patient has rising alkaline phosphatase or bone pain. 
Я  If prestudy history and physical exam, weight and performance status are obtained within 28 days prior to registration, they do not need  
 
to be repeated for Cycle 1, Day 1.   
¶   If patient is taken off protocol treatment due to toxicity or other reason besides recurrence, they must continue to be followed for recurrence  
 
with physical exams and scans every 4 months (18 weeks) during Year 1 (regardless of early protocol treatment  
 
discontinuation), every 6 months for Years 2 and 3, and yearly thereafter until recurrence, death, or 10 years after registration whichever comes  
 
first. 
 
 

 
 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Recurrence 
 
See Section 9.0 for recurrence assessment schedule. 
 
The following are the only acceptable criteria for renal cell cancer recurrence. Anything 
not listed as acceptable should not be an indication to alter protocol therapy. Any 
recurrence of malignant disease should be proven by tissue biopsy whenever possible. 
Supporting documentation must be submitted following diagnosis of renal cell carcinoma 
recurrence. 
 
The following criteria of treatment failure constitute the only acceptable evidence of 
disease recurrence.  Supporting documentation includes a copy of radiology and 
pathology reports. 
 
Lung: (i) positive cytology or biopsy in the presence of a solitary lesion, (ii) radiologic 
evidence of multiple lesions felt to be consistent with metastases. (iii) neoplastic pleural 
effusion should be established by cytology or pleural biopsy.  
 
Liver: (i) positive cytology or biopsy (ii) multiple new focal defects on MRI scan, CT or 
ultrasound that are enlarging in size as documented by repeat scans. (iii) proof of 
neoplastic abdominal ascites should be established by cytology or pleural biopsy.  
 
Central Nervous System: positive brain CT scan or MRI scan or cerebral spinal fluid 
cytology.  
 
Subcutaneous and Lymph Node Recurrence: (i) positive biopsy (ii) progressively 
enlarging solid mass or node(s) as evidenced by repeat CT or MRI scans (iii) ureteral 
obstruction in the presence of a mass as documented on CT or MRI scan.  
 
Other Organs: (i) positive radiographic study and biopsy/aspiration cytology (ii) 
progressively enlarging solid mass or node(s) as evidenced by repeat CT or MRI scans.  
 
Renal Bed: (i) positive radiographic study and biopsy/aspiration cytology (ii) progressively 
enlarging solid mass or node(s) as evidenced by two CT or MRI scans separated by at 
least a 4 week interval. 
 
Skeletal: (i) positive radiographic study such as bone scan, (ii) for a solitary lesion or 
equivocal finding on scan, a biopsy is required to demonstrate recurrence, (iii) MRI or CT 
of solitary or equivocal lesion seen on bone scan that confirms metastasis is also 
acceptable. 
 
10.2 
Symptomatic deterioration 
 
Global deterioration of health status requiring discontinuation of treatment without 
objective evidence of progression.  Efforts should be made to obtain objective evidence 
of progression after discontinuation. 

 
 
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10.3 
Performance Status 
 
Patients will be graded according to the Zubrod performance status scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework, office work.   
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair.   
 
10.4 
Recurrence-Free Survival 
 
From date of registration to date of first documentation of recurrence outlined in Section 
10.1 or death due to any cause.  Patients last known to be alive and recurrence-free are 
censored at date of last contact. 
 
10.5 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual Goal 
 
ECOG's ASSURE trial randomized on average, 480 patients per year (40 per month).  To 
be slightly more conservative, we anticipate that 28 patients per month (336 per year) will 
be randomized to this study.  Based on the distribution of risk groups observed on E2805 
including half of the patients falling into the very-high risk group, it will be assumed that 
the placebo arm will produce a median recurrence-free survival of 4.9 years.  E2805 has 
also experienced a significant proportion of patients who have not completed the one 
year of protocol-specified treatment.  Based on data from a recent amendment to E2805, 
twenty-five percent of patients have withdrawn from treatment on this study within the first 
three months.  Although we expect everolimus to be better tolerated than sorafenib or 
sunitinib, we would estimate that about 15% of patients will stop protocol treatment within 
the first three months.  Using a weighted average of the log hazard rates to obtain the 
effective hazard rate for the treatment arm under the alternative hypothesis, the ideal 
hazard ratio (HR) of 0.75 becomes an effective hazard ratio of 0.78 when lack of 
compliance is considered.  Assuming exponential survival, 3.5 years of patient accrual, 
four additional years of follow-up and a sample size of 1170 patients (585 experimental, 
585 placebo), the study has 85% power to detect a 22% reduction in the hazard rate of 
recurrence-free survival with everolimus compared to placebo (hazard ratio 0.78).  This 
corresponds to an improvement in the median RFS from 4.9 to 6.3 years if the RFS 

 
 
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distributions are exponential.  We will use a one sided stratified log rank test with α = 
0.025. 
 
July 2015 Revision:  As we now have a large amount of data to evaluate the rate of 
compliance to everolimus, we see that our original assumption of a 15% non-compliance 
rate was an underestimate.  We propose to adjust the study design based on the 
observed compliance data from this trial in consultation with the study Data and Safety 
Monitoring Committee, and based on the following assumptions:  those who receive less 
than 3 months of study drug have the same risk of recurrence as the placebo group, and 
those who receive 3-6 months of study drug have half the treatment benefit as those who 
receive more than six months. 
 
We still assume an ideal HR=0.75, but we increase the accrual duration by one year to 
4.5 years, and keep 4 years of follow-up.  We are also reducing the statistical power from 
85% to 80% in order to achieve a sample size that seems achievable within a reasonable 
amount of time.  By making the prior assumptions about treatment efficacy, we will have 
an effective HR of 0.82 based on the proportion of dropouts and when they became 
noncompliant. 
 
Assuming exponential recurrence-free survival, 4.5 years of patient accrual, four 
additional years of follow-up and an updated sample size of 1464 eligible patients (732 
per arm), the study has 80% power to detect a 18% reduction in the hazard rate of 
recurrence free survival with everolimus compared to placebo (HR=0.82). This 
corresponds to an improvement in the median RFS from 4.9 to 6.0 years if the RFS 
distributions are exponential. We will use a one sided stratified log rank test with 
alpha=0.025. 
 
11.2 
Analysis of Primary Endpoint 
 
This study’s design is based on assumptions about the accrual rate, the distribution of 
intermediate-high and very-high risk patients that have been randomized on ASSURE 
and histology. The total projected accrual adjusted for a 5% ineligibility rate is 1,537 
patients (previously 1,218).  If accrual to the intermediate-high risk strata reaches 50% of 
the total projected accrual then the stratum will be closed to further accrual.  If accrual to 
the clear cell histology stratum reaches 85% of the total projected accrual then the 
stratum will be closed to further accrual.  This will ensure accrual patterns in the strata 
with high event rates are comparable to those assumed in the study design.  If the event 
rate information becomes available from ASSURE, the study team may consider 
recommending that the sample size be reevaluated.  The sample size adjustment would 
be based on baseline characteristics.  Only the number of patients accrued would 
possibly change, but the number of events and formal analysis timepoints, which are 
based on number of events, would not change. 
 
The first interim analysis will be conducted after approximately 1,000 patients have been 
entered (n=500 per arm), approximately 4 years after the study opens and when 30% of 
the expected number of recurrences have occurred on the placebo arm.  A second 
interim analysis will be conducted approximately 5 years after the study opens and when 
50% of the expected events on the placebo arm have been observed.  The third interim 
analysis will be conducted when 70% of the expected events on the placebo arm have 
been observed. The fourth interim analysis will occur approximately 7.5 years after study 
activation when 90% of the expected events on the placebo arm have been observed.  
For each interim analysis, timing of analysis will be based on percent of expected 
information and not on calendar time.  Evidence suggesting early termination of the trial 
and a conclusion that everolimus is not better than placebo would be if the alternative 
hypothesis of a 22% improvement in recurrence-free survival with the experimental arm 
is rejected at the 0.002 level.  In addition, the null hypothesis of no difference in 
recurrence-free survival will be tested at the one-sided level of 0.001.  If the decision is to 
continue the study to completion, the final analysis will be done after complete accrual 

 
 
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and approximately four years of follow-up at complete information when 804 total events 
have occurred across both arms.  A stratified, one-sided log-rank test will be used for 
testing the primary hypothesis at the 0.022 level to account for interim testing. 
 
December 2020 Update: 
 
The expected endpoint rate in the placebo arm is lower than anticipated.  Although three 
interim analyses have been conducted to date, the number of events is slowing making it 
difficult to reach the targeted number of events.  Therefore, we consider some 
modification to the statistical analysis plan.  This plan was developed by two independent 
biostatisticians who had not seen and had no access to endpoint data for this trial, with 
medical input from the primary study chair.  The SWOG Data and Safety Monitoring 
Committee reviewed and approved this revision   
 
The median recurrence-free survival of ASSURE (6.6 years) was longer than the six 
years assumed for this trial so the actual number of events in the placebo arm may be 
less than originally projected.  
 
To keep power at 80% under current trial conditions, we continue to use the 4.5 years of 
accrual but allow 6 additional years of follow-up after the last accrual for a total of 10.5 
years.  Assuming a more conservative control arm hazard rate of 0.1027 (median 
RFS=6.75 years), the expected date of data maturity (804 total events) under the 
alternative hypothesis is September 2021.  However, the necessary 804 events may 
never be attained because of drop out or failure of the underlying exponential distribution 
assumption and so the final analysis is expected in March 2022 even if 804 events have 
not been observed.  In addition, the 4th and final interim analysis should be conducted 
one year prior in March 2021 regardless of the percent of expected information.  The 
futility analysis is being changed from a one-sided 0.001 to a 1-sided value of 0.025 in 
the last interim analysis.  This will have minimal effect on power if the true hazard ratio is 
0.82 but would lead to earlier reporting if the observed hazard ratio is close to 1.0. 
 
Updated Timing of Scheduled Analyses on S0931, December 2020 Update  
 
Analysis 
Estimated 
Study Time 
# of Events 
on Placebo 
Arm* (% of 
total 
expected) 
# of Events on 
Everolimus Arm 
(assuming Ha) 
Testing Ho, 
Level of 
significance 
Testing Ha,  
Level of 
significance 
1st interim 
analysis 
4 years after 
activation 
119 (30%) 
104 
.002 
.001 
2nd interim 
5 years after 
activation 
208 (50%) 
183 
.002 
.001 
3rd interim 
6 years after 
activation 
297 (70%) 
264 
.002 
.001 
4th interim 
 
 March 2021 
.002 
.025 
Final 
analysis 
 
422 (100%)# 
382# 
0.022 
N/A 
* timing of all planned analyses is based on the number of events in this column 
# timing of final analysis at 804 total events or a maximum time of March 2022 
 
11.3 
Analysis of Secondary Endpoints 
 
Secondary analyses will be performed for comparison between the two arms regarding 
survival and adverse events. With 732 patients on each arm, toxicity rates can be 
estimated to within at worst ± 3.7% (95% confidence interval).  Additional exploratory 
analyses will include assessing the treatment effect within subgroups defined by the 
stratification factors as well as the interaction of everolimus with each of the stratification 

 
 
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factors, and whether the surgery was partial or a radical nephrectomy.  With at least 15% 
of the patients having non-clear cell histology, for this subgroup the difference in the 
survival rates between the treatment arms can be estimated to within at worst ± 5% (95% 
confidence interval). 
 
11.4 
Analysis of Translational Medicine Endpoints 
 
(A) Prognostic significance:  Proportional hazards regression will be used to evaluate the 
association between genes and pathways and recurrence-free survival and overall 
survival.  Additional exploratory methodology may include classification and regression 
trees or logic regression to identify combinations of markers that may be associated with 
the endpoints of interest.  The following table shows the minimally detectable RFS hazard 
ratio for various prevalence of markers and rates of sample submission with 80% 
statistical power and a two-sided alpha=0.05.  This table assumes no treatment by 
marker interaction, and a median RFS of 4.9 years in those with the biomarker of interest. 
 
Minimally Detectable Hazard Ratios for Recurrence-Free Survival 
 
 
sample  
submission 
(n=1170) 
sample 
submission 
(n=936) 
sample 
submission 
(n=702) 
10% prev of a SNP 
1.46 
1.52 
1.63 
20% prev. of a SNP 
1.33 
1.38 
1.45 
30% prev. of a SNP 
1.28 
1.32 
1.38 
 
(B) Predictive significance: In order to evaluate whether molecular biomarkers in the 
AKT/mTOR pathway are predictive factors for everolimus, we will assess the interaction 
of the biomarker with treatment in a proportional hazards regression model assessing 
RFS.  The entry in the following table is the minimally detectable ratio of the HR’s of 
placebo/everolimus for those without the pathway activation relative to those that do have 
the activation.  For simplicity of calculations, we assume that there is no prognostic 
association of biomarker activation and RFS in the placebo group, and the treatment 
effect for those without activation is null.  That is, everolimus only has an impact on RFS 
among those with marker activation. 
 
Minimally Detectable Interaction for Recurrence-Free Survival 
 
Table entry is the hazard ratio of (Everolimus/Placebo) for those without marker 
activation relative to the HR of (Ever/Pl) for those with marker activation, assuming 
80% statistical power and a two-sided α=0.05 
 
100% sample 
submission 
80% sample 
submission 
60% sample 
submission 
10% prev. of a 
marker 
2.40 
2.75 
3.49 
20% prev. of a 
marker 
1.85 
2.00 
2.28 
30% prev. of a 
marker 
1.68 
1.80 
1.99 
 
If 936 of patients randomized to this trial provide a usable tissue sample for these 
translational objectives, and the prevalence of the biomarker of interest is 20%, then we 
will have reasonable power (80%) to detect a hazard ratio of approximately 0.50 for those 
with a marker compared to a HR of 1.0 for those without the marker (1.0/0.50 = 2.00). 
Frequency and severity of adverse events and proximity to sample collection will be 
correlated with steady-state Cmin.  Assuming 90% of those randomized to everolimus will 
submit one or more serum samples, we will have approximately 526 subjects to analyze.  

 
 
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Initially, correlations of adverse events and the Cmin in closest proximity to the adverse 
event will be explored in a manner analogous to multiple t-tests.  Logistic regression 
modeling will be used to assess whether Cmin is a predictor for the presence of the 
adverse events after adjusting for other patient and disease covariates.  Proportional 
odds (PO) models may be used to model severity of an adverse event in ordinal 
categories, if the PO modeling assumption is supported by the data. 
 
11.5 
Pharmacokinetic Analysis of Blood Samples 
 
For the pharmacokinetic analysis of blood samples, we will use blood samples that were 
collected at Week 7 or Week 13 and the patient must have been randomized to the 
everolimus arm and be receiving protocol treatment at the time of the blood draw.  At the 
time of the on-study analysis in the winter of 2014, there were 83 patients with one blood 
draw and 165 with two for a total of 248 patients.  For those with two on-treatment 
measurements, the average of the two will be used for analysis to reduce measurement 
error bias. 
 
The purpose of the analysis is to correlate everolimus blood concentrations from early 
blood draws with the experience of adverse events by the patients, both in terms of 
general grades of toxicities but also by specific adverse events that have been more 
frequently reported on the everolimus arm.  The following calculations assume a PK 
analysis will be conducted prior to accrual completion in order to gain insight into the 
relationship between blood levels of the study drug and adverse events.  We anticipate 
there will be more samples to evaluate later in the trial and so effect sizes will be smaller 
with larger sample sizes. 
 
Most Prevalent Grade 2-4 Adverse Events in the Everolimus Arm of EVEREST 
Among all Randomized Patients on the Everolimus Arm Who Received Any Study Drug 
Toxicity 
% of Evaluable with Grade 2-4 
High Cholesterol 
10% 
Fatigue 
19% 
Hyperglycemia 
14% 
Hypertriglyceridemia 
27% 
Oral mucositis 
35% 
Rash 
14% 
Composite Endpoints 
Any Toxicity Grade 2-4 
87% 
Any Toxicity Grade 3-4 
46% 
Refusal/Tox within first 3 months 
25% 
Refusal/Tox within first 6 months 
41% 
Refusal/Tox prior to 12 months 
52% 
 
In order to simplify power calculations related to everolimus blood concentrations, we will 
assume the distribution of values will be divided into quartiles.  The following table 
indicates the minimally detectable odds ratio that could be detected between the lowest 
and highest quartile in terms of predicting an adverse event.  A range of prevalences are 
illustrated below to show how the effect size changes with the prevalence of the adverse 
event. 
 
Minimally Detectable Odds Ratio for Highest versus Lowest Quartile of everolimus in the 
blood, assuming 80% Statistical Power and a Two-sided Alpha=0.05. 
 
 
Prevalence of Adverse Event Endpoint  
 
10% 
20% 
30% 
40% 
50% 

 
 
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Q4 vs. Q1 of 
everolimus 
concentration 
6.5 
3.6 
3.0 
2.7 
2.7 
 
An individual adverse event that is only reported by 10% of patients who receive 
everolimus will need to have a very strong association with concentration of everolimus in 
the blood (odds ratio 6.5 between highest and lowest concentration) in order to be 
detected as a significant association.  An association of any Grade 3-4 toxicity only needs 
to be in the range of an odds ratio of 2.7 to be detectable. 
 
For patients who have had a dose reduction of protocol therapy at the time of their blood 
draw, we will handle this in two ways.  First, we will just analyze the everolimus level as it 
appears in the blood and ignore the dose received, and the second approach will 
standardize the amount of everolimus in the blood conditional on the dose of drug taken. 
 
Logistic regression will be used to model adverse event outcomes with everolimus blood 
concentration as a predictor, adjusting for other stratification factors and age, gender and 
race. 
 
11.6 
Data and Safety Monitoring Committee Oversight 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of SWOG, 3 SWOG members, 3 non-
voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary.  The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study. 
 
 
12.0 
DISCIPLINE REVIEW 
 
There will be no formal discipline review done in conjunction with this study. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than ten working days 
prior to planned start of treatment). 
 
13.2 
Investigator/Site Requirements 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.  Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature and Financial 
Disclosure Form with original signature) to the Pharmaceutical Management Branch, 
CTEP, DCTD, NCI.  These forms are available on the CTSU Web site 
(http://ctep.cancer.gov/investigatorResources/investigator_registration.htm).Questions 
should be directed to the CTEP Investigator Registration Help Desk by e-mail at 
pmbregpend@ctep.nci.nih.gov. 
 

 
 
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Each investigator or group of investigators at a clinic site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients.  Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
 
Requirements for site registration: 
 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
 
Note:  Sites participating on the NCI CIRB initiative and accepting CIRB approval for the 
study are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review.  This information will be 
provided to the CTSU Regulatory Office from the CIRB at the time the site’s Signatory 
Institution accepts the CIRB approval.  The Signatory site may be contacted by the CTSU 
Regulatory Office or asked to complete information verifying the participating institutions 
on the study.  Other site registration requirements (i.e., laboratory certifications, protocol-
specific training certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Oncology Patient Enrollment Network (OPEN) will also ask additional questions that are 
not present on the SWOG Registration Worksheet.  The individual registering the patient 
must be prepared to provide answers to the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Cooperative Group Credit 
 
f. 
Credit Investigator 
 
g. 
Patient Initials 
           
h. 
Patient’s Date of Birth    
 
i. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
j. 
Country of Residence 
 
k. 
ZIP Code 
 
l. 
Gender (select one): 
 
• 
Female Gender 
• 
Male Gender 

 
 
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m. 
Ethnicity (select one): 
 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
n. 
Method of Payment (select one): 
 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
o. 
Race (select all that apply): 
 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff (SWOG and CTSU Sites) will use OPEN to enroll patients to this 
study.  OPEN is a web-based application that is integrated with the CTSU 
Enterprise System for regulatory and roster data and, at the time of patient 
registration, initializes the patient in the Rave database.  OPEN can be accessed 
at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on 
the SWOG CRA Workbench.  
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes 
and the affirmation of eligibility on the Registration Worksheet has been 
signed 
by 
the 
registering 
investigator 
or 
another 
investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
• 
The study site is listed as "approved" in the CTSU RSS. 
 
c. 
Access requirements for OPEN: 
 
• 
Site staff will need to be registered with CTEP and have a valid and 
active CTEP-IAM account. This is the same account (user ID and 
password) used for the CTSU members' web site.  Additional information 
about 
obtaining 
a 
CTEP-IAM 
account 
can 
be 
found 
at 

 
 
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http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  
Questions should be directed to the CTEP Associate Registration Help 
Desk by e-mail at ctepreghelp@ctep.nci.nih.gov. 
 
• 
To perform registrations, the site must have been assigned the 
'Registrar' role on the SWOG or CTSU roster:  
 
1. 
If you are a SWOG member, to perform registrations on SWOG protocols 
you must have an equivalent 'Registrar' role on the SWOG roster.  Role 
assignments are handled through SWOG. 
 
2. 
If you are not a SWOG member, to perform registrations on SWOG 
protocols you must have the role of Registrar on the CTSU roster. Site 
and/or Data Administrators can manage CTSU roster roles via the new 
Site Roles maintenance feature under RSS on the CTSU members' web 
site. This will allow them to assign staff the "Registrar" role.  
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.   Please print this confirmation for your 
records. 
 
d. 
Further instructional information is provided on the OPEN tab of the CTSU 
members’ 
side 
of 
the 
CTSU 
website 
at 
https://www.ctsu.org 
or 
at 
https://open.ctsu.org.  For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 

 
 
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13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms are included in Section 18.0 and (with the exception of the sample consent 
form and the Registration Worksheet) must be submitted to the Data Operations Center 
in Seattle.  Data from approved SWOG institutions must be submitted on-line via the 
Web; see Section 14.3a for details.  Exceptions to online data submission are patient-
completed 
(e.g. 
Quality 
of 
Life) 
forms 
and 
source 
documents 
(e.g. 
pathology/operative/lab reports). 
 
14.3 
Data Submission Procedures 
 
a. 
SWOG institutions must submit data electronically via the Web by using the 
SWOG CRA Workbench.  To access the CRA Workbench, go to the SWOG Web 
site (http://swog.org) and logon to the Members Area.  After you have logged on, 
click on the CRA Workbench link to access the home page for CRA Workbench 
website.  Next, click on the Data Submission link and follow the instructions.  For 
new users, the link to a "Starter Kit" of help files may be found by clicking on the 
Starter Kit link at the Members’ logon page. 
 
 
To submit data via the web the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, and 
3. 
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to submit data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.   
 
b. 
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 

 
 
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submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do 
not use cover sheet for faxed data.  Please make sure that each page of all faxed 
data include the SWOG patient number, study ID and patient initials. 
 
c. 
Data Submission Instructions for non-SWOG Institutions (CTSU):  See the CTSU 
participation table. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS OF REGISTRATION: 
 
Submit copies of the following: 
 
S0931 Prestudy Form  
 
S0931 Tumor Specimen Processing Form (for patients who consent to the 
translational medicine studies) 
 
Surgical and Radiology Reports 
 
Pathology Report confirming renal cell carcinoma including subtypes. 
 
b. 
IF PATIENT CONSENTED: 
 
Submit specimens within 28 days of obtaining as outlined in Section 15.0. 
 
c. 
WITHIN 7 DAYS OF COMPLETION OF EACH CYCLE (EVERY SIX WEEKS) 
WHILE ON PROTOCOL TREATMENT: 
          
S0931 Treatment Form  
 
S0931 Adverse Event Form 
 
d. 
EVERY EIGHTEEN WEEKS FOR THE FIRST 54 WEEKS (REGARDLESS OF 
EARLY PROTOCOL TREATMENT DISCONTINUATION), AND THEN EVERY 6 
MONTHS FOR THE FOLLOWING 2 YEARS, AND THEN ANNUALLY UNTIL 10 
YEARS AFTER REGISTRATION, RECURRENCE OR DEATH WHICHEVER 
COMES FIRST: 
 
S0931 Recurrence Assessment Form 
 
e. 
WITHIN 14 DAYS OF DISCONTINUATION OF ALL PROTOCOL TREATMENT: 
 
Off Treatment Notice   
 
Final S0931 Treatment Form   
 
Final S0931 Adverse Event Form 
 
f. 
AFTER OFF ALL PROTOCOL TREATMENT, EVERY SIX MONTHS FOR TWO 
YEARS AND ANNUALLY UNTIL TEN YEARS AFTER REGISTRATION OR 
UNTIL DEATH: 
 
Submit copies of the S0931 Specific Follow Up Form 

 
 
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g. 
WITHIN 14 DAYS OF RECURRENCE: 
 
S0931 Adverse Event Form  
 
Off Treatment Notice  
 
If patient was off protocol treatment: 
 
S0931 Specific Follow-Up Form  
 
For all patients: 
 
S0931 Recurrence Assessment Form  
 
Radiology and pathology reports documenting recurrence. 
 
h. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
If patient was still on protocol treatment: 
 
Notice of Death  
 
Final S0931 Treatment Form  
 
Final S0931 Adverse Event Form  
 
If patient was off protocol treatment: 
 
Notice of Death  
 
S0931 Specific Follow-Up Form 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Tissue Specimen Banking 
 
Tissue specimens for banking and future translational medicine studies will be submitted 
to the SWOG Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division, 
Lab #201.  Specimen banking is optional for the patient. 
 
a. 
With patient’s consent tissue specimens must be submitted at the timepoint listed 
below in Section 15.1b (see Section 9.0): 
 
b. 
A paraffin embedded block of tumor or 10 unstained slides obtained from the 
prestudy nephrectomy specimen must be submitted to Lab #201 within 7 days of 
registration.  This specimen will be banked until funding is obtained to perform 
translational medicine studies which will include assessing molecular biomarkers 
relevant to the AKT/mTOR and other pathways implicated in the pathogenesis of 
renal carcinoma and investigating their potential predictive and prognostic value. 
 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp), or via the 
link on the S0931 protocol abstract page on the SWOG website (www.swog.org). 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 

 
 
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15.2 
Plasma, Buffy Coat, and Whole Blood Specimen Banking 
 
Plasma, buffy coat and whole blood specimens for banking and future translational 
medicine studies will be submitted to the SWOG Specimen Repository – Solid Tissue, 
Myeloma and Lymphoma Division, Lab #201.  Specimen banking is optional for the 
patient. 
 
a. 
With patient’s consent plasma and buffy coat and whole blood specimens must 
be submitted at the timepoints listed below in Section 15.2b.  Collection 
instructions are outlined in Section 15.2c and submission instructions are 
outlined in Section 15.2e. 
 
b. 
With patient’s consent plasma and whole blood specimens must be submitted at 
the following times (see Section 9.0): 
 
1. 
Plasma and Buffy Coat 
 
Blood specimens (two purple top EDTA tubes for plasma and buffy 
coats) will be collected after registration, but prior to Cycle 1 treatment; 
at the beginning of Cycles 2 and 3; at the time of removal from protocol 
treatment (regardless of timepoint); and at the time of disease 
recurrence.  These specimens must be shipped within 28 days after 
obtaining to Lab #201.  These specimens will be banked until funding 
is obtained to perform translational medicine studies which will include 
assessing molecular biomarkers relevant to the AKT/mTOR and other 
pathways implicated in the pathogenesis of renal carcinoma and 
investigating their potential predictive and prognostic value. 
 
2. 
Whole Blood 
 
Five mL of venous blood will be collected in a purple-top EDTA tube 
immediately prior to Cycles 1-3 and at the time the patient is removed 
from protocol treatment.  Prior to Cycles 1-3, patients must be 
instructed not to take their morning everolimus dose until after 
the samples have been obtained.  These specimens must be 
shipped within 28 days after obtaining to Lab #201.  These specimens 
will be banked until funding is obtained to perform translational 
medicine studies which will include determining the steady-state 
everolimus trough levels. 
 
c. 
Plasma and Whole Blood Specimen Collection Instructions: 
 
1. 
Plasma 
and 
Buffy 
Coat 
Specimen 
Collection 
and 
Processing 
Instructions: 
 
a. 
Blood samples should be collected using standard venipuncture 
technique. 
 
b. 
Cryovials must be labeled with the protocol number (S0931), 
SWOG patient number, patient’s initials, and date and time of 
specimen collection. 
 
c. 
Collect ~6 mL whole blood in each of two (2) purple top tubes 
(EDTA tubes). 
 

 
 
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d. 
Immediately invert tube (gently) 8-10 times.  This reduces the 
possibility of clot formation. 
 
e. 
Centrifuge sample at 800 x g for 10 minutes (~1500-2000 rpm, 
determined by centrifuge rotor size). 
 
f. 
Immediately after centrifuging, transfer plasma in 1 mL aliquots 
to labeled cryovials. 
 
g. 
Pipette slowly to avoid disturbing the buffy coat layer. 
 
h. 
Leave a small amount of plasma (~.5 cm) above the buffy coat 
layer in each tube. 
 
i. 
After removing plasma from both tubes, transfer buffy coat to 
labeled cryovials. 
• 
The buffy layer is the off-white layer between the plasma and 
the red blood cells. 
• 
Pipette slowly in a circular motion to obtain as many buffy 
coat cells as possible. 
• 
Contamination of the buffy coat with red blood cells is 
expected and not a concern. 
 
j. 
Immediately freeze vials in a freezing apparatus (ex. Mr. Frosty). 
If not available, slow freeze vials on dry ice or in a -70°C freezer. 
Store frozen plasma vials in a -70°C to -80°C freezer until ready 
to ship.  If a -70°C to -80°C freezer is not available, a -20°C 
would be sufficient. 
 
2. 
Whole Blood Specimen Collection Instructions: 
 
a. 
Prior to each scheduled appointment, patients must be instructed 
not to take their morning everolimus dose until after the sample 
has been obtained. 
 
b. 
Blood samples should be collected using standard venipuncture 
technique. 
 
c. 
Cryovials must be labeled with the protocol number (S0931), 
SWOG patient number, patient’s initials, and date and time of 
specimen collection. 
 
d. 
Collect 5 mL of venous blood into a purple top EDTA tubes. 
 
e. 
Immediately invert tube (gently) 8-10 times.  This reduces the 
possibility of clot formation. 
 
f. 
If you are using plastic vacutainer tubes, samples can be directly 
frozen at -20°C.  If the blood collection tubes are glass, whole 
blood should be transferred to an appropriately labeled 
polypropylene freezer vial and frozen at <-20°C.  Note:  Plasma 
should not be separated from whole blood.  Whole blood 
should be frozen directly without separation. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 

 
 
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e. 
SHIPPING SAMPLES 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked 
using the SWOG online Specimen Tracking system. SWOG members 
may log on the online system via the CRA Workbench. To access the 
CRA Workbench, go to the SWOG Web site (http://swog.org) and logon 
to the Members Area. After you have logged on using your SWOG roster 
ID number and password, click on the CRA Workbench link to access 
the home page for CRA Workbench website. First time non- SWOG 
users 
must 
refer 
to 
start-up 
instructions 
located 
at 
https://gill.crab.org/SpecTrack/. 
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. The 
Specimen Submission Form is NOT required when the online system is 
used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as 
database errors or connectivity issues, please send an email to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page 
 
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact 
the Data Operations Center at 206/652-2267 to be routed to the Data 
Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate SWOG 
laboratory for submission of plasma, whole blood and tissue specimens 
for SWOG Repository submission is identified as follows: 
 
Lab #201:  SWOG Specimen Repository – Solid Tissue, Myeloma and 
Lymphoma Division 
Contact: 
Erin Grundy 
Phone: 
614/355-3099 
Email: 
bpcbank@nationwidechildrens.org 
 
2. 
Plasma, buffy coats, and whole blood must be shipped on dry ice by 
overnight courier Monday through Wednesday. 
 
3. 
Federal guidelines for the shipment of blood products: 
 
a. 
The tube must be wrapped in an absorbent material. 
 
b. 
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
 
c. 
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 

 
 
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d. 
Pack the Styrofoam shipping container in a cardboard box. 
 
e. 
Mark the box "Biohazard". 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data colle n and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol. 
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 

 
 
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CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS. When Internet connectivity is disrupted, a 24-hour notification is to be 
made to the SWOG Operations Office by telephone at 210-614-8808 or by email 
at adr@swog.org. Once Internet connectivity is restored, a 24-hour notification 
that was made by phone or using adr@swog.org must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event specified in Table 16.1.  
 
d. 
Other recipients of adverse event reports 
 
The Operations Office will forward reports and documentation to the appropriate 
regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agent used in this study is everolimus. If there is 
any question about the reportability of an adverse event or if on-line CTEP-AERS 
cannot be used, please telephone or email the SAE Specialist at the SWOG 
Operations Office, 210-614-8808 or adr@swog.org, before preparing the report. 

 
 
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Table 16.1: 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on studies under a Non-CTEP IND within 30 Days1 of the Last Administration of the 
Investigational Agent/Intervention1 (Everolimus). 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) 
A congenital anomaly/birth defect.  
6) 
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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or [Section 
16.1f.]  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
May 5, 2011 

 
 
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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Trials Utilizing an Agent under 
a Non-CTEP IND: 
 
1) 
Group-specific instructions. 
 
Supporting Documentation Submission - Within 5 calendar days 
submit the following to the SWOG Operations Office by fax to 210-614-
0006 or mail to the address below: 
• 
Printed copy of the first page of the CTEP-AERS report 
• 
Copies of clinical source documentation of the event 
• 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center, copies of Off Treatment 
Notice and/or Notice of Death. 
 
2) 
The adverse event listed below does not require expedited reporting 
via CTEP-AERS: 
• 
Grade 4 myelosuppression 
 
g. 
Reporting of Secondary Malignancy Including AML/ALL/MDS 
 
1.  
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
 
SWOG requires all secondary malignancies that occur following 
treatment with an agent under a non-NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting mechanisms 
outlined in each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf. 
 
2. 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  A copy of the 
report and the following supporting documentation must also be 
submitted to SWOG Operations Office within 30 days by fax to 210/614-
0006 or mail to the address below: 
 

 
 
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• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the 
report must be submitted for the most recent trial. 
 
h. 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – 
Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence 
of respiration, heartbeat, or definite movement of a voluntary muscle 
after expulsion from the uterus, without possibility of resuscitation” 
should be reported expeditiously as Grade 4 “pregnancy, puerperium 
and perinatal conditions – Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.   
 
3. 
Death Neonatal Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed 
and faxed with any additional medical information to 301/230-0159.  The 
potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm 
 
 
 

 
 
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17.0 
BIBLIOGRAPHY 
 
1  
Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin 59:225-249, 2009. 
 
2  
Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy 
for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 
30:843-52, 2003. 
 
3  
Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: new 
frontiers in staging, prognostication and targeted molecular therapy. J Urol 173:1853-62, 2005. 
 
4  
Atzpodien J, Schmitt E, Gertenbach U, et al. Adjuvant treatment with interleukin-2- and interferon-
alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results 
of a prospectively randomized trial of the German Cooperative Renal Carcinoma 
Chemoimmunotherapy Group (DGCIN). Br J Cancer 92:843-6, 2005. 
 
5  
Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-
risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol 21:3133-40, 
2003. 
 
6  
Pizzocaro G, Piva L, Colavita M, et al. Interferon adjuvant to radical nephrectomy in Robson 
stages II and III renal cell carcinoma: a multicentric randomized study. J Clin Oncol 19:425-31, 
2001. 
 
7  
Messing EM, Manola J, Wilding G, et al. Phase III study of interferon alfa-NL as adjuvant 
treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup 
trial. J Clin Oncol 21:1214-22, 2003. 
 
8  
Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell vaccine and risk of 
tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, 
randomized controlled trial. Lancet 363:594-9, 2004. 
 
9  
Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-
96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy 
for renal cell carcinoma: a multicentre, open-label, randomized phase III trial. Lancet 372:145-54, 
2008. 
 
10  
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell 
carcinoma. N Engl J Med 356:115-24, 2007. 
 
11  
Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N 
Engl J Med 356:125-34, 2007. 
 
12  
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced 
renal-cell carcinoma. N Engl J Med 356:2271-81, 2007. 
 
13  
Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment 
of metastatic renal cell carcinoma: a randomized, double-blind phase III trial. Lancet 370:2103-11, 
2007. 
 
14  
Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon 
alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 
26:5422-8, 2008. 
 
15  
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: 
a double-blind, randomized, placebo-controlled phase III trial. Lancet 372:449-56, 2008. 

 
 
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16  
Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance 
protocol for patients with localized and locally advanced renal cell carcinoma based on a 
validated prognostic nomogram and risk group stratification system. J Urol 174:466-72; 
discussion 72; quiz 801, 2005. 
 
17  
Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1alpha expression 
and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004-14, 2002. 
 
18  
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced 
renal-cell carcinoma. N Engl J Med 356:2271-81, 2007. 
 
19  
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative 
treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 
20:289-96, 2002. 
 
20  
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: 
a double-blind, randomized, placebo-controlled phase III trial. Lancet 372:449-56, 2008. 
21  
Everolimus Investigators Brochure, Edition 12, Novartis Pharmaceuticals, 2013. 
 
22  
O'Donnell A, Faivre S, Burris HA, 3rd, et al. Phase I pharmacokinetic and pharmacodynamic 
study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced 
solid tumors. J Clin Oncol 26:1588-95, 2008. 
 
23  
Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the mammalian 
target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients 
with advanced solid tumors. J Clin Oncol 26:1603-10, 2008. 
 
24  
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: 
a double-blind, randomized, placebo-controlled phase III trial. Lancet 372:449-56, 2008. 
 
25  
Motzer RJ, et al.  Phase III trial of everolimus for metastatic renal cell carcinoma:  final results and 
analysis of prognostic factors.  Cancer 116(18):4256-65, 2010. 
 
26  
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: 
a double-blind, randomized, placebo-controlled phase III trial. Lancet 372:449-56, 2008. 
 
27  
Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: 
a double-blind, randomized, placebo-controlled phase III trial. Lancet 372:449-56, 2008. 
 
28  
O'Donnell A, Faivre S, Burris HA, 3rd, et al. Phase I pharmacokinetic and pharmacodynamic 
study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced 
solid tumors. J Clin Oncol 26:1588-95, 2008. 
 
29  
Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the mammalian 
target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients 
with advanced solid tumors. J Clin Oncol 26:1603-10, 2008. 
 
30  
http://clinicaltrials.gov/ct/show/NCT00326898. 
 
31  
Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin 
RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging 
system. J Clin Oncol Mar 15;19(6):1649-57, 2001. 
 
32  
Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance 
protocol for patients with localized and locally advanced renal cell carcinoma based on a 
validated prognostic nomogram and risk group stratification system. J Urol 174:466-72; 
discussion 72; quiz 801, 2005. 

 
 
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33  
Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin 
RA, Belldegrun AS. Improved prognostication of renal cell carcinoma using an integrated staging 
system. J Clin Oncol Mar 15;19(6):1649-57, 2001. 
 
34  
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced 
renal-cell carcinoma. N Engl J Med 356:2271-81, 2007. 
 
35  
Dutcher JP et al.  26(2):202-9. Epub 2009 Feb 20. 
 
36  
Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of everolimus in de novo renal 
transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response 
relationships, and influence on cyclosporine. Clin Pharmacol Ther 69:48-56, 2001. 
 
37  
Vitko S, Margreiter R, Weimar W, et al. Everolimus (Certican) 12-month safety and efficacy 
versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 78:1532-40, 
2004. 
 
38  
Kovarik JM, Kaplan B, Tedesco Silva H, et al. Exposure-response relationships for everolimus in 
de novo kidney transplantation: defining a therapeutic range. Transplantation 73:920-5, 2002. 
 
39  
Kovarik JM, Kahan BD, Kaplan B, et al. Longitudinal assessment of everolimus in de novo renal 
transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response 
relationships, and influence on cyclosporine. Clin Pharmacol Ther 69:48-56, 2001. 
 
40  
Mabasa VH, Ensom MH. The role of therapeutic monitoring of everolimus in solid organ 
transplantation. Ther Drug Monit 27:666-76, 2005. 
 
41  
Kovarik JM, Kaplan B, Tedesco Silva H, et al. Exposure-response relationships for everolimus in 
de novo kidney transplantation: defining a therapeutic range. Transplantation 73:920-5, 2002. 
 
42  
Kovarik JM, Tedesco H, Pascual J, et al. Everolimus therapeutic concentration range defined 
from a prospective trial with reduced-exposure cyclosporine in de novo kidney transplantation. 
Ther Drug Monit 26:499-505, 2004. 
 
43  
O'Donnell A, Faivre S, Burris HA, 3rd, et al. Phase I pharmacokinetic and pharmacodynamic 
study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced 
solid tumors. J Clin Oncol 26:1588-95, 2008. 
 
44  
Tabernero J, Rojo F, Calvo E, et al. Dose- and schedule-dependent inhibition of the mammalian 
target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients 
with advanced solid tumors. J Clin Oncol 26:1603-10, 2008. 
 
45  
Pocock SJ, Simon R.  Sequential treatment assignment with balancing for prognostic factors in 
controlled clinical trials.  Biometrics 31:103-115, 1975. 
 
 
 
 

 
 
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18.0 
APPENDIX 
 
18.1 
New York Heart Association Classifications 
 
18.2 
Emergency Unblinding Guidelines 
 
18.3 
Examples of Clinically Relevant Drug Interactions:  Substrates, Inducers and Inhibitors of 
the Isoenzyme CYP3A4 
 
18.4 
Intake Calendar  
 

 
 
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18.1 
New York Heart Association Classifications 
 
 
TABLE I, NEW YORK HEART ASSOCIATION CLASS 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
 
 
 
 
 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. 
 
** At accustomed occupation or usual tasks. 
 

 
 
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18.2 
Emergency Unblinding Guidelines 
 
a. 
General Considerations 
 
The randomized regimen for this study includes a blinded drug, which is either 
everolimus or placebo.  During the course of this study it may become 
necessary to identify (or unblind) a patient's treatment assignment.  The 
circumstances that will warrant emergency unblinding and the procedure for 
emergency unblinding are described in this Appendix. 
 
PLEASE NOTE:  Unblinding requests for disease recurrence MUST be 
handled by the planned unblinding instructions outlined in Section 7.5.  Do not 
contact the Washington Poison Center with these requests. 
 
b. 
Criteria for Emergency Unblinding 
 
In general, treatment assignments will not be emergency unblinded unless 
there is a compelling medical or ethical reason that the treatment should be 
identified.  In most circumstances it will be appropriate to treat the patient or 
person who received blinded drug as though he or she received everolimus, 
irrespective of the drug actually received.  Therefore, emergency unblinding 
should seldom be necessary. 
 
The following events MAY require emergency unblinding of treatment 
assignments in this study: 
 
1. 
A compelling medical need as determined by a physician, e.g., 
existence of a condition for which knowledge of the patient's treatment 
assignment is necessary for the selection of appropriate care. 
 
2. 
Administration of blinded drug to a person other than the patient. 
 
c. 
Procedure for Emergency Unblinding 
 
Emergency unblinding of treatment assignments for patients on this study will 
be performed by the Washington Poison Center (WPC), upon approval from a 
designated physician (either one of the WPC's resource physicians or Dr. 
Christopher Ryan).  The procedure for emergency unblinding the treatment 
assignment for a patient on this study is as follows: 
 
1. 
All requests for emergency unblinding must be made by the registering 
physician or his/her designee. 
 
2. 
Call the WPC collect at 206/526-2121 from outside Washington State or 
toll free at 800/222-1222 from within Washington State.  The WPC is 
accessible 24 hours per day, 365 days per year. 
 
3. 
The person calling the WPC must be prepared to provide the following 
information: 
 
Study number (S0931) 
 
SWOG Patient Number (e.g., "999999") 
 
Patient Initials 
 
Name and telephone number of the caller 
 
Reason emergency unblinding is thought to be required 

 
 
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4. 
The WPC will contact one of its resource physicians and provide the 
information received from the caller.  If none of the WPC's resource 
physicians can be contacted, then the WPC will contact Dr. Christopher 
Ryan.  The contacted physician will evaluate the need for emergency 
unblinding and provide the WPC either approval to unblind or a 
recommendation for treatment, if any, while maintaining blinding.  The 
WPC will then call the person who initiated the unblinding request and 
tell him/her either the treatment assignment or the resource physician's 
treatment recommendation. 
 
5. 
If the WPC is unable to contact any of its resource physicians or Dr. 
Ryan within three hours after receiving the request for emergency 
unblinding, then the WPC will notify the person who initiated the 
unblinding request that treatment assignment will not be unblinded at 
that time and treatment of the patient or person who received blinded 
drug should proceed as if the blinded drug is everolimus.  In such cases, 
the WPC will continue to attempt to contact the resource physicians, and 
when one of them is contacted, will proceed as in #4 above. 
 
6. 
Any patient whose treatment assignment is emergency unblinded will 
receive no further blinded drug, but should continue all other protocol 
treatment if his/her medical condition permits. 
 
7. 
Unblinding of treatment assignments for any reason must be 
documented on the Off Treatment Notice. 
 
Questions regarding the unblinding may be directed to any of the 
following resource physicians: 
 
Christopher W. Ryan, M.D. 
Oregon Health & Science University 
3303 SW Bond Avenue, CH14R 
Portland, OR 97239 
Phone:  503/494-8487 
 
Bruce G. Redman, D.O. 
SWOG 
24 Frank Lloyd Wright Drive 
P.O. Box 483 
Ann Arbor, MI  48106 
Phone:  734/998-7154 
 
Washington Poison Center 
Phone:  206/526-2121 

 
 
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18.3 
Examples of Clinically Relevant Drug Interactions:  Substrates, Inducers and Inhibitors of 
the Isoenzyme CYP3A4 
 
Only the strong CYP3A4 inducers and inhibitors listed in Section 5.2e are prohibited 
during study treatment.  Refer to Sections 7.1c and 7.3 for guidance regarding the use of 
moderate CYP3A4 inducers and inhibitors while on treatment. 
 
CYP3A4 Substrates 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Dasatinib (1) 
Delavirdine 
Diazepam 
Dihydroergotamine  
Diltiazem  
Disopyramide  
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., synthetic 
Estrogens, conj., equine 
Estrogens, conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine  
Itraconazole 
Ketamine  
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole  
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 

 
 
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CYP3A4 Inhibitors 
Acetominophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 

 
 
S0931 
 
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CYP3A4 Inducers 
 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
 
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
 
Rifapentine 
St. John’s wort 
(3) 
 
When drugs classified as ‘substrates’ are co-administered with everolimus, there is the 
potential for higher concentrations of the ‘substrate’. When everolimus is co-
administered 
with 
compounds 
classified 
as 
‘inhibitors’, 
increased 
plasma 
concentrations of everolimus is the potential outcome. The co-administration of 
‘inducers’ would potentially lower plasma everolimus concentrations. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: 
Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH 
ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912.   
 
Only major substrates and effective inducers are listed.  Additional information for drug 
interactions 
with 
cytochrome 
P450 
isoenzymes 
can 
be 
found 
at 
http://medicine.iupui.edu/flockhart/. 
 
PgP Inhibitors 
PgP Substrates 
PgP Inhibitors in vivo 
PgP Inducers 
digoxin, fexofenadine, 
indinavir, vincristine, 
colchicine, topotecan, 
paclitaxel 
amiodarone, 
azithromycin, captopril, 
carvedilol, 
clarithromycin, 
conivaptan, 
cyclosporine, 
diltiazem, elacridar, 
erythromycin, 
felodipine, 
(GF120918), 
itraconazole, 
ketocoanzole, 
lopinavir, (LY335979), 
mibefradil, nifedipine, 
nitrendipine, 
(PSC833), quinidine, 
ranolazine, ritonavir, 
talinolol, valspodar, 
verapamil 
rifampin, St John’s wort 
 

 
 
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18.4 
Intake Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature: 
 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________
 
 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 
take each day.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day 
you note the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your next appointment is: _______________________ 
Special instructions: 
 
Month: 
 
Year: 
 

 
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Informed Consent Model for S0931 
 
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:  
 
This model informed consent form has been reviewed by the DCTD/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed.  (Institutions 
should attempt to use sections of this document that are in bold type in their entirety.)  Editorial 
changes to these sections may be made as long as they do not change information or intent.  If 
the institutional IRB insists on making additions, deletions or more substantive modifications to 
the risks or alternatives sections, they may be justified in writing by the investigator and 
approved by the IRB.  Under these circumstances, the revised language, justification and a copy 
of the IRB minutes must be forwarded to the SWOG Operations Office for approval before a 
patient may be registered to this study.   
 
Please particularly note that the questions related to banking of specimens for future study 
are in bolded type and may not be changed in any way without prior approval from the 
SWOG Operations Office. 
Readability Statistics:   
 
Flesch Reading Ease  
64.7 (targeted above 55) 
Flesch-Kincaid Grade Level 8.0 (targeted below 8.5) 
 
• 
Instructions and examples for informed consent authors are in [italics].  
• 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
• 
The term "study doctor" has been used throughout the model because the local 
investigator for a cancer treatment trial is a physician.   If this model is used for a 
trial in which the local investigator is not a physician, another appropriate term 
should be used instead of "study doctor".  
• 
The dates of protocol updates in the header and in the text of the consent is for 
reference to this model only and should not be included in the informed consent 
form given to the prospective research participant.  
• 
The local informed consent must state which parties may inspect the research 
records. This includes the NCI, the drug manufacturer for investigational studies, 
any companies or grantors that are providing study support (these will be listed in 
the protocol's model informed consent form) and SWOG.  
 
SWOG must be listed as one of the parties that may inspect the research records in 
all protocol consent forms for which patient registration is being credited to 
SWOG.  This includes consent forms for studies where all patients are registered 
directly through the SWOG Data Operations Office, all intergroup studies for 
which the registration is being credited to SWOG (whether the registration is 
through the SWOG Data Operations Office or directly through the other group), as 
well as consent forms for studies where patients are registered via CTSU and the 
registration is credited to SWOG. 

 
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• 
When changes to the protocol require revision of the informed consent document, 
the IRB should have a system that identifies the revised consent document, in order 
to preclude continued use of the older version and to identify file copies.  An 
appropriate method to identify the current version of the consent is for the IRB to 
stamp the final copy of the consent document with the approval date.  The stamped 
consent document is then photocopied for use.  Other systems of identifying the 
current version of the consent such as adding a version or approval date are allowed 
as long as it is possible to determine during an audit that the patient signed the most 
current version of the consent form.  
 
*NOTES FOR LOCAL INVESTIGATORS:  
• 
The goal of the informed consent process is to provide people with sufficient 
information for making informed choices.   The informed consent form provides a 
summary of the clinical study and the individual's rights as a research participant.  
It serves as a starting point for the necessary exchange of information between the 
investigator and potential research participant.  This model for the informed consent 
form is only one part of the larger process of informed consent. For more 
information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared 
by the Comprehensive Working Group on Informed Consent in Cancer Clinical 
Trials for the National Cancer Institute.  The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/ 
• 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
• 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is 
available for your patients.  The pamphlet is titled: "Taking Part in Cancer 
Treatment Research Studies".  This pamphlet may be ordered on the NCI Web site 
at https://cissecure.nci.nih.gov/ncipubs or call 1-800-4- CANCER (1-800-422-
6237) to request a free copy.  
• 
Optional feature for Local Investigators: Reference and attach drug sheets, 
pharmaceutical information for the public, or other material on risks.  Check with 
your local IRB regarding review of additional materials. 
 
*These notes for authors and investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant.  

 
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S0931, "EVEREST:  EVErolimus for Renal Cancer Ensuing Surgical 
Therapy, a Phase III Study" 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.  Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
 
You are being asked to take part in this study because you have cancer of the kidney that has 
been surgically removed. 
 
Why is this study being done? 
 
The purpose of this study is to see whether treatment with everolimus after surgery for 
kidney cancer will increase the time without cancer returning.  The current standard 
treatment after surgery is careful monitoring with no immediate treatment.  Studies 
suggest that one way kidney cancer may grow is through chemical signaling through a 
protein named “mTOR”.  Everolimus is a drug that stops signaling through mTOR and 
may therefore stop the growth of kidney cancer.  Everolimus is a drug currently approved 
for the treatment of patients with advanced or metastatic kidney cancer.  It is considered 
investigational for use after surgery.  In this study, you will get either everolimus or 
placebo (a pill with no medication).  You will not get both. 
 
How many people will take part in the study? 
 
About 1,537 people will take part in this study.  
 
What will happen if I take part in this research study?   
 
Before you begin the study …  
 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
• Medical history including screening for hepatitis B and C risk and physical examination, 
• Blood tests for blood counts and to test your kidney and liver function, 
• Blood tests to check your blood sugar (glucose) and lipids (cholesterol and triglycerides), 
• CT scan to assess your disease. 
 
During the study … (section updated 5/6/14) 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures.  They are part of regular cancer care.  

 
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• History and physical exam at the beginning of Week 1 and Week 4. (NOTE:  If you receive a 
prestudy history and physical exam within 28 days prior to starting on this study, then these 
tests do not need to be repeated during Week 1.) 
• Physical exam at the beginning of each 6 week cycle (Week 7, 13, 19, etc.) for a maximum 
of 9 cycles, (2/11/16) 
• Blood tests for blood counts and to test your kidney and liver function at the beginning of 
each 6 week cycle (Week 7, 13, 19, etc.) for a maximum of 9 cycles, (2/11/16) 
• Blood tests to check your blood sugar (glucose) and lipids (cholesterol and triglycerides) at 
the beginning of each 6 week cycle (Week 7, 13, 19, etc.) for a maximum of 9 cycles, 
(2/11/16) 
• CT scan to assess your disease every eighteen weeks. 
 
You will be "randomized" into one of the study groups described below. Randomization means 
that you are put into a group by chance.  It is like flipping a coin except that a computer program 
will place you in one of the study groups.  Neither you nor your doctor can choose the group you 
will be in.  You will have an equal chance of being placed in either group.  Once you have been 
placed into one of the groups, neither you nor your doctor will know which group you are in.  
The treatment in each group will be identical except that half of the patients will receive the 
investigational drug everolimus and half will take an identical placebo pill.  Placebo pills do not 
contain any medication.  These pills will look just like the pills containing everolimus. (5/6/14) 
 
You will take two pills once a day by mouth with a glass of water and no more than a light fat-
free meal. (7/11/12)  Tablets must be swallowed whole and not chewed or crushed.  Due to 
interaction with everolimus, you must not consume grapefruit or grapefruit juice while on study. 
 
You will record the number of pills you take each day and any side effects you experience on a 
calendar.  For the first 6 weeks, your doctor’s office will call you to see how you are doing on 
the weeks that you don’t have visits scheduled.  You should bring your calendar with you each 
time you have a doctor’s visit.  During your visits, your pills will be counted and your calendar 
reviewed.  For this study, each six-week treatment period is called a cycle.  Treatment will 
continue for nine cycles (54 weeks) as long as you are able to tolerate treatment and your cancer 
hasn’t returned.  All treatment can be given without being admitted to a hospital.   
 
If your cancer returns, your treatment may be unblinded by your doctor to find out if you were 
receiving everolimus or placebo.  Your doctor may want this information to decide on additional 
treatment options for you.  You or your insurance company will be responsible for the cost of 
treatment with everolimus if and when your doctor prescribes it for you off study.  (paragraph 
added 7/11/12) 
 
How long will I be in the study? 
 
You will be asked to take the study drug for nine six-week cycles, or until your side effects 
become too great, or until your cancer returns.  While you are receiving study treatment, you will 

 
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need to come to the clinic for doctor visits every six weeks for the first 54 weeks including visits 
for scans every 18 weeks (or every 4 months). (12/15/14) After you are finished with the study 
treatment, you will return to the clinic with scans every six months for Years 2 and 3, and then 
yearly thereafter until 10 years after registration. (12/15/14) 
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely. It is important to tell the 
study doctor if you are thinking about stopping so any risks from the study drug can be evaluated 
by your doctor.  Another reason to tell your doctor that you are thinking about stopping is to 
discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the study?  
 
You may have side effects while on the study.  Everyone taking part in the study will be 
watched carefully for any side effects.  However, doctors don’t know all the side effects that 
may happen.  Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects. Many side effects go away soon after you stop taking 
the study drug. In some cases, side effects can be serious, long lasting, or may never go 
away.  There also is a risk of death. 
 
You should talk to your study doctor about any side effects that you have while taking part 
in the study.    
 
Risks and side effects related to everolimus/placebo include those which are: (section updated 
12/15/14, 5/6/14, 2/11/16, updated 6/6/16, 11/11/16) (10/3/17) 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Everolimus/Placebo, more than 20 and up to 100 may have: 
• Anemia which may require blood transfusion 
• Diarrhea 
• Sores in the mouth which may cause difficulty swallowing 
• Tiredness 
• Rash 

 
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OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving everolimus, from 4 to 20 may have: 
• Pain 
• Constipation, nausea, vomiting 
• Swelling of the arms, legs 
• Fever 
• Infection, especially when white blood cell count is low 
• Bruising, bleeding 
• Weight loss, loss of appetite 
• Changes in taste 
• Headache 
• Cough, shortness of breath 
• Nose bleed 
• Damage to the lungs which may cause shortness of breath 
• Dry skin 
• Itching 
 
RARE, AND SERIOUS 
In 100 people receiving everolimus, 3 or fewer may have: 
• Non-healing surgical site 
• Kidney damage which may require dialysis 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
and for at least 8 weeks following completion of therapy because the drugs in this study can 
affect an unborn baby.  Women should not breastfeed a baby while on this study and for at 
least 8 weeks following completion of therapy.  It is important you understand that you 
need to use birth control while on this study.  Check with your study doctor about what 
kind of birth control methods to use and how long to use them.  Some methods might not 
be approved for use in this study. 
 
The study drug may interact with other medications.  Cases of a type of pneumonia (caused 
by a fungus called Pneumocystis jirovecii), some with a fatal outcome, have been reported 
in patients who received everolimus.  This type of pneumonia has been linked to the use of 
corticosteroids or other drugs that can weaken the immune system while using everolimus.  
Patients taking angiotensin converting enzyme (ACE) inhibitor therapy may be at an 
increased risk for swelling of the airways or tongue, with or without damage to the lungs.  
You should tell your study doctor about all medications (over the counter, herbal, and 
prescription) you are currently taking and check with your study doctor before beginning 
any new medications.  (Paragraph updated 12/15/14) 
 

 
S0931 
 
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Vaccines help protect people from certain illnesses.  There is a chance that receiving 
everolimus could interfere with any vaccinations you receive.  Some vaccines are made 
from live bacteria or live viruses.  You cannot receive this kind of vaccine (for example 
FluMist™ or BCG) for seven days prior to going on study or during the study. 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the study? 
 
Taking part in this study may or may not make your health better.  While doctors hope the 
study drug will be more useful against cancer compared to the usual treatment, there is no 
proof of this yet. We do know that the information from this study will help doctors learn 
more about everolimus as a treatment for cancer.  This information could help future 
cancer patients. 
 
What other choices do I have if I do not take part in this study? 
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting no treatment 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• SWOG 
• Qualified representative from Novartis Pharmaceuticals (manufacturer of everolimus) 
• The National Cancer Institute (NCI) and other government agencies, like the Food and Drug 
Administration (FDA), involved in keeping research safe for people 
• The Cancer Trials Support Unit (CTSU), a research group sponsored by the National Cancer 
Institute (NCI) to provide greater access to cancer trials. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. law.  (12/15/14) This Web site will not include information that can identify you.  At 
most, the Web site will include a summary of the results.  (12/15/14) You can search this Web 
site at any time. (paragraph added 7/11/12) 
 

 
S0931 
 
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[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
What are the costs of taking part in this study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
Administration of the drug will be (provided free of charge/charged in the usual way).  The parts 
of the research consisting of keeping research records will be paid by those organizing and 
conducting the research.  The research requires that you receive certain standard medical tests 
and examinations.  These standard tests and examinations will be (charged in the usual 
way/provided at a reduced rate).  (local institutions must choose the option that best fits the 
hospital's situation) 
 
Novartis Pharmaceuticals will supply the investigational agent everolimus or placebo at no 
charge while you take part in this study.  Novartis Pharmaceuticals does not cover the cost of 
getting the everolimus or placebo ready and giving it to you, so you or your insurance company 
may have to pay for this.   
 
Even though it probably won’t happen, it is possible that Novartis Pharmaceuticals may not 
continue to provide the everolimus or placebo for some reason.  If this would occur, other 
possible options are: 
 
1. 
You might be able to get the everolimus from your pharmacy but you or your insurance 
company may have to pay for it. 
 
2. 
If there is no everolimus or placebo available at all, no one will be able to get more and 
the study would close. 
 
If a problem with getting everolimus or placebo occurs, your study doctor will talk to you about 
these options.  (paragraph added 7/11/12) 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/about-cancer/treatment/clinical-trials/paying/insurance.  
You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web 
site. (revised 2/11/16) 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 

 
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What happens if I am injured because I took part in this study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.   
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study. We will tell you about important new information 
from this or other studies that may affect your health, welfare, or willingness to stay in this study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people who 
review the research to protect your rights) at __________________ (telephone number).  [Note to 
Local Investigator: Contact information for patient representatives or other individuals in a local 
institution who are not on the IRB or research team but take calls regarding clinical trial questions 
can be listed here.]    
 
 *You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) 
at 888-657-3711 (from the continental US only).   [*Only applies to sites using the CIRB.] 
 
(paragraph deleted 7/11/12) 
 

 
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Please note:  This section of the informed consent form is about additional research studies that 
are being done with people who are taking part in the main study.   You may take part in these 
additional studies if you want to.  You can still be a part of the main study even if you say 'no' to 
taking part in any of these additional studies. 
 
You can say "yes" or "no" to each of the following studies.  Please mark your choice for each 
study.   
 
 (paragraph deleted 7/11/12) 
 
Future Contact 
I agree to allow my study doctor, or someone approved by my study doctor, to contact me 
regarding future research involving my participation in this study. 
 
Yes 
No 
Consent Form for Use of Specimens for Research 
 
About Using Specimens for Research 
 
We would like to keep some specimens for future research. (7/11/12)  If you agree, these 
specimens will be kept and may be used in research to learn more about cancer and other 
diseases. Please read the information sheet called "How are Specimens Used for 
Research" to learn more about specimen research. (paragraph moved up 7/11/12) 
 
If you agree, a sample of your blood and tumor tissue will be banked for future research 
to study the biology of your cancer and how everolimus works. (7/11/12) The blood 
samples will be obtained to measure the level of everolimus in your blood.  We will see if 
those levels correspond to the risk of getting certain side effects.  In the tumor samples 
we will measure the levels of certain proteins to see if they predict how well everolimus 
will work.  The blood sample (about 3 ½ teaspoons) will be collected before you begin 
study treatment, before Cycles 2 and 3, when you go off protocol treatment, and if your 
cancer recurs.  The blood sample must be taken before your daily dose of study drug.  
The tumor tissue sample will be taken from your kidney cancer specimen (obtained from 
your recent operation).  (You will not need to have another surgery for this purpose.)  
These collections are optional.  (sentences deleted 7/11/12) 
 
(section deleted 7/11/12) 
 
The research that may be done with your specimens is not designed specifically to help 
you. It might help people who have cancer and other diseases in the future.  
 
Reports about research done with your specimens will not be given to you or your doctor. 
These reports will not be put in your health record. The research will not have an effect 
on your care.  
 
Things to Think About  

 
S0931 
 
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Version Date 12/11/2020 
 
 
 
 
The choice to let us keep the left over specimens for future research is up to you. No 
matter what you decide to do, it will not affect your care.  
 
If you decide now that your specimens can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use your 
specimens. Then any specimens that remain will no longer be used for research.  
 
In the future, people who do research may need to know more about your health. While 
SWOG may give them reports about your health, it will not give them your name, 
address, phone number, or any other information that will let the researchers know who 
you are.  
 
Sometimes specimens are used for genetic research (about diseases that are passed on in 
families).   Even if your specimens are used for this kind of research, the results will not 
be put in your health records.  
 
If your confidential genetic information is discovered, you may suffer from genetic 
discrimination. Genetic discrimination occurs if people are treated unfairly because of 
differences in their genes that increase their chances of getting a certain disease. In the 
past, this could have resulted in the loss of health insurance or employment. Because of 
this, The Genetic Information Nondiscrimination Act of 2008, also referred to as GINA, 
was passed by Congress to protect Americans from such discrimination. The new law 
prevents discrimination from health insurers and employers. This act was signed into 
federal law on May 21, 2008, and went into effect May 2009. This law does not cover life 
insurance, disability insurance and long-term care insurance.  (paragraph added 7/11/12) 
 
While this study has safeguards in place to protect your confidential genetic information 
and to make it extremely unlikely that your identity would be connected with any special 
studies that are performed on your tissue, it is possible that this information could be 
discovered by someone who is unauthorized to have access to it. (paragraph added 
7/11/12) 
 
Your specimens will be used only for research and will not be sold. The research done 
with your specimens may help to develop new products in the future.  
 
Benefits   
 
The benefits of research using specimens include learning more about what causes cancer 
and other diseases, how to prevent them, and how to treat them.  

 
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Risks  
 
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
 
Making Your Choice  
 
Please read each sentence below and think about your choice. After reading each 
sentence, circle "Yes" or "No."  If you have any questions, please talk to your doctor or 
nurse, or call our research review board at IRB's phone number.  
 
Making Your Choice  
 
Please read each sentence below and think about your choice. After reading each 
sentence, circle "Yes" or "No."  If you have any questions, please talk to your doctor or 
nurse, or call our research review board at IRB's phone number.  
 
No matter what you decide to do, it will not affect your care. 
 
1.  
My specimens may be kept for use in research to learn about, prevent, treat 
or cure cancer.  
Yes 
No 
 
2.  
My specimens may be kept for use in research about other health problems 
(for example: diabetes, Alzheimer's disease, or heart disease).  
Yes 
No 
 
3.  
Someone may contact me in the future to ask me to allow other uses of my 
specimens.  
Yes 
No 
 
If you decide to withdraw your specimens from a SWOG Specimen Repository in the 
future, a written withdrawal of consent should be submitted through your study doctor to 
the SWOG Operations Office.  Please designate in the written withdrawal whether you 
would prefer to have the specimens destroyed or returned to the study doctor. 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) (revised 2/11/16) 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 

 
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• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form.    If you want more information about this study, ask your study 
doctor. 
 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
Participant ________________________________ 
 
Date _____________________________________ 

 
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Specimen Consent Supplemental Sheets 
 
How are Specimens Used for Research? 
 
Where do specimens come from? 
 
A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials.  
People who are trained to handle specimens and protect donors' rights make sure that the highest 
standards of quality control are followed by SWOG.  Your doctor does not work for SWOG, but has 
agreed to help collect specimens from many patients.  Many doctors across the country are helping in the 
same way.   
 
Why do people do research with specimens? 
 
Research with specimens can help to find out more about what causes cancer, how to prevent it, how to 
treat it, and how to cure it.  Research using specimens can also answer other health questions.  Some of 
these include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's. 
 
What type of research will be done with my specimen? 
 
Many different kinds of studies use specimens.  Some researchers may develop new tests to find 
diseases.  Others may develop new ways to treat or even cure diseases.  In the future, some of the 
research may help to develop new products, such as tests and drugs.  Some research looks at diseases 
that are passed on in families (called genetic research).  Research done with your specimen may look for 
genetic causes and signs of disease. 
 
How do researchers get the specimen? 
 
Researchers from universities, hospitals, and other health organizations conduct research using 
specimens.  They contact SWOG and request samples for their studies.  SWOG reviews the way that 
these studies will be done, and decides if any of the samples can be used. SWOG gets the specimen and 
information about you from your hospital, and sends the specimen samples and some information about 
you to the researcher.  SWOG will not send your name, address, phone number, social security number 
or any other identifying information to the researcher. 
 
Will I find out the results of the research using my specimen? 
 
You will not receive the results of research done with your specimen.  This is because research can take 
a long time and must use specimen samples from many people before results are known.  Results from 
research using your specimen may not be ready for many years and will not affect your care right now, 
but they may be helpful to people like you in the future. 
 
Why do you need information from my health records? 
 
In order to do research with your specimen, researchers may need to know some things about you.  (For 
example:  Are you male or female?  What is your race or ethnic group? How old are you?  Have you ever 
smoked?)  This helps researchers answer questions about diseases.  The information that will be given to 
the researcher may include your age, sex, race, diagnosis, treatments and family history.  This 
information is collected by your hospital from your health record and sent to SWOG.  If more information 
is needed, SWOG will send it to the researcher. 
 
Will my name be attached to the records that are given to the researcher? 
 
No.  Your name, address, phone number and anything else that could identify you will be removed before 
they go the researcher.  The researcher will not know who you are. 
 

 
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How could the records be used in ways that might be harmful to me? 
 
Sometimes, health records have been used against patients and their families.  For example, insurance 
companies may deny a patient insurance or employers may not hire someone with a certain illness (such 
as AIDS or cancer).  The results of genetic research may not apply only to you, but to your family 
members too.  For disease caused by gene changes, the information in one person's health record could 
be used against family members. 
 
How am I protected? 
 
SWOG is in charge of making sure that information about you is kept private.  SWOG will take careful 
steps to prevent misuse of records.  Your name, address, phone number and any other identifying 
information will be taken off anything associated with your specimen before it is given to the researcher.  
This would make it very difficult for any research results to be linked to you or your family.  Also, people 
outside the research process will not have access to results about any one person which will help to 
protect your privacy. 
 
What if I have more questions? 
 
If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert 
IRB's Phone Number).