Clinical trial NCT01198158
Conditions: Clear Cell Renal Cell Carcinoma Recurrent Renal Cell Carcinoma Stage III Renal Cell Cancer AJCC v7 Stage IV Renal Cell Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2010-09-15; Completion date: 2017-12-16
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies giving everolimus together with bevacizumab to see how well it works compared to everolimus alone in treating patients with advanced kidney cancer that progressed after first-line therapy. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can interfere with tumor growth by blocking the ability of tumor cells to grow and spread. Everolimus and bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor. It is not yet known whether giving everolimus together with bevacizumab is better than everolimus alone in treating patients with advanced kidney cancer that has progressed after first-line therapy.

Detailed description:
PRIMARY OBJECTIVES:

l. To compare the overall survival of patients receiving bevacizumab plus everolimus and everolimus alone among patients with advanced renal cell carcinoma progressing after first line vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) treatment.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival and proportion who experience an objective response (defined as complete clinical response \[cCR\] + partial response \[PR\]) in patients with advanced renal cell carcinoma receiving bevacizumab plus everolimus and everolimus alone.

II. To compare grade 3 or higher toxicity in patients receiving each treatment regimen.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive everolimus orally (PO) once daily (QD) on days 1-28.

ARM II: Patients receive everolimus PO QD on days 1-28 and bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 8 weeks until disease progression and then every 6 months for up to 5.5 years.

Arms: arm 1: Patients receive everolimus PO QD on days 1-28. arm 2: Patients receive everolimus PO QD on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 15.
Interventions: intervention 1: Bevacizumab intervention 2: Everolimus intervention 3: Laboratory Biomarker Analysis intervention 4: Pharmacological Study
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Correlative studies intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
 
1
Update #05 
07/01/2014 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_______________________________________________________ 
PROTOCOL UPDATE TO CALGB 90802 
_______________________________________________________ 
 
RANDOMIZED PHASE III TRIAL COMPARING EVEROLIMUS VERSUS EVEROLIMUS 
PLUS BEVACIZUMAB FOR ADVANCED RENAL CELL CARCINOMA PROGRESSING 
AFTER TREATMENT WITH TYROSINE KINASE INHIBITORS 
 
NCI-supplied agent(s): Bevacizumab (NSC 704865, IND #113911) 
 
X 
Update: 
 
 
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Pre-Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Activation 
 
 
 
 
 
X 
Informed Consent changes 
 
 
Closure 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
Reactivation 
 
 
 
 
 
X 
Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X 
Other: Bevacizumab CAEPR Update 
 
 
 
  
 
The changes included in this update to CALGB 90601 have been made in response to the NCI Request 
for Amendment (RA) from Dr. Helen Chen dated May 09, 2014. 
 
This update contains modifications to the risk information in the model consent form consistent with 
the new NCI Model Consent Template instructions. There are no changes to the risk/benefit ratio and 
this information would have already been communicated to study participants in the previous version 
of the informed consent document. The Alliance does not require patient re-consent. 
 
IRB review of this update is required within 90 days. Full Board review is recommended. 
 
Please follow your local IRB guidelines. 
 
 
UPDATES TO THE PROTOCOL: 
 
Cover Page   
• 
“Vance E. Erese” replaces “Michele M. Seiler, MS” as Protocol Coordinator. 
 


 
2
Section 16.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for bevacizumab 
(rhuMAb VEGF, NSC 704865) 
An updated CAEPR for bevacisumab (Version 2.3, August 1, 2013) has replaced the previous version. In 
this updated version, the following revisions have been made: 
• 
Added New Risk:  
• 
Less Likely:  Dehydration; Wound complication  
• 
Rare But Serious:  Infections and infestations – Other (necrotizing fasciitis) 
• 
Also Reported on Bevacizumab Trials But With the Relationship to Bevacizumab Still 
Undetermined:  Acidosis; Activated partial thromboplastin time prolonged; Agitation; 
Alopecia; Anxiety; Arachnoiditis; Arterial injury; Arthritis; Ascites; Ataxia; Atelectasis; 
Atrioventricular block complete; Atrioventricular block first degree; Back pain; Bladder 
spasm; Blood antidiuretic hormone abnormal; Blurred vision; Bone marrow hypocellular; 
Bone pain; Breast pain; Bruising; Burn; Carbon monoxide diffusing capacity decreased; 
Cardiac arrest; Cataract; CD4 lymphocytes decreased; Central nervous system necrosis; 
Cerebrospinal fluid leakage; Chelitis; Chest wall pain; Cholecystitis; Chronic kidney disease; 
Cognitive disturbance; Colonic stenosis; CPK increased; Cystitis noninfective; Death NOS; 
Depressed level of consciousness; Depression; Dermatitis radiation; Dry eye; Dry mouth; Dry 
skin; Dysesthesia; Dysphagia; Dysphasia; Ear and labyrinth disorders – Other (tympanic 
membrane perforation); Edema face; Edema limbs; Edema trunk; Electrocardiogram QT 
corrected interval prolonged; Encephalopathy; Enterocolitis; Erectile dysfunction; 
Esophageal pain; Esophageal stenosis; Extraocular muscle paresis; Extrapyramidal disorder; 
Eye disorders – Other (blindness); Eye disorders – Other (conjunctival hemorrhage); Eye 
disorders – Other (corneal epithelial defect); Eye disorders – Other (floaters); Eye disorders – 
Other (ischemic CRVO); Eye disorders – Other (macular pucker); Eye disorders – Other 
(transient increased IOP > or = 30 mm Hg); Eye disorders – Other (vitreous hemorrhage); 
Eye pain; Facial nerve disorder; Facial pain; Fever; Fibrosis deep connective tissue; 
Flatulence; Flu like symptoms; Flushing; Forced expiratory volume decreased; Fracture; 
Gallbladder necrosis; Gallbladder obstruction; Gastrointestinal disorders – Other (peritonitis); 
Generalized muscle weakness; GGT increased; Head soft tissue necrosis; Hearing impaired; 
Hemolysis; Hepatic necrosis; Hot flashes; Hydrocephalus; Hypercalcemia; Hyperglycemia; 
Hyperhidrosis; 
Hyperkalemia; 
Hypermagnesemia; 
Hypernatremia; 
Hyperthyroidism; 
Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; 
Hypomagnesemia; Hypophosphatemia; Hypotension; Hypothyroidism; Hypoxia; Injection 
site reaction; INR increased; Insomnia; Irregular menstruation; Joint effusion; Keratitis; 
Leukoencephalopathy; Libido decreased; Lipase increased; Localized edema; Lymphocele; 
Lymphocyte count decreased; Memory impairment; Multi-organ failure; Muscle weakness 
lower limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder – 
Other (polymyalgia rheumatic); Myocarditis; Nail loss; Nasal congestion; Neck pain; 
Nervous system disorders – Other (increased intracranial pressure); Optic nerve disorder; 
Oral pain; Pain in extremity; Pain of skin; Pancreatitis; Paresthesia; Pelvic pain; Pelvic soft 
tissue necrosis; Phlebitis; Photophobia; Photosensitivity; Proctitis; Psychosis; Pulmonary 
fibrosis; Purpura; Pyramidal tract syndrome; Rash acneiform; Rectal mucositis; Rectal 
stenosis; Renal and urinary disorders – Other (dysuria); Renal and urinary disorders – Other 
(ureterolithiasis); Renal hemorrhage; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders – Other (dry nares); Respiratory, thoracic and mediastinal disorders – 
Other (pulmonary infarction); Restrictive cardiomyopathy; Retinal detachment; Retinal tear; 
Retinopathy; Right ventricular dysfunction; Serum amylase increased; Skin and subcutaneous 
tissue disorders – Other (diabetic foot ulcer); Skin and subcutaneous tissue disorders – Other 
(skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin induration; Soft tissue 
necrosis lower limb; Somnolence; Stevens-Johnson syndrome; Tinnitus; Tremor; Tumor 


 
3
pain; Typhlitis; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract 
obstruction; Urinary tract pain; Vaginal discharge; Vasculitis; Vasovagal reaction; Watering 
eyes; Weight gain 
• 
Increase in Risk Attribution: 
• 
Changed to Likely from Less Likely:  Neutrophil count decreased 
• 
Changed to Less Likely from Reported But Undetermined:  Platelet count decreased 
• 
Decrease in Risk Attribution: 
• 
Changed to Reported But Undetermined from Less Likely:  Vertigo   
• 
Provided Further Clarification: 
• 
Supraventricular tachycardia is now reported as Cardiac disorders – Other (supraventricular 
arrhythmias) and the following footnote (#3) was added, “Supraventricular arrhythmias may 
include supraventricular tachycardia, atrial fibrillation and atrial flutter.” 
• 
Gastrointestinal anastomotic leak is now reported as Injury, poisoning and procedural 
complications – Other (anastomotic leak) and the following footnote (#10) was added, 
“Anastomotic leak may include Gastrointestinal anastomotic leak; Gastric anastomotic leak; 
Large intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; 
Urostomy leak; Vaginal anastomotic leak.” 
• 
Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) reporting requirements:   
• 
Added:  Dehydration; Platelet count decreased; Wound complication 
• 
Deleted Risk:  
• 
Also Reported on Bevacizumab Trials But With the Relationship to Bevacizumab Still 
Undetermined:  Pneumonitis; Pneumothorax 
 
 
UPDATES TO THE MODEL CONSENT: 
 
Beneath “What side effects or risks can I expect from being in the study?” 
The risk list for “Group 2 (Everolimus and bevacizumab)” has been replaced with two risk lists, one for 
Everolimus and the NCI condensed risk profile* for bevacizumab**.  
* 
Note that CTEP does not include laboratory abnormalities in the NCI condensed risk profiles (i.e. 
hypoglycemia, low thyroid hormone, etc.) 
** Based on the revisions to the bevacizumab CAEPR described above, the NCI added the following 
risks to the NCI condensed risk profile:  
• 
Occasional:  Dehydration; Delay in healing of wounds or spontaneous opening of wounds 
• 
Rare:  Flesh-eating bacteria syndrome, an infection in the deep layers of skin 
Based on the revisions to the bevacizumab CAEPR described above, the NCI removed the following 
risks from the NCI condensed risk profile: 
• 
Feeling of spinning or whirling 
 
 
This protocol remains closed to accrual. 
 
A replacement protocol and model consent have been issued. 
 
__________________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
__________________________________________________________________ 
 
 


NCI Version Date 06/20/14 
Update #05 
1 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
CALGB 90802 
 
 
RANDOMIZED PHASE III TRIAL COMPARING EVEROLIMUS VERSUS EVEROLIMUS PLUS 
BEVACIZUMAB FOR ADVANCED RENAL CELL CARCINOMA PROGRESSING AFTER 
TREATMENT WITH TYROSINE KINASE INHIBITORS 
 
NCI-supplied agent(s): Bevacizumab (NSC 704865, IND #113911) 
 
 
Study Chair 
George Philips MBBS, MD, MPH, FACP 
3800 Reservoir Rd., N.W. 
Georgetown University Hospital 
Washington, D.C.  20007 
Tel: 202-444-2198  Fax: 202-444-9429 
George.K.Philips@gunet.georgetown.edu 
 
Correlative Science Co-Chair and GU  
PET Co-Chair 
Committee RCC Cadre Leader 
Federico Innocenti, MD 
Daniel George MD 
University of Chicago 
Duke University 
Tel: 773-834-2452  
Tel: 919-668-8108  Fax: 919-668-7117 
Fax: 773-702-2770 
daniel.george@duke.edu 
finnocen@medicine.bsd.uchicago.edu 
 
GU Committee Chair 
PET Committee Chair 
GU Committee Correlative Science  
Michael J. Morris, MD 
Mark Ratain, MD 
Cadre Leader 
Memorial Sloan-Kettering 
University of Chicago 
Mary-Ellen Taplin, MD 
Cancer Center 
Tel: 773-702-4400 
Dana-Farber Cancer Institute 
Tel: 646-422-4469 
mratain@medicine.bsd.uchicago.edu 
Tel: 617-632-3237 
morrism@mskcc.org 
 
mtaplin@partners.org 
 
Faculty Statistician 
Staff Statistician 
Susan Halabi, PhD 
Ben Sanford, MS 
Tel: 919-681-5430 
Tel: 919-681-5009 
Fax: 919-681-8028 
Fax: 919-681-8028 
susan.halabi@duke.edu 
ben.sanford@duke.edu 
 
Data Coordinator 
Protocol Coordinator 
Nick Jeffries 
Vance N. Erese 
Tel: 919-668-9360 
Tel: 773-834-4518 
Fax: 919-668-9348 
Fax: 312-345-0117 
nick.jeffries@duke.edu 
verese@uchicago.edu 
 
Participating NCTN Groups:  
ALLIANCE / Alliance for Clinical Trials in Oncology (lead) 
ECOG-ACRIN / ECOG-ACRIN Medical Research Foundation, Inc. 
NRG / NRG Oncology Foundation Inc. 
SWOG / SWOG 


CALGB 90802 
NCI Version Date 06/20/14 
Update #05 
 
2 
Alliance Central Protocol Operations Program 
Office 
230 West Monroe Street, Suite 2050 
Chicago, IL  60606 
Tel:  773-702-9171 
Fax: 312-345-0117 
www.allianceforclinicaltrialsinoncology.org  
Alliance Biorepository at Ohio State University 
(OSU) 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073  Fax: 614-293-7967 
path.calgb@osumc.edu 
Alliance Statistics and Data Center 
Hock Plaza 
2424 Erwin Road, Suite 802 
Durham, NC 27705 
Tel: 919-668-9350 
Data Operations Fax: 919-668-9348 
Biostatistics Fax: 919-681-8028 
Alliance Registration/Randomization Office 
Tel:  507-284-4130 
Fax: 507-284-0885 
Adverse Event Reporting 
https://eapps-ctep.nci.nih.gov/ctepaers 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Protocol Coordinator, and (where 
applicable) Data Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol and model 
informed consent documents: 
Protocol Coordinator 
Questions related to IRB review: 
regulatory@alliancenctn.org 
Questions regarding CTEP-AERS reporting: 
Tonya Hanes, thaynes2@uchicago.edu 
312-702-9814 
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at Ohio State University 
(OSU) 
 
 
Document History 
Effective Date: 
 
 
Activation 
September 15, 2010 
 
 
Update #01 
July 15, 2011 
 
 
Update #02 
December, 16, 2011 
 
 
Update #03 
February 15, 2012 
 
 
Closure 
February 15, 2013 
 
 
Update #04 
May 15, 2013 
 
 
Update #05 
July 01, 2014 
 
 
 


CALGB 90802 
NCI Version Date 06/20/14 
Update #05 
 
3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments:  Submit study data directly to the 
Lead National Clinical Trial 
Network (NCTN) Group unless 
otherwise specified in the protocol:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Please refer to the patient 
enrollment section. 
 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions.   
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Sites must use the 
current form version and adhere to the instructions and submission schedule outlined in the protocol. 
CTSU sites should follow procedures outlined in the protocol for Site registration, Patient Enrollment, 
Adverse Event Reporting, Data Submission (including ancillary studies), and Drug Procurement. 
For patient eligibility or treatment-related questions see the Protocol Contacts, Page 2. 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU 
Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or 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. 
The CTSU Web site is located at https://www.ctsu.org. 
 
The pharmacogenomic component of this study is conducted as part of the NIH Pharmacogenomics Research Network, which is 
funded through a separate U01 mechanism (see http://www.nigms.nih.gov/pharmacogenomics/research_net.html for details. 


CALGB 90802 
NCI Version Date 06/20/14 
Update #05 
 
4 
RANDOMIZED PHASE III TRIAL COMPARING EVEROLIMUS VERSUS EVEROLIMUS PLUS BEVACIZUMAB FOR 
ADVANCED RENAL CELL CARCINOMA PROGRESSING AFTER TREATMENT WITH TYROSINE KINASE 
INHIBITORS 
 
ELIGIBILITY CRITERIA (see Section 4.0) 
Required Initial Laboratory Values 
Stage IV, pathologically proven, metastatic renal carcinoma with clear cell component 
Granulocytes 
Platelet Count 
Bilirubin 
AST 
≥ 1500/µL 
≥ 100,000/µL 
≤ 1.5 x ULN 
≤ 2.5 x ULN 
Failure of at least 1 prior VEGFR TKI therapy defined as progressive disease or 
treatment intolerance.  
No prior systemic therapy with a VEGF binding agent 
No prior systemic therapy with any mTOR inhibitor 
Calc. Creatinine   
(e.g., sirolimus, temsirolimus, everolimus) 
Clearance 
≥ 30 mL/min 
Prior cytokine therapy is allowed 
Fasting serum glucose 
≤ 1.5 x ULN 
Any systemic therapy must be completed at  
Serum Cholesterol 
≤ 300 mg/dL 
least 4 weeks prior to registration 
Trigylcerides 
≤ 200 mg/dL 
≥ 2 weeks since any prior radiation (including palliative) 
UPC Ratio < 1 or urine protein ≤ 1+ 
≥ 4 weeks since any major surgery and fully recovered (see Sec. 4.2) 
Measurable disease by RECIST criteria  
No active brain metastases (effectively treated brain metastases are allowed, see Sec. 4.4) 
No serious non-healing wound, ulcer, or bone fracture 
No arterial thrombotic events within 6 months of registration (see Sec. 4.6) 
Patients who have experienced a deep venous thrombosis or pulmonary embolus with the past 6 months must be on therapeutic 
anticoagulation 
Patients receiving anti-platelet agents and prophylactic anticoagulation are eligible (see Sec. 4.8) 
Patients with history of hypertension must be well controlled (< 160/90) 
No known severe impairment of lung function (see Sec. 4.10) 
No active or severe liver disease (e.g. acute or chronic hepatitis, cirrhosis) and no evidence of hepatitis B or C infections (see Sec. 
4.11) 
No NYHA Class ≥ 2 congestive heart failure 
No active bleeding or chronic hemorrhagic diathesis or increased risk for bleeding (see Sec. 4.13)  
No history of abdominal fistula, GI perforation or intra-abdominal abscess within 6 months (see Sec. 4.14) 
No ongoing immunosuppressive therapy including chronic systemic treatment with corticosteroids  
(≥10 mg/day prednisone equivalent) 
Available archival tissue for submission (see Sec. 4.16) 
Not pregnant or nursing 
Age ≥18 years 
ECOG performance status 0-2 or Karnofsky score ≥ 60% 
Schema 
1 Cycle = 28 Days 
R 
 
ARM A 
A 
 
Everolimus 10 mg daily p.o. 
N 
 
 
D 
 
 
O 
 
 
M 
 
 
I 
 
ARM B 
Z 
 
Everolimus 10 mg daily PO  and 
E 
 
Bevacizumab 10 mg/kg IV on Days 1 and 15 
* See Section 8.0 for complete treatment details. 
Treatment is to continue until disease progression or unacceptable toxicity. 
 
Stratification Factors: 
1) Number of the following risk factors present: Karnofsky performance status < 80%; corrected serum calcium ≥ 
10mg/dL; and Hb ≤ 13 for males and ≤ 11.5 for females. 
a) Zero risk factors 
b) One risk factor 
c) Two or three risk factors 
2) Total duration of prior VEGFR TKI therapy 
a) < 12 weeks of therapy 
b) ≥ 12 weeks of therapy 


CALGB 90802 
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5 
TABLE OF CONTENTS 
SECTION 
PAGE 
1.0 
Introduction ............................................................................................................................... 8 
1.1 
Biology and therapeutic targets in renal cell carcinoma (RCC) ......................................... 8 
1.2 
Treatment of RCC patients after failure of initial VEGFR targeted therapy .................. 8 
1.3 
Bevacizumab for RCC ........................................................................................................................ 9 
1.4 
Clinical Development of bevacizumab and everolimus ........................................................ 9 
1.5 
Risk assessment in second-line treatment of RCC ............................................................... 10 
1.6 
Protocol Update #3 ......................................................................................................................... 11 
1.7 
Predictive significance of plasma and urine biomarkers in TKI refractory RCC...... 11 
1.8 
Tumor-based predictors of mTOR sensitivity....................................................................... 11 
1.9 
Inclusion of Women and Minorities .......................................................................................... 11 
2.0 
Objectives .................................................................................................................................. 12 
2.1 
Primary Objective ........................................................................................................................... 12 
2.2 
Secondary Objectives ..................................................................................................................... 12 
3.0 
On-Study Guidelines .............................................................................................................. 12 
4.0 
Eligibility Criteria ................................................................................................................... 13 
4.1 
Documentation of Disease ............................................................................................................ 13 
4.2 
Prior Treatment ............................................................................................................................... 13 
4.3 
Patients must have Measurable Disease by RECIST criteria ............................................ 13 
4.4 
No active brain metastases: ......................................................................................................... 14 
4.5 
No serious non-healing wound, ulcer, or bone fracture .................................................... 14 
4.6 
No arterial thrombotic events within 6 months of registration: .................................... 14 
4.7 
Deep venous thrombosis or pulmonary embolus: .............................................................. 14 
4.8 
Anti-platelet agents and prophylactic anticoagulation: .................................................... 14 
4.9 
No inadequately controlled hypertension: ............................................................................ 14 
4.10 
No known severe impairment of lung function. ................................................................... 14 
4.11 
No active or severe liver disease (e.g. acute or chronic hepatitis, cirrhosis). ........... 14 
4.12 
No NYHA Class ≥ 2 congestive heart failure ........................................................................... 14 
4.13 
No active bleeding or chronic hemorrhagic diathesis or increased risk for bleeding:
 
15 
4.14 
No history of abdominal fistula, gastrointestinal perforation or intra-abdominal 
abscess ............................................................................................................................................................... 15 
4.15 
No ongoing immunosuppressive therapy: ............................................................................. 15 
4.16 
Archival tissue must be available for submission: .............................................................. 15 
4.17 
Patients who are pregnant or nursing are not eligible. ..................................................... 15 
4.18 
Age ≥ 18 years of age ...................................................................................................................... 15 
4.19 
Performance Status  ECOG 0-2 or Karnofsky Score ≥ 60% ............................................... 15 
4.20 
Required Initial Laboratory Values: ......................................................................................... 15 
5.0 
Registration/Randomization and Stratification ......................................................... 17 
5.1 
Registration Requirements.......................................................................................................... 17 
5.2 
Registration and randomization procedures ........................................................................ 17 
5.3 
Registration to companion studies ........................................................................................... 18 
5.4 
Stratification ..................................................................................................................................... 18 
6.0 
Data And Sample Submission ............................................................................................ 18 
6.1 
Data Submission: ............................................................................................................................. 18 


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6 
6.2 
Specimen Submission for Correlative Studies ...................................................................... 21 
7.0 
Required Data ......................................................................................................................... 24 
8.0 
Treatment Plan ....................................................................................................................... 25 
8.1 
Bevacizumab: .................................................................................................................................... 25 
8.2 
Everolimus: ........................................................................................................................................ 25 
8.3 
Duration of treatment: .................................................................................................................. 25 
9.0 
Dose Modifications And Management of Toxicity ...................................................... 26 
9.1 
Dose Levels ........................................................................................................................................ 26 
9.2 
Hematologic toxicity ....................................................................................................................... 26 
9.3 
Pulmonary toxicity .......................................................................................................................... 27 
9.4 
Management of oral mucositis (see also Section 12.5) ...................................................... 27 
9.5 
Hypertension .................................................................................................................................... 27 
9.6 
Suspected reversible posterior leukoencephalopathy syndrome (RPLS) .................. 27 
9.7 
Bevacizumab dose modifications for thromboembolic events: ..................................... 28 
9.8 
Hemorrhage/bleeding: .................................................................................................................. 28 
9.9 
Congestive Heart Failure or LV dysfunction: ......................................................................... 28 
9.10 
Fistula, perforation involving any organ, bowel obstruction, and wound dehiscence
 
29 
9.11 
Proteinuria ........................................................................................................................................ 29 
9.12 
Hepatotoxicity (CTCAE v. 4.0, Infections and infestations - hepatitis viral) .............. 29 
9.13 
Hypersensitivity or bevacizumab infusion reactions ........................................................ 30 
9.14 
Surgery ................................................................................................................................................ 30 
9.15 
Other non-hematologic toxicities .............................................................................................. 30 
9.16 
Dose Modifications for Obese Patients .................................................................................... 30 
10.0 Companion Studies (150907 and 60903) ...................................................................... 31 
10.1 
Predictive significance of plasma and urine biomarkers in TKI-refractory RCC ..... 31 
10.2 
Tumor-based predictors of mTOR sensitivity....................................................................... 33 
10.3 
Pharmacogenetic companion study ......................................................................................... 34 
11.0 Drug Formulation, Availability, And Preparation ...................................................... 37 
11.1 
Qualified personnel: ....................................................................................................................... 37 
11.2 
Discard unused portions: ............................................................................................................. 37 
11.3 
The total administered dose: ...................................................................................................... 37 
11.4 
Changes in weight: .......................................................................................................................... 37 
11.5 
Bevacizumab (NSC #704865, IND #113911) ......................................................................... 37 
11.6 
Everolimus (RAD-001, NSC #733504) ...................................................................................... 41 
12.0 Ancillary Therapy .................................................................................................................. 43 
12.1 
Patients should receive full supportive care: ........................................................................ 43 
12.2 
Treatment with hormones or other chemotherapeutic agents:..................................... 43 
12.3 
Palliative radiation therapy may not be administered while the patient is on study 
treatment. ......................................................................................................................................................... 43 
12.4 
CALGB Policy Concerning the Use of Growth Factors ......................................................... 43 
12.5 
Recommendations for management of oral mucositis: ..................................................... 43 
12.6 
Recommendations for management of hyperlipidemia: .................................................. 44 
12.7 
Recommendations for management of hyperglycemia: .................................................... 44 
13.0 Criteria For Response And Progression ......................................................................... 44 
13.1 
Target Lesions .................................................................................................................................. 44 


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13.2 
Non-target Lesions .......................................................................................................................... 44 
13.3 
Cytology and Histology .................................................................................................................. 45 
13.4 
Evaluation of Best Overall Response ........................................................................................ 45 
13.5 
Guidelines for Evaluation of Measurable Disease ............................................................... 46 
13.6 
Confirmation Measurement/Duration of Response ........................................................... 47 
14.0 Removal Of Patients From Protocol Therapy .............................................................. 48 
15.0 Statistical Considerations ................................................................................................... 48 
15.1 
Endpoints ........................................................................................................................................... 48 
15.2 
Randomization and Stratification ............................................................................................. 48 
15.3 
Power Considerations .................................................................................................................... 48 
15.4 
Interim Analysis ............................................................................................................................... 49 
15.5 
Data Analysis ..................................................................................................................................... 50 
15.6 
Accrual Rate ....................................................................................................................................... 50 
15.7 
Plasma- and urine-based biomarker studies ........................................................................ 50 
15.8 
Tumor-based biomarker studies ............................................................................................... 51 
15.9 
Statistical considerations for pharmacogenetics studies (60901) ................................ 53 
16.0 Adverse Event Reporting (AER) ........................................................................................ 59 
16.1 
CALGB 90802 Reporting Requirements: ................................................................................. 59 
16.2 
Additional Instructions or Exclusions from CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent under a CTEP-IND: ....................... 60 
16.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for Bevacizumab 
(rhuMAb VEGF, NSC 704865) ..................................................................................................................... 61 
17.0 References ................................................................................................................................ 67 
Appendix I: UPC (Urine Protein to Creatinine) Ratio ............................................................. 72 
Appendix II: Collaborative Agreement Provisions .................................................................. 73 
Appendix III: Inhibitors and Inducers of CYP3A4 .................................................................... 75 


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8 
 
1.0 
INTRODUCTION 
1.1 
Biology and therapeutic targets in renal cell carcinoma (RCC) 
Recent advances in understanding the genetics and biology of renal cell carcinoma have 
promoted the successful development of therapies directed at novel targets and pathways, 
including the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin 
(mTOR) pathways (1, 2). Regarding VEGF, several lines of data support a unique dependency 
of renal cell carcinoma (RCC), in particular those of clear cell histology, on this growth factor 
for carcinogenesis and progression. Patients with a germline deletion in the von Hippel Lindau 
(VHL) gene frequently develop multiple clear cell RCC tumors in their kidneys at an early 
age. Similarly, biallelic loss of the VHL gene occurs in the majority of patients who develop 
sporadic clear cell RCC. VHL protein functions to regulate the transcriptional activity of 
hypoxia-inducible factor (HIF) and HIF regulated gene products including VEGF. VEGF 
binds to cell surface tyrosine kinase receptors (VEGFR) located on endothelial cells to 
promote tumor angiogenesis and progression.  
mTOR is an intracellular signal transduction regulator critical for cellular growth and 
metabolism particularly in response to nutrient and hypoxic stress (3). In RCC, activation of 
the mTOR pathway is commonly detected in clinical specimens and RCC cell lines (4). 
Preclinically, mTOR inhibition demonstrates both antiproliferative and antiangiogenic effects 
(5). Particularly relevant to RCC, mTOR activation results in increased HIF mRNA and 
protein levels which are suppressed by mTOR inhibition (6, 7). In addition, mTOR inhibition 
reverses tumor vessel growth and permeability resulting in overall decreased tumor growth (8). 
For VEGF pathway targeted therapy, all VEGF receptor tyrosine kinase inhibitor (VEGFR-
TKI) and VEGF binding agents have demonstrated anti-tumor activity in renal carcinoma and 
several such as sunitinib (9), sorafenib (10), pazopanib, and the combination of bevacizumab 
and interferon (11, 12) have been found to be effective in phase III trials where a progression 
free survival advantage has been established leading to FDA approvals. 
Rapamycin (sirolimus) is a naturally occurring inhibitor of mTOR that is the prototype for 
several clinically effective mTOR inhibitors. Rapamycin and related compounds bind with the 
intracellular chaperone FK506 binding protein-12 (FKBP-12) forming a complex that 
sequesters mTOR and blocks its phosphorylation and activation. Temsirolimus functions in a 
similar manner and in a phase III study of metastatic, untreated poor prognosis RCC patients, 
resulted in an overall survival advantage compared to interferon alfa (2). Furthermore, 
everolimus, an orally absorbed mTOR inhibitor, demonstrated a PFS advantage compared with 
placebo in patients previously treated with VEGFR targeted therapy (see below) (13). 
1.2 
Treatment of RCC patients after failure of initial VEGFR targeted therapy 
Most patients diagnosed with metastatic or recurrent RCC today are treated first with a multi-
targeted VEGFR-inhibitor such as sunitinib or sorafenib. Unfortunately, the vast majority of 
these patients will develop disease progression on one or both of these agents. In this context, 
a recent phase III study showed that everolimus dramatically improves progression free 
survival (PFS) over placebo in patients whose disease progresses after one or more multikinase 
VEGFR inhibitor therapies, establishing a new standard of care for patients in this setting (13). 
Median PFS was 4.0 months (95% CI 3.7–5.5) in the everolimus group and 1.9 months (1.8–
1.9) for placebo. The probability of being progression-free at 6 months was 26% (95% CI 14–
37) for patients receiving everolimus compared with 2% (95% CI 0–6) for patients in the 
placebo group. Overall tolerance of everolimus in this setting was very good; specifically, 


CALGB 90802 
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9 
grade 3/4 toxicities in ≥ 5% of patients, included only anemia, hyperglycemia and 
lymphopenia, suggesting there is an opportunity to build upon this monotherapy. 
In RCC patients previously treated with a multikinase VEGFR inhibitor, preliminary data 
suggests lack of absolute cross-resistance to an alternate multikinase VEGFR inhibitor, and 
that continued inhibition of the VEGF/VEGFR pathway remains therapeutically relevant in 
such patients (14). Currently, it is not known whether any particular mechanism of VEGF 
pathway inhibition is superior to another in the clinical setting following disease progression 
on or after treatment with a multikinase VEGFR inhibitor.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4 
Clinical Development of bevacizumab and everolimus 
A phase I trial of bevacizumab (10 mg/kg IV every 2 weeks) and daily doses of either 5 or 10 
mg of everolimus has been conducted in patients with advanced solid tumors (15). Adverse 
events in 14 patients were primarily grade 1 or 2 class-specific toxicities. One patient 
experienced a myocardial infarction at day 72 and one developed nephrotic syndrome at day 
70. Seven of 14 patients had stable disease as best response and the 10 mg/day dose of 
everolimus was recommended for further clinical testing in combination with bevacizumab. A 
phase II trial of the combination of bevacizumab and everolimus in 59 RCC patients was also 
reported at the 2008 ASCO meeting (16). In 18 patients previously treated with sorafenib 
and/or sunitinib, 11% experienced a partial response, 72% stable disease, and the median 
progression free survival was 6 months. Updated results (Hainsworth JD, personal 
communication, submitted for publication) showed that in 30 previously treated patients, the 
overall objective response rate was 23%, median progression free survival was 7.1 months and 
the median overall survival was 14.5 months. The most common grade 3/4 toxicities were 
proteinuria (26%), mucositis (15%), fatigue (12%) and diarrhea (9%) but there were no 
episodes of symptomatic pneumonitis or serious cardiac events. Treatment was well tolerated 
overall but eleven patients (14% of entire cohort of 80 patients) discontinued treatment 
because of toxicity including proteinuria, pulmonary embolism, stomatitis or acute kidney 
injury. 
Re
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The combination of bevacizumab and everolimus, both of which carry the capacity to 
modulate the VEGF pathway and have independently shown activity in RCC, is a rational 
mechanistic and clinical strategy for treatment of clear cell RCC. This is particularly relevant 
after failure of VEGFR TKI therapy where HIF modulation (17) and elevation of VEGF levels 
(18) may constitute a specific mechanism of resistance. Furthermore, non-overlapping 
toxicities and relative ease of administration improve the likelihood of successful long-term 
drug administration. This phase III study continues CALGB’s successful exploration of 
rational combinations for the treatment of advanced renal cell carcinoma and advancing 
knowledge of the biologic basis for the disease and its therapy. Demonstration of efficacy for 
the proposed combination has the potential to establish a post-VEGFR TKI standard of care as 
well as a new comparator for testing the efficacy of other agents or combinations in this 
setting. 
1.5 
Risk assessment in second-line treatment of RCC 
The stratification factors for overall survival to be used in this study (Section 5.4) are derived 
from 251 previously treated patients with advanced RCC participating in sequential clinical 
trials at the Memorial Sloan-Kettering Cancer Center (MSKCC) between 1975 and 2002 (19). 
The median survival of the post 1990 cohort was 12.7 months, and 42, 35 and 23% of all 
patients were in the good, intermediate and poor risk categories. Since these trials used mostly 
ineffective agents, the outcomes represent the natural history of previously treated advanced 
RCC. It should be noted in this context that although everolimus prolonged PFS in the 
RECORD-1 trial, no effect on OS has been established thus far. The median survival in the 
placebo arm of the second line phase III registration trial of sorafenib was 14.7 months among 
patients who had mostly been treated previously with immunotherapy. 
In the VEGFR-TKI era, Choueiri (20) determined the outcomes of patients treated with a 
variety of VEGF-targeted therapies in clinical trials at a single institution. Of 120 patients, 75 
(63%) were previously treated with non-VEGF targeted therapies (mostly immunotherapy) 
and the rest received first line VEGFR targeted therapies. However there was no difference in 
the PFS outcome for the two subgroups defined by prior therapy and the overall PFS was 13.8 
months and OS was not defined. This multivariate prognostic model also contained serum 
calcium and ECOG PS as in the Motzer MSKCC model, but additionally included time from 
diagnosis, neutrophilia and thrombocytosis. The median PFS for good (53% of patients), 
intermediate (23%) and poor (25%) risk patients were 20.1, 13 and 3.9 months and overall 
survival data was unavailable. In both the MSKCC and Cleveland Clinic cohorts, about a 
quarter of patients were in the poor risk category. 
The RECORD-1 study was an international trial in previously VEGFR-TKI treated advanced 
RCC patients and used the MSKCC stratification system. The trial cohort consisted of 29% 
good risk, 56% intermediate and only 15% poor risk patients. The median PFS in the 
everolimus arm of that study (which is the closest representation to the control arm of this 
study) was 4 months, and the median OS was 8.8 months for the placebo group and had not 
been reached for the everolimus arm. 
In the phase II of bevacizumab plus RAD001 in 59 patients (21) 74% were designated as 
intermediate risk by the Motzer criteria and the PFS was 6 months (11 months at meeting 
presentation update) among 18 previously VEGFR-TKI treated patients; however OS was not 
described. 
The CALGB conducted a trial of gemcitabine and capecitabine in 56 evaluable patients, 75% 
of whom received prior systemic therapy, with 34%, 43%, and 16% of patients in good, 
intermediate and poor risk groups respectively (22). The median overall survival was 14.5 
months. 


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Overall, despite the wide variability in survival outcome for the discrete risk categories in 
advanced RCC, it is reasonable to expect that 15-25% accrued to a clinical trial of second line 
therapy in the cooperative group setting will represent a poor risk subset. Despite this, multiple 
lines of evidence support the contention that the median survival of the overall trial cohort will 
approximate one year in the control arm of this trial. 
1.6 
Protocol Update #3 
Since CALGB 90802 was activated on September 15, 2010, concerns have been raised that the 
placebo infusions present barriers to study activation at local institutions, patient enrollment 
and continued participation. In an effort to address concerns raised by local investigators and 
to lessen barriers to enrollment, the protocol study design has been amended to an open-label 
trial design. The primary endpoint, stratification factors and the total number of patients 
enrolled in this study will not change. The details of implementing this change are described 
on the Update #3 cover page. 
 
 
 
 
 
 
 
 
 
 
 
 
1.8 
Tumor-based predictors of mTOR sensitivity 
Despite the clinical benefit associated with mTOR inhibition in RCC patients, little is known 
about why this disease is uniquely sensitive to monotherapy treatment with mTOR inhibitors 
(such as everolimus) or mechanisms of resistance to this class of agent. In order to investigate 
potential tissue predictors of response or resistance to everolimus-based therapy we propose to 
collect primary, and when available, metastatic paraffin-embedded tissue and to evaluate these 
tissues for predictors of response or resistance. The most common and important genetic 
alteration in RCC tumors occurs in the VHL gene and subsequent HIF modulation (26). 
Therefore, we propose to evaluate VHL mutational status by DNA sequencing and HIF 
expression levels, and to correlate these findings with clinical outcomes on everolimus-based 
treatment.  
1.9 
Inclusion of Women and Minorities  
Minorities will be eligible for this study without alteration in eligibility criteria. From prior 
knowledge, gender or race/ethnicity differences in the intervention effect are not expected. 
Based on previous data from advanced renal carcinoma patients enrolled on CALGB 90206, 
the accrual targets in individual cells are not large enough to perform subgroup analysis by the 
two treatment groups. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. However, we plan to perform exploratory analyses within 
gender, racial, and ethnic groups. Both men and women of all races and ethnic groups are 
eligible for this study. 
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12 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
15 
+ 
45 
= 
60 
Not Hispanic or Latino 
189 
+ 
451 
= 
640 
Ethnic Category: Total of all subjects 
204 
+ 
496 
= 
700 
Racial Category 
 
American Indian or Alaskan Native 
3 
+ 
4 
= 
7 
Asian 
5 
+ 
18 
= 
23 
Black or African American 
11 
+ 
30 
= 
41 
Native Hawaiian or other Pacific 
Islander 
2 
+ 
3 
= 
5 
White 
183 
+ 
441 
= 
624 
Racial Category: Total of all subjects 
204 
+ 
496 
= 
700 
2.0 
OBJECTIVES  
2.1 
Primary Objective 
2.1.1 To compare the overall survival of patients receiving bevacizumab plus everolimus and 
everolimus alone among patients with advanced renal cell carcinoma progressing after 
first line VEGFR-TKI treatment. 
2.2 
Secondary Objectives 
2.2.1 To compare the progression-free survival and proportion who experience an objective 
response (defined as cCR + PR) in patients with advanced renal cell carcinoma receiving 
bevacizumab plus everolimus and everolimus alone. 
2.2.2 To compare grade 3 or higher toxicity in patients receiving each treatment regimen. 
3.0 
ON-STUDY GUIDELINES 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of 
any therapy, and therefore only enroll patients for whom this treatment is appropriate. Although 
they will not be considered formal eligibility (exclusion) criteria, physicians should recognize that 
the following may seriously increase the risk to the patient entering this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers. 
Patients are not considered to have a “currently active” malignancy if they have completed 
therapy and are free of disease for ≥ 3 years.  


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13 
• 
Women and men of reproductive potential should agree to use an appropriate method of birth 
control throughout their participation in this study and for up to 6 months after discontinuation 
of study treatment due to the teratogenic potential of the therapy utilized in this trial. 
Appropriate methods of birth control include abstinence, oral contraceptives, implantable 
hormonal contraceptives (Norplant), or double barrier method (diaphragm plus condom). 
• 
Patients should not have anticipation for major surgical procedures during the course of the 
study. 
• 
Strong inducers (e.g., rifampin, phenobarbital, phenytoin) and strong inhibitors (e.g., 
itraconazole, ketoconazole) of CYP3A4 should be avoided. A list of inhibitors and inducers can 
be found in Appendix III. 
4.0 
ELIGIBILITY CRITERIA 
All questions regarding eligibility criteria should be directed to the CALGB Study Chair. Please 
note that the Study Chair cannot grant waivers to eligibility requirements.  
4.1 
Documentation of Disease 
4.1.1 Histologic Documentation: Renal cell carcinoma with some component of clear cell 
histology 
4.1.2 Stage: Metastatic or unresectable disease 
4.2 
Prior Treatment 
• 
Must have been treated with at least 1 prior VEGFR tyrosine kinase inhibitor treatment 
and have progressed or have been intolerant to treatment. 
• 
No prior systemic therapy with a VEGF binding agent (e.g., bevacizumab) 
• 
No prior systemic therapy with any mTOR inhibitor (e.g., sirolimus, temsirolimus, 
everolimus)  
• 
Prior cytokine therapy is allowed 
• 
Any systemic therapy must be completed at least 4 weeks prior to registration  
• 
≥ 2 weeks since any prior radiation (including palliative)  
• 
Patients must not have had a major surgical procedure, open biopsy, or significant 
traumatic injury within 4 weeks prior to study registration, and must have fully recovered 
from any such procedure.  
The following are not considered to be major procedures: Thoracentesis, paracentesis, port 
placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic 
procedures, mediastinoscopy, skin biopsies, incisional biopsies and routine dental 
procedures.  
4.3 
Patients must have Measurable Disease by RECIST criteria 
Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan. 


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14 
4.4 
No active brain metastases:  
Patients with treated, stable brain metastases for at least three months are eligible as 
long as they meet the following criteria: 
Treated brain metastases are defined as having no ongoing requirement for steroids and no 
evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by 
clinical examination and brain imaging (MRI or CT). (Stable dose of anticonvulsants are 
allowed). Treatment for brain metastases may include whole brain radiotherapy (WBRT), 
radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed 
appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical 
resection or brain biopsy performed within 3 months prior to Day 1 are not eligible. 
Baseline brain imaging (MRI/CT) is required.  
4.5 
No serious non-healing wound, ulcer, or bone fracture 
4.6 
No arterial thrombotic events within 6 months of registration: 
Including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial 
thrombus, unstable angina or angina requiring surgical or medical intervention in the past 6 
months, or myocardial infarction (MI). Patients with clinically significant peripheral artery 
disease (i.e., claudication on less than one block), significant vascular disease (i.e., aortic 
aneurysm, history of aortic dissection), or any other arterial thrombotic event are ineligible.  
4.7 
Deep venous thrombosis or pulmonary embolus: 
Patients who have experienced a deep venous thrombosis or pulmonary embolus within the 
past 6 months must be on stable therapeutic anticoagulation to be enrolled to this study.  
4.8 
Anti-platelet agents and prophylactic anticoagulation:  
Patients receiving anti-platelet agents and prophylactic anticoagulation are eligible.  
4.9 
No inadequately controlled hypertension: 
(defined as a blood pressure of ≥ 160 mmHg systolic and/or ≥ 90 mmHg diastolic on 
medication), or any prior history of hypertensive crisis or hypertensive encephalopathy 
4.10 
No known severe impairment of lung function. 
No known severe impairment of lung function, defined as ≥ grade 2 dyspnea or cough, or 
either:  
a) Requirement of supplemental oxygen, or  
b) in cases where pulmonary function or pulse oximetry tests have been obtained, FEV1 or 
FVC are < 50% of predicted, or single breath DLCO is < 35% of predicted or resting room 
oxygen saturation is less than 90%. 
4.11 
No active or severe liver disease (e.g. acute or chronic hepatitis, cirrhosis).  
No positive serology for anti-HBC or anti-HCV antibodies. HBV seropositive patients 
(HBsAg positive) are eligible if they are closely monitored for evidence of active HBV 
infection by HBV DNA testing and agree to receive suppressive therapy with lamivudine or 
other HBV-suppressive therapy until at least 4 weeks after the last dose of everolimus. 
4.12 
No NYHA Class ≥ 2 congestive heart failure 


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15 
4.13 
No active bleeding or chronic hemorrhagic diathesis or increased risk for bleeding: 
Including but not limited to history of major bleeding within 6 months (e.g. gastrointestinal, 
lung, CNS sites; or required transfusion support).  
4.14 
No history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess 
within 6 months prior to the initiation of treatment. 
4.15 
No ongoing immunosuppressive therapy: 
Including chronic systemic treatment with corticosteroids (≥ 10 mg/day prednisone 
equivalent). 
4.16 
Archival tissue must be available for submission: 
Though it is optional patients to choose to participate in the correlative substudies or not. 
4.17 
Patients who are pregnant or nursing are not eligible.  
Women of child bearing potential must have a negative serum or urine pregnancy test within 
16 days prior to registration. This is because the effects of everolimus and bevacizumab on a 
developing fetus at the recommended therapeutic doses are unknown. 
Women of child-bearing potential include:  
• 
Any female who has experienced menarche and who has not undergone surgical 
sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not 
postmenopausal [defined as amenorrhea ≥12 consecutive months].  
• 
Women on hormone replacement therapy (HRT) with documented serum follicle 
stimulating hormone (FSH) level > 35m IU/mL.  
• 
Women who are using oral, implanted or injectable contraceptive hormones or 
mechanical products such as an intrauterine device or barrier methods (diaphragm, 
condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is 
sterile (e.g., vasectomy). 
4.18 
Age ≥ 18 years of age   
4.19 
Performance Status  ECOG 0-2 or Karnofsky Score ≥ 60% 
4.20 
Required Initial Laboratory Values: 
Granulocytes 
≥ 1,500/µL 
Platelet count 
≥ 100,000/µL 
Calculated creatinine clearance 
≥ 30 mL/minute (modified Cockroft and 
Gault formula; see below) 
Bilirubin 
≤ 1.5 x upper limits of normal 
AST 
≤ 2.5 x ULN  
Fasting serum triglycerides 
≤ 200 mg/dL 
Serum cholesterol 
≤ 300 mg/dL 
Fasting serum glucose 
≤ 1.5 x ULN 
Urine protein to creatinine ratio* < 1.0 or Urine protein ≤ 1+ 
* 
See Appendix I for information regarding the calculation of UPC ratio. 
Cockcroft and Gault Formula for Estimated Creatinine Clearance (CLcr) 
For Serum Creatinine Concentration (Sr Cr) in mg/dL: 
 


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Clcr (mL/min) = 
(140 - age) (actual weight)a 
 
(72) (Sr Cr) 
a 
Age in years and weight in kilograms  
For females, use 85% of calculated Clcr value 
 


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17 
5.0 
REGISTRATION/RANDOMIZATION AND STRATIFICATION 
5.1 
Registration Requirements 
Informed Consent: The patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental 
nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. 
Human protection committee approval of this protocol and a consent form are required. 
5.2 
Registration and randomization procedures 
This study uses the CALGB Web-based Patient Registration system. Randomization will be 
accepted only through CALGB Main Member Institutions, selected affiliate institutions and 
CCOPs using the Web-based Patient Registration system. Registration must occur prior to the 
initiation of therapy. 
Confirm eligibility criteria (Section 4.0). Complete the Registration Worksheet. Access the 
Web-based Patient Registration system via the Patient Registration tab on the CALGB 
Member Website at www.allianceforclinicaltrialsinoncology.org. If the study does not appear 
on the list of studies in the Patient Registration system, the registration must be performed by 
the CALGB Registrar via phone or fax. If the registering CRA requires assistance, he/she may 
consult the on-line help file at the bottom of the screen or call the IS Help Desk at 1-888-
44CALGB. If further assistance is required, the registering CRA may call the CALGB 
Registrar (919)-668-9396, Monday-Friday, 9 AM – 5 PM, Eastern Time. Enter the following 
information: 
 
CALGB patient ID #, if applicable 
Study 
Name of group (CALGB) 
Name of institution where patient is being treated 
Name of treating physician 
Name of person in contact with the patient record (responsible contact) 
Protocol IRB approval date 
Date of signed consent 
Treatment Start Date 
Date [of] HIPAA authorization signed by the patient 
Patient’s initials (L, F, M) 
Patient’s Social Security #, date of birth, hospital ID #, and survival status 
Patient’s gender 
Patient’s race 
Patient’s ethnicity 
ECOG performance status 
Patient’s height (cm) and weight (kg) 
Type of insurance (Method of Payment) 
Patient’s postal code 
Disease, type and stage, if applicable 
Eligibility criteria met (no, yes) 
Companion studies (see Section 5.3)   
 
When the patient is registered, a CALGB patient identification number will be generated. 
Please write the number in your records. Registration to any mandatory or optional companion 
studies will be done at the same time as registration to the treatment study. Registration to both 


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treatment and companion studies will not be completed if eligibility requirements are not met 
for all selected trials (treatment and companions). 
After registration is complete, the patient may be randomized. The patient is randomized 
according to the stratification factors indicated in Section 5.4 below, which must be entered to 
obtain a treatment assignment. Treatment is to begin within 14 days of randomization. 
The Main Member Institution and registering institution will receive a Confirmation of 
Registration and a Confirmation of Randomization. Please check both confirmations for errors. 
Submit corrections in writing to the data coordinator at the CALGB Statistical Center, Data 
Operations, 2424 Erwin Rd, Ste 802 Hock Plaza, Durham, NC 27705, or fax to 919-668-9397. 
5.3 
Registration to companion studies 
There are two substudies within CALGB 90802. These substudies must be offered to all 
patients enrolled on CALGB 90802 (although patients may opt not to participate). The 
substudies included within CALGB 90802 are: 
• 
Correlative science studies: CALGB 150907 (Sections 10.1 and 10.2) 
• 
Pharmacogenomic studies: CALGB 60903 (Section 10.3) 
If a patient answers “yes” to “I agree that my specimens may be used for the research studies 
described above.” (Question #1) in the Model Consent, s/he has consented to participate in the 
biomarker studies described in Sections 10.1 and 10.2. The patient should be registered to 
CALGB 150907 at the same time that s/he is registered to the treatment trial (90802) and 
samples submitted per Sections 6.2.2 and 6.2.3. 
If a patient answers “yes” to “I agree that my blood may be used for the genetic research 
studies described above” (Question #2) in the Model Consent, s/he has consented to participate 
in the studies described in Section 10.3. Patients should be registered to CALGB 60903 and 
samples should be submitted per Section 6.2.4. 
5.4 
Stratification 
5.4.1 Number of risk factors present: The risk factors are: Karnofsky performance status < 
80%; corrected serum calcium ≥10mg/dL; and Hb ≤13 for males and ≤11.5 for females. 
a) Zero risk factors 
 
 
c) 
Two or three risk factors 
b) One risk factor 
5.4.2 Total duration of prior VEGFR TKI therapy 
a) < 12 weeks of therapy 
b) ≥ 12 weeks of therapy 
6.0 
DATA AND SAMPLE SUBMISSION  
6.1 
Data Submission:  
Forms should be submitted to the CALGB Statistical Center, Data Operations in compliance 
with the Data Submission schedule below. There are three options for submitting forms that 
use the Teleform barcode and cornerstones: 
• 
The preferred method is to submit the forms electronically using the “Submit to CALGB” 
button located at the bottom of the last page of each form. Forms submitted electronically 
should not be submitted by fax or mail. 


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19 
• 
The forms may be faxed at 919-416-4990. Please note that the four cornerstones and the 
form id ("bitmap") must appear on the form. Copies must be 100% of the original form 
size. 
• 
The forms may be mailed to the CALGB Statistical Center, Data Operations, Hock Plaza, 
2424 Erwin Rd, Suite 802, Durham, NC 27705. Please note that the four cornerstones and 
the form id (“bitmap”) must appear on the form. Copies must be 100% of the original form 
size.  
For the most up-to-date data forms, please visit the CALGB or CTSU web site at 
www.allianceforclinicaltrialsinoncology.org or www.ctsu.org. 


CALGB 90802 
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Data Submission Schedule: 
Form 
 
Submission Schedule 
 
Baseline  
 
 
 
C-1931 
 
C-2000 
 
 
Reports 
CALGB 90802 Registration Worksheet 
CALGB 90802 Eligibility Checklist 
CALGB 90802 On Study Form 
 
CALGB Solid Tumor Evaluation Form (RECIST) 
 
Copies of baseline metastatic pathology reports, Brain 
Imaging CT/MRI scans, Chest/abdomen/ pelvis MRI/CT 
scans* 
Submit within 2 weeks after registration 
 
 
 
 
Treatment 
 
C-1934 
C-1935 
C-1936 
 
C-1937 
S-072 
CALGB 90802 Treatment Form 
CALGB 90802 Adverse Event Form 
CALGB 90802 Supplemental Adverse Event Form 
(thromboembolic events)† 
CALGB 90802 Follow Up Form 
CALGB 90802 Patient Medication Calendar 
Every cycle during protocol therapy. 
 
 
 
C-1936 
 
CALGB 90802 Adverse Event Form  (Thromboembolic 
Events)† 
Within 24 hrs of knowledge of ≥ grade 3 
thromboembolic event. 
 
 
 
C-2000 
Reports 
CALGB Solid Tumor Evaluation Form (RECIST)  
Copies of follow-up metastatic pathology reports, Brain 
Imaging CT/MRI scans, Chest/abdomen/ pelvis MRI/CT 
scans* 
Every 2 cycles and at the end of protocol 
treatment. 
 
 
 
 
Follow-up (after end of protocol treatment) 
C-1937 
CALGB 90802 Follow Up Form 
For patients who discontinue treatment 
for reasons other than progression: Every 
8 weeks until progression.  
After progression for all patients: Every 
6 months until 5 ½ years after 
registration to report survival and new 
primary or secondary malignancies. 
 
 
 
C-2000 
Reports 
CALGB Solid Tumor Evaluation Form (RECIST) 
Copies of restaging metastatic pathology reports, Brain 
Imaging CT/MRI scans, Chest/abdomen/ pelvis MRI/CT 
scans** 
Submit after each post-treatment 
restaging through progression. 
* 
Submit copies of all required reports to confirm eligibility and restaging results. 
 
Common Terminology Criteria for Adverse Events (CTCAE): This study will utilize the Common 
Terminology Criteria for Adverse Events version 4.0 for toxicity and adverse event reporting. 


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6.2 
Specimen Submission for Correlative Studies 
All participating institutions must ask patients for their consent to participate in the correlative 
substudies planned for CALGB 90802, although patient participation is optional. Biomarker 
and pharmacogenomic studies will be performed. Rationale and methods for the scientific 
components of these studies are described in Section 10.0. For patients who consent to 
participate, tissue, blood, and urine will be collected at the following time points for these 
s
t
u
d
i
e
s
: 
 
 
 
 
 
 
1 
Archival paraffin-embedded tissue from primary and metastatic tissue (when available) to be 
used for correlative studies described in Section 10.2 (150907). 
2 
Plasma and urine to be used for correlative studies described in Section 10.1 (150907). 
3 
To be used for pharmacogenomic assays described in Section 10.3 (60903).  
6.2.1 Specimen Submission Instructions:  
Use of the Alliance Biospecimen Management System (BioMS) is mandatory and all 
specimens must be logged and shipped via this system.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL:  
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, 
and training videos. To report technical problems, such as login issues or application 
errors, please contact: 1-855-55-BIOMS or Bioms@alliancenctn.org. For assistance in 
using the application or questions or problems related to specific specimen logging, please 
contact: 1-855-55-BIOMS or Bioms@alliancenctn.org. 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (90802), Alliance 
patient number, patient’s initials and date and type of specimen collected (e.g., serum, 
whole blood). 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in 
the shipment with the specimens. 
 
Pre-treatment  
Every 2 cycles (i.e., before 
cycles 3, 5, 7, etc.) 
Ship to 
Tumor block1 
X 
 
PCO 
 
Number and volume of tubes to draw 
EDTA plasma 
(Lavender top)2 
1 x 6 mL 
1 x 6 mL 
PCO 
Urine2 
1 x 5 mL 
1 x 5 mL 
PCO 
Citrate plasma (Light 
blue top)2 
4 x 2.7 mL 
 
PCO 
Whole blood 
(Lavender top)3 
1 x 10 mL 
 
PCO 


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Instructions for the collection of samples are included below. Please be sure to use a 
method of shipping that is secure and traceable. Extreme heat precautions should be taken 
when necessary.  
Shipment on Monday through Friday by overnight service to assure receipt is encouraged. 
If shipping on Friday, FedEx or UPS must be used and the air bill must be marked “For 
Saturday delivery.” Do not ship specimens on Saturdays. 
All specimens should be sent to the following address: 
CALGB Pathology Coordinating Office 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH  43240 
Tel: 614-293-7073  Fax: 614-293-7967 
6.2.2 Blood and urine sample submission 
For patients who consent to participate, plasma and urine samples will be used for the 
biomarker analyses described in Section 10.1.  
For EDTA plasma, collect 6 mL of peripheral venous blood in one lavender top tube 
(K2EDTA anti-coagulant) prior to the initiation of treatment and every two cycles (i.e., 
prior to chemotherapy on Day 1 of Cycles 3, 5, 7, etc.).  
Draw 1 x 6 mL of blood into lavender top vacutainer. Invert several times and centrifuge 
for 15 minutes at 2500 x g. Remove plasma and transfer to clean 5 mL tube. Repeat 
centrifuge at 2500 x g for 15 minutes. Aliquot 1.0 mL plasma into each cryovial.* Label 
and freeze cryovials at –80°C. (If –80°C is not available, temporary storage at -20°C prior 
to shipment is acceptable.) Ship on dry ice to the CALGB PCO. 
For citrate plasma, collect 10 mL of peripheral venous blood in 3 x 2.7 mL light blue top 
tubes (3.2% sodium citrate anti-coagulant) prior to the initiation of treatment. 
Draw 4 x 2.7 mL of blood into light blue top vacutainer. Invert several times and 
centrifuge for 15 minutes at 2500 x g. Remove plasma and transfer to clean 5 mL tube. 
Repeat centrifuge at 2500 x g for 15 minutes. Aliquot 1.0 mL plasma into each cryovial.* 
Label and freeze cryovials at –80°C. (If –80°C is not available, temporary storage at –
20°C prior to shipment is acceptable.) Ship on dry ice to the CALGB PCO. 
For urine, antiseptically collect 5 mL urine (mid-stream collection), voided directly into a 
sterile container. Specimens must be stored at ≤ –20° as soon as possible after collection. 
Ship on dry ice to the CALGB PCO. 
Label samples with the following identification: 
1) 
Procurement date 
2) 
CALGB patient number 
3) 
CALGB study number (i.e., 90802) 
4) 
EDTA plasma, citrated plasma or urine. 
* Cryovial Choices: Some examples of acceptable 2.0 ml cryovials are: Nalgene (Cat 
#5012-0020), Fisher (Cat #05-669-57), Corning (Cat #430488), VWR (Cat #16001-
102). 


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6.2.3 Submission of paraffin blocks of archived renal tumors 
For patients who consent to participate, tumor blocks will be used for the analyses 
described in Section 10.2. 
Paraffin blocks of primary and, when available, metastatic tissue obtained from archival 
RCC tumor specimens should be sent to the CALGB Pathology Coordinating Office. 
Please specify the source of the tumor block (primary or metastatic site).  
The CALGB has instituted special considerations for the small percentage of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of 
hospitals whose policies prohibit release of any block. If, due to institutional policy, a 
block cannot be sent, please call the CALGB PCO at 614-293-7073 to obtain instructions 
for an adequate block alternative. 
The goal of the PCO is to provide investigators with quality histology sections for their 
research while maintaining the integrity of the tissue. All paraffin blocks that are to be 
stored at the PCO will be vacuum packed to prevent oxidation and will be stored at 4º C to 
minimize degradation of cellular antigens. For these reasons it is preferred that the PCO 
bank the block until the study investigator requests thin sections. Please contact the PCO if 
additional assurances with your hospital pathology department are required. 
6.2.4 Blood submission (for pharmacogenomic studies) 
For patients who consent to participate, whole blood samples will be used for the 
pharmacogenomic studies described in Section 10.3. This sample should be collected prior 
to the initiation of protocol treatment. 
Collect 10 mL of peripheral venous blood in an EDTA (lavender) tube. The tubes should 
be inverted several times to mix the EDTA and refrigerated until shipped on cool pack by 
overnight mail to the CALGB PCO. The samples should be shipped the same day that the 
blood is drawn.  
 


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7.0 
REQUIRED DATA 
Pre-Study Testing Intervals  
To be completed within 16 DAYS before registration: 
- 
All laboratory studies, history and physical 
To be completed within 28 DAYS before registration: 
- 
Brain Imaging (MRI or CT), CT/MRI chest/abd/pelvis, and Bone Scan. PET scans are not allowed for tumor 
measurement.  
To be completed within 42 DAYS before registration: 
- 
Any baseline exams used for screening 
 
Prior to Registration* 
Day 1 of each cycle  
Post Treatment Follow up** 
Tests & Observations 
 
 
 
History and Progress Notes 
X 
X 
 
Physical Examination  
X 
X 
X 
Pulse, Blood Pressure 
X 
F 
 
Weight† 
X 
X 
 
Performance Status 
X 
X 
 
Tumor Measurements 
X 
PRN 
PRN 
Drug Toxicity Assessment   
 
X 
 
Laboratory Studies 
 
 
 
CBC, Differential, Platelets 
X 
X 
 
Serum Creatinine,  
X 
X 
 
LDH, albumin, glucose 
X 
X 
 
AST, ALT, Alk. Phos., Bili 
X 
X 
 
Triglycerides, cholesterol 
X 
X 
 
Serum or Urine HCG 
X*** 
 
 
HBsAg, HBsAb, HB core 
antibody, HCV Ab 
X 
 
 
HBV DNA testing 
A 
A 
 
UPC ratio/Dipstick 
X 
B 
 
Staging 
 
 
 
Brain Imaging (MRI or CT) 
X 
C 
C 
CT/MRI chest/abd/pelvis 
X 
D 
X 
Bone Scan  
X 
E 
E 
Correlative studies‡ 
 
Tissue, Blood, and Urine Samples See Section 6.2. 
* Pre-registration labs may be used for day 1 of cycle 1 tests if obtained within 16 days prior to Day 1 of Cycle 1. For 
subsequent cycles labs may be obtained within 72 hours prior to day of treatment. 
** Physical examination and staging scans must be repeated after the end of protocol treatment unless performed within the prior 
4 weeks; then every 8 weeks until progression or until 5½ years after registration, whichever comes first. 
*** For women of childbearing potential (see Section 4.16). 
† The dose of bevacizumab need not be changed unless the calculated dose changes by ≥ 10%. 
‡ For those patients who consent to participate in the substudies. 
A HBV DNA testing should be performed at baseline and every 8 weeks during treatment with everolimus, and at 4 weeks after 
the last dose of everolimus, only if hepatitis B seropositive at baseline. In carriers of hepatitis B, lamivudine or other HBV 
suppressive therapy is required. 
B All patients receiving bevacizumab will have a urinalysis or urine dipstick performed within 72 hours prior to every 
bevacizumab dose; if urine protein is ≥ 2+, 24-hour urine collection or UPC ratio will be required (see Section 9.10). 
C Required only if signs or symptoms suggestive of metastases develop. 
D CT scans/MRI are required every 2 cycles until evidence of progression or relapse. Scans may be done up to 10 days prior to 
beginning a cycle. 
E Bone imaging (after baseline) is required only if indicative of metastases at baseline or if signs or symptoms suggestive of 
metastases develop. 
F For patients receiving bevacizumab (Arm B), blood pressure is to be measured on Days 1 and 15 of every cycle for the first 
six months of protocol therapy, then on Day 1 only of every cycle. For patients receiving everolimus alone, blood pressure is 
to be measured on Day 1 of every cycle. 


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8.0 
TREATMENT PLAN 
Protocol treatment is to begin within 14 days of registration. Questions regarding treatment should 
be directed to the CALGB Study Chair. 
 
Each cycle is 28 days (4 weeks) 
 
R 
 
ARM A 
A 
 
Everolimus 10 mg daily p.o. and 
N 
 
 
D 
 
 
O 
 
 
M 
 
 
I 
 
ARM B 
Z 
 
Everolimus 10 mg daily p.o. and  
E 
 
Bevacizumab 10 mg/kg IV on Days 1 and 15 
All patients must be screened for hepatitis B before starting treatment. Carriers of hepatitis B 
should be closely monitored, including HBV DNA testing (see Section 6.0), for evidence of active 
HBV infection and hepatitis during and at four weeks after the last dose of everolimus treatment. 
For patients with evidence of prior HBV infection, lamivudine or other HBV suppressive therapy is 
required. 
8.1 
Bevacizumab:  
10 mg/kg IV every 14 days. The initial dose is to be given over 90 minutes, second dose over 
60 minutes, and all subsequent doses over 30 minutes if prior infusions are tolerated without 
infusion-associated adverse events (see Section 11.5). 
8.2 
Everolimus:  
10 mg p.o. daily. Everolimus should be administered on an empty stomach or with a light, fat-
free meal. 
8.3 
Duration of treatment:  
Treatment with everolimus and bevacizumab will continue until disease progression or 
unacceptable toxicity. 
 


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9.0 
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITY 
• 
Missed doses for either agent will not be made up. 
• 
Doses will not be re-escalated once reduced. 
• 
If more than one dose modification applies, use the most stringent (i.e., the greatest dose 
reduction). 
9.1 
Dose Levels 
Everolimus  
• 
No dose reduction below dose level -2 for everolimus is allowed. If dose reduction below -
2 is required, everolimus must be discontinued. 
Dose Level 
Everolimus  
0 
10 mg daily 
-1 
5 mg daily 
-2 
5 mg every other day 
Bevacizumab 
• 
There are no dose reductions for bevacizumab. Bevacizumab may be skipped or 
discontinued for toxicity as described below. 
9.2 
Hematologic toxicity 
9.2.1 For ANC 500-999/µL, interrupt everolimus until ANC ≥1000/µL, then resume with one 
dose level reduction of everolimus.  
If everolimus is interrupted for > 4 weeks for ANC, discontinue everolimus. Continue 
bevacizumab if everolimus is interrupted or discontinued for ANC 500-999/µL. 
9.2.2 For ANC < 500/µL, skip bevacizumab and interrupt everolimus. When ANC improves to 
500-999/µL, resume bevacizumab.  
When ANC improves to ≥1000/µL, resume everolimus with one dose level reduction. 
If everolimus is interrupted for > 4 weeks for ANC, discontinue everolimus (and 
discontinue bevacizumab if ANC < 500/µL). 
9.2.3 For platelets < 50,000/µL, skip bevacizumab and interrupt everolimus until platelets ≥ 
50,000/µL, then resume bevacizumab and resume everolimus with one dose level 
reduction. 
If platelets do not recover to ≥ 50,000/µL within 4 weeks, discontinue everolimus and 
bevacizumab. 
9.2.4 Febrile neutropenia: For febrile neutropenia (defined as temperature ≥ 38.5° C [101° F] 
sustained for more than one hour concomitant with ANC < 500/mm3), interrupt 
everolimus until ANC ≥ 1500/µL and fever has resolved. Resume everolimus at one lower 
dose level. If febrile neutropenia recurs, discontinue everolimus. Continue bevacizumab. 
Febrile neutropenia should be evaluated as appropriate at the discretion of the treating 
physician.  


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9.3 
Pulmonary toxicity 
If everolimus is interrupted for ≥ 4 weeks for pulmonary toxicity, discontinue everolimus. If 
everolimus is interrupted or discontinued for pulmonary toxicity, continue bevacizumab. 
Grade 1: Obtain CT scan with lung windows. Continue previous dose of everolimus. 
Grade 2: Obtain CT scan with lung windows. Consider pulmonary function testing including 
spirometry, DLCO, room air O2 saturation at rest, and bronchoscopy. Interrupt everolimus 
until toxicity improves to ≤ grade 1, then resume everolimus with one dose level reduction. 
Steroids may be used at the discretion of the treating physician for relief of symptoms 
associated with pulmonary toxicity. 
Grade 3: Obtain CT scan with lung windows and pulmonary function testing including 
spirometry, DLCO, and room air O2 saturation at rest. Interrupt everolimus until recovery to ≤ 
grade 1, then resume everolimus with one dose level reduction. Steroids should be used for 
relief of symptoms associated with pulmonary toxicity. 
For grade 3 pneumonitis considered related to everolimus, continue everolimus only if there 
is evidence of antitumor activity. If there is a second episode of grade 3 pneumonitis, 
discontinue everolimus. 
Grade 4: Obtain CT scan with lung windows and pulmonary function testing including 
spirometry, DLCO, room air O2 saturation at rest, and bronchoscopy. Permanently discontinue 
everolimus. Steroids should be used for relief of symptoms associated with pulmonary 
toxicity. 
9.4 
Management of oral mucositis (see also Section 12.5) 
For grade 3 oral mucositis, interrupt everolimus until mucositis improves to ≤ grade 1, then 
resume at one lower dose level. If everolimus is interrupted for mucositis for > 4 weeks, 
discontinue everolimus. 
For grade 4 oral mucositis, discontinue everolimus. 
If everolimus is interrupted or discontinued for oral mucositis, continue bevacizumab. 
See Section 12.5 for recommendations for management of oral mucositis. 
9.5 
Hypertension 
• 
For hypertension controlled with medication (to < 160/90): Continue therapy. 
• 
For persistent or symptomatic hypertension despite antihypertensive therapy, skip 
bevacizumab and adjust antihypertensive treatment. If treatment is skipped for two cycles 
(> 8 weeks) due to uncontrolled hypertension, discontinue bevacizumab. Continue 
everolimus. 
• 
Grade 4 hypertension: Discontinue of bevacizumab. Continue everolimus. 
9.6 
Suspected reversible posterior leukoencephalopathy syndrome (RPLS) 
For signs and symptoms suggestive of RPLS (e.g., confusion headache, seizures, cortical 
blindness) skip bevacizumab. Suspected RPLS should be investigated with brain MRI as 
described in Section 11.5 If diagnosis of RPLS is confirmed, bevacizumab should be 
permanently discontinued. 
If RPLS is ruled out by MRI, the decision on resuming bevacizumab should be based on the 
nature of the signs/symptoms: For grade 4 events with likely relationship to bevacizumab, 
discontinue bevacizumab; for grade 3 events, bevacizumab may be resumed if toxicities 


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completely reverse within 8 weeks. If bevacizumab is skipped or discontinued for (suspected) 
RPLS, continue everolimus. 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.8 
Hemorrhage/bleeding:  
• 
For grade 1 intracranial or pulmonary hemorrhage/bleeding: For patients receiving 
full-dose anticoagulation, discontinue bevacizumab, but continue everolimus. For patients 
not receiving full-dose anticoagulation, hold bevacizumab until the bleeding has resolved, 
hemoglobin is stable, AND there is no bleeding diathesis  or pathologic condition that 
would increase the risk of bleeding from bevacizumab therapy. 
• 
For grade 2 intracranial or pulmonary hemorrhage/bleeding, discontinue 
bevacizumab. Interrupt everolimus until bleeding resolves to < grade 2, then resume 
everolimus. 
• 
For grade 3 or 4 hemorrhage/bleeding, discontinue bevacizumab. Interrupt everolimus 
until bleeding resolves to < grade 3, then resume everolimus.  
9.9 
Congestive Heart Failure or LV dysfunction: 
For grade 3 or 4 congestive heart failure or LV dysfunction, discontinue bevacizumab; 
continue everolimus. 
Re
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9.10 
Fistula, perforation involving any organ, bowel obstruction, and wound dehiscence 
• 
For any grade perforation of any organ, GI leak, or any fistula: Discontinue all 
protocol therapy. 
• 
For any grade bowel obstruction requiring medical intervention: Skip bevacizumab 
and interrupt everolimus until complete resolution, then resume. If surgery is required, 
protocol therapy may be resumed after full recovery from surgery (at least 4 weeks after 
surgery for bevacizumab) and after consultation with the Study Chair.  
• 
For would dehiscence requiring medical or surgical intervention: Discontinue all 
protocol therapy. 
9.11 
Proteinuria 
Urine protein is to be measured within 72 hours prior to each bevacizumab dose. For 2+ 
proteinuria, the scheduled dose of bevacizumab may be given while awaiting the results of the 
UPC (urine protein to creatinine) ratio or 24-hour collection. The UPC ratio can be used in the 
place of a 24-hour urine protein collection. 
 For > 2+ proteinuria, omit bevacizumab while awaiting results of the UPC ratio or 24-hour 
urine collection. See Appendix I for information regarding the calculation of UPC ratio. 
• 
For UPC Ratio < 2.0 or urine protein < 2 g/24 hours: Bevacizumab may be given as 
scheduled.  
• 
For UPC Ratio ≥ 2.0 or urine protein ≥ 2.0 g/24 hours: Hold bevacizumab therapy until 
proteinuria resolves to UPC < 2.0 or urine protein < 2.0 g/24 hours. If bevacizumab 
treatment is delayed for more than one cycle (4 weeks) due to proteinuria, discontinue 
bevacizumab; continue everolimus. 
• 
For UPC Ratio ≥ 4.0 or Nephrotic Syndrome: Discontinue bevacizumab; continue 
everolimus. 
9.12 
Hepatotoxicity (CTCAE v. 4.0, Infections and infestations - hepatitis viral)  
9.12.1 Hepatitis B: 
• 
Reactivation of hepatitis B in patients already receiving antiviral therapy is defined as 
an increase of 1 log in HBV DNA over baseline or the appearance of new measurable 
HBV DNA and ALT > 5 x ULN. 
For reactivation of hepatitis B in patients already receiving antiviral therapy, interrupt 
everolimus until ALT improves to less than or equal to grade 1, and HBV DNA 
improves to less than or equal to baseline level, and add a second antiviral. When ALT 
and HBV DNA improve, resume everolimus with one dose level reduction.  
• 
Reactivation of hepatitis B in patients not receiving antiviral therapy is defined as new 
appearance of measurable HBV DNA.  
For reactivation of hepatitis B in patients not receiving antiviral therapy, interrupt 
everolimus until HBV DNA improves to less than or equal to baseline level, and add 
lamuvidine (or other HBV-suppressive therapy). When HBV DNA improves, resume 
everolimus with one dose level reduction.  
If everolimus is interrupted for > 4 weeks, discontinue everolimus.  
Reactivation of hepatitis B is considered a grade 3 (or in the case of a life-threatening 
event, grade 4) event. Therefore, when everolimus is interrupted bevacizumab should be 


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skipped, or when everolimus is discontinued, bevacizumab should be discontinued (see 
also Section 9.15).  
9.13 
Hypersensitivity or bevacizumab infusion reactions 
The initial bevacizumab dose should be administered over a minimum of 90 minutes. If no 
hypersensitivity or infusion reactions occur, the second dose should be administered over a 
minimum of 60 minutes. If no hypersensitivity or infusion reactions occur with the second 
dose, the third and subsequent doses should be administered over a minimum of 30 minutes. If 
infusion-related reactions occur, subsequent bevacizumab infusions should be administered 
over the shortest period that is well-tolerated. Patients may receive premedication with 
antihistamines prior to bevacizumab if they have previously experienced allergic reactions 
(grade 1 or 2).  
For infusion-associated symptoms not specified above, infusion should be slowed to 50% or 
less or interrupted. Upon complete resolution of the symptoms, infusion may be continued at 
no more than 50% of the rate prior to the reaction and increased in 50% increments every 30 
minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle.  
For grade 1 or 2 hypersensitivity reactions, bevacizumab infusion should be interrupted for 
subjects who develop dyspnea or clinically significant hypotension.  
For grade 3 or 4 hypersensitivity reactions, discontinue bevacizumab; continue everolimus. 
For bronchospasm of any grade, discontinue bevacizumab; continue everolimus. 
9.14 
Surgery  
For patients who require surgery while on study, bevacizumab should be discontinued for at 
least 28 days prior to surgery whenever possible. Everolimus may be continued. Re-initiation 
of bevacizumab therapy should be discussed with the CALGB Study Chair. 
9.15 
Other non-hematologic toxicities 
For all other ≥ grade 3 non-hematologic toxicities not described above, hold all protocol 
treatment and monitor toxicity at least weekly. If toxicity resolves to ≤ grade 1 within 4 weeks, 
treatment may be resumed, with everolimus at one lower dose level. Bevacizumab will not be 
dose-modified. 
9.16 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing is 
performed according to actual body weight. Therefore, all dosing is to be determined solely 
by actual weight without any modification unless explicitly described in the protocol. This 
will eliminate the risk of calculation error and the possible introduction of variability in dose 
administration. Failure to use actual body weight in the calculation of drug dosages will be 
considered a major protocol deviation. Physicians who are uncomfortable with calculating 
doses based on actual body weight should recognize that doing otherwise would be a protocol 
violation. 


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10.1 
Predictive significance of plasma and urine biomarkers in TKI-refractory RCC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Redact
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10.2 
Tumor-based predictors of mTOR sensitivity 
10.2.1 Background 
Despite the clinical success of mTOR-based strategies in RCC patients, little is known 
about why this disease is uniquely sensitive to monotherapy treatment with mTOR 
inhibitors (such as everolimus) or mechanisms of resistance to this class of agent. In order 
to investigate potential tissue predictors of response or resistance to everolimus-based 
therapy we propose to collect primary, and when available, metastatic paraffin-embedded 
tissue from patients enrolled onto treatment and to evaluate these tissues for predictors of 
response or resistance. The most common and important genetic alteration in RCC tumors 
occurs in the VHL gene. To date no correlations between the VHL gene and response to 
mTOR inhibition has been completed. In preclinical RCC models, silencing of VHL and 
resultant increase in HIF activation results in an mTOR sensitive phenotype (26). 
Therefore, we propose to evaluate VHL mutational status by DNA sequencing and HIF 
protein expression to correlate their status with clinical outcomes on everolimus-based 
treatment. To do so, submission of primary and/or metastatic tumor blocks from patients 
enrolled to this study, will be requested. Following completion of the study, these samples 
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will be used to sequence the VHL gene, assess protein levels of HIF as well as to perform 
a global CGH analysis and correlated with survival.  
10.2.2 Objectives 
• 
Evaluate the association between VHL mutational status and overall survival. 
• 
Evaluate the association between pretreatment HIF protein expression and overall 
survival. 
10.2.3 Methods 
We propose to test whether the presence, type, and location of VHL mutations or promoter 
methylation predict overall survival in patients treated with everolimus with or without 
bevacizumab. The VHL status will be combined with clinical, pathologic, genomic, IHC, 
and plasma/urine VEGF levels. We expect that at least 560 samples treated with 
everolimus alone and with everolimus plus bevacizumab will be available. DNA will be 
extracted from paraffin sections and sequenced bi-directionally for the 3 exons of VHL 
(four amplicons). Patient DNA samples showing no mutations will be further 
characterized by methylation status of the VHL promoter. 
DNA extraction 
An H&E-stained section from each sample will be reviewed (at the CALGB Pathology 
Coordinating Office) to identify tumor content. Tumor cells will be manually 
microdissected from areas indicated to maximize tumor content to at least 70% tumor 
cells. DNA will then be isolated from three 10-micron sections using a 3-day proteinase K 
treatment. Following extraction, DNA will be purified and concentrated with Microcon 
YM-30 columns.  
DNA Quantification, Amplification, and Sequencing 
Purified genomic DNA will be quantified by Quantitative Microsatellite Analysis. PCR 
will be performed in 25 uL reaction mixtures consisting of 10 ng of template DNA, 0.2 
uM of each primer pair, 4% DMSO, 1% Triton X-100, 0.1% gelatin, and 12.5 uL of 
AmpliTaq Gold PCR Master Mix (ABI). Reaction mixtures will be incubated at 95°C for 
5’ prior to 35 cycles of 2-step PCR (15s at 95°C, 60s at 62°C), followed by 7’ at 72°C. 
Amplification products will be treated with ExoSAP-IT (USB) according to the 
manufacturer’s instructions. Normal reference DNA will also be amplified and sequenced 
as a negative control for VHL mutation; RCC cell lines 769-p and 786-O will serve as 
positive controls for VHL mutation. Mutation analysis will be performed using Mutation 
Surveyor software (SoftGenetics). 
VHL gene methylation status 
Methylation status will be determined using VHL methylation-specific PCR primers after 
DNA bisulfite modification. Genomic DNA will be modified using the CpGenomeTM 
DNA modification kit according to the manufacturer’s protocol (Chemicon International, 
Temecula, CA). The product will then undergo PCR-based amplification using 
methylation-specific primers, and methylation status will be determined by gel 
electrophoresis of the PCR products. 
10.3 
Pharmacogenetic companion study 
10.3.1 Background 
In CALGB 80303, a phase III trial of gemcitabine plus bevacizumab or placebo in 
advanced pancreatic cancer, it was discovered that the rs763780 variant in the IL17F gene 
was a prognostic factor in advanced pancreatic cancer patients treated with chemotherapy 


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(Innocenti, Proc ASCO 2009). Germline DNA was isolated from peripheral blood on 352 
patients, and was typed for more than 550,000 SNPs using the Illumina550 platform. The 
associations between overall survival (OS) and SNPs were investigated using the log-rank 
test. A review of the clinical data and ancestry genomic analysis identified 294 patients 
who were clinically eligible and determined to be genetically European, and this subset 
was used for the primary analysis. 
For the analysis of OS, patients in both arms were pooled, and a nonsynonymous SNP in 
the IL17F gene (rs763780) with an allelic frequency of 3.9% (H161R, p<2.7x10-8) was 
associated with OS. Median OS was significantly shorter for the H/R heterozygotes (3.1 
months, 95% CI 2.3-4.3, n=23), as compared to the H/H homozygotes (6.8 months, 95% 
CI 5.8-7.3, n=271). This association remained highly significant when the analysis was 
stratified by extent of disease or previous radiotherapy. There was no evidence of an 
interaction with bevacizumab, suggesting that this SNP is prognostic rather than 
predictive.  
IL17F codes for interleukin-17F, a cytokine with the ability to induce several types of cells 
to secrete pro-inflammatory cytokines in various inflammatory diseases. In vitro 
functional experiments demonstrated that the 161R variant form of IL17F lacks the ability 
to activate the mitogen-activated protein kinase pathway, cytokine production, and 
chemokine production, unlike the wild-type 161H IL17F (48, 49). Wild-type 161H IL17F 
has also demonstrated a strong anti-angiogenesis effect in vitro by markedly inhibiting the 
angiogenesis of human endothelial cells and inducing them to produce IL2, TGF-beta, and 
monocyte chemoattractant protein-1 (Starnes et al., 2001). The variant 161R form of 
IL17F is a natural antagonist of the anti-angiogenetic effects of wild-type IL17F.  
Our hypothesis is that the angiogenesis potential of RCC patients with the variant 161R 
IL17F is higher than tumors with wild-type 161H interleukin-17F, conferring worse 
prognosis. As 1) the biology of RCC is dependent upon angiogenesis, 2) angiogenesis is a 
mechanism that is primarily host-mediated (50) and 3) the heritable variant 161R IL17F 
seems to have a prognostic effect (Innocenti Proc ASCO 2009), the prognosis of RCC 
patients might be affected by heritable variation in the IL17F gene.  
In addition to IL17F, among several pro-angiogenic factors, VEGF appears to be a key 
regulator in neovascularization and enhanced vascular permeability. The VEGF family 
consists of VEGF-A (commonly referred to as VEGF), -B, -C, -D, -E, and PGF. The 
VEGF receptors are tyrosine kinases and are classified as VEGFR-1, -2, -3. VEGF and 
VEGFR-2 represent the most important ligand and receptor mediating the functions of 
endothelial cells during the process of tumor angiogenesis. SNPs in the VEGF gene are 
commonly found in Caucasian populations. In the VEGF gene, -634G>C (also referred to 
as +405G>C, rs2010963) has been found to be associated with increased overall survival 
(OS) in Korean HCC patients (34), similar to studies in NSCLC (35) and breast cancer 
(36). The -634C allele has been associated with lower VEGF levels in some studies (37, 
38) but not in others (34).  
Most pharmacogenetic analyses have taken a candidate gene approach that utilizes 
biological data to guide the selection of drug response genes in a pathway. This approach 
is limited by our knowledge of the mechanisms underlying the phenotypes. In the case of 
drug response phenotypes, most candidate gene studies have focused on drug metabolizing 
enzymes and transporters, thus limiting the chance of discovering causal SNPs not 
involved in mediating drug levels (52,53). In contrast, a genome-wide approach collects 
SNP data across the entire human genome and has significant power to detect common 
variants that confer a modest risk for a complex phenotype (54). Genome-wide studies 
capitalize on the large number of SNPs (more than 10 million available in dbSNP) that 


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have been localized and validated across the genome, a majority of which have resulted 
from the HapMap project (55). This valuable collection of publicly available, validated 
SNPs has provided the framework for performing genome-wide association studies. 
Recent technological advancements in genotyping platforms have also enabled the 
development of genome-wide associations. Searching the whole genome in an association 
study requires genotyping of anywhere between 105 to 106 markers across the genome (56-
59). Until recently, this approach was fiscally prohibitive and impractical. However, new 
gene chip platforms from Affymetrix and Illumina have made large scale genotyping 
feasible and cost effective. This new capability represents a paradigm shift in the number 
of genotypes that can be evaluated in any given individual with one genotyping assay and 
provides a platform for the identification of novel genes involved in the response to and 
toxicity associated with the drug(s) of interest. 
An increasing number of reports of significant findings from genome-wide association 
studies in cancer are being published. To date, these have all focused on SNPs associated 
with risk of developing cancer, and include studies in prostate (60-64), colorectal (65-67), 
lung (68) and breast cancer (69-71). The success of these studies illustrates the power and 
validity of this approach for identifying genetic causes of disease. To date, there are no 
published reports of genome wide association analyses in cancer pharmacogenetics. The 
relatively large size of CALGB 90802 and robust response and toxicity phenotype data 
make it an ideal sample set for whole genome analysis. The identification of SNPs that 
contribute to response and toxicity of the widely used drugs studied in CALGB 90802 will 
lead to additional studies to understand the mechanism for these associations and to 
investigate the application of genetic information for the optimization of cancer therapy. 
10.3.2 Objectives 
The primary objective of the pharmacogenetic companion is the investigation of the effect 
of IL17F on OS in the self-reported Caucasian population. 
Secondary objectives include 1) a potential interaction between bevacizumab and the 
VEGFA -634G>C variant (rs2010963) with respect to OS in the self-reported Caucasian 
population, 2) the identification of additional markers of OS, PFS, and toxicity through a 
genome-wide association study (GWAS).  
10.3.3 Methods 
In the present study, the pharmacogenetic investigation will take place in germline DNA 
extracted from a single 5 to 10 ml peripheral whole blood sample collected using EDTA 
vacutainer tubes (lavender tops) prior to beginning the study treatment. Samples will be 
shipped to the CALGB Pathology Coordinating Office at Ohio State University. Genomic 
DNA will be extracted using a commercially available kit from Qiagen. The concentration 
and quality of DNA will be quantified by ultraviolet spectroscopy. All DNA samples will 
be stored in the DNA bank at the CALGB PCO. Aliquots of DNA will be sent to the 
laboratory responsible for the genotyping.  
Genotyping for IL17F rs763780 and VEGF rs2010963 will be performed using previously 
published methods and assay conditions (35, 51). For genome-wide genotyping, the 
Illumina 610-Quad platform will be used. If more efficient alternative genotyping methods 
become available in the future, the PET committee will consider changing the genotyping 
approach to optimize resource utilization. The genotype information will be correlated 
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11.0 DRUG FORMULATION, AVAILABILITY, AND PREPARATION 
11.1 
Qualified personnel: 
Who are familiar with procedures that minimize undue exposure to themselves and to the 
environment 
should 
undertake 
the 
preparation, 
handling, 
and 
safe disposal 
of 
chemotherapeutic agents in a self-contained, protective environment. 
11.2 
Discard unused portions: 
Of injectable antineoplastic agents that do not contain a bacteriostatic agent or are prepared 
with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% Sodium Chloride for 
Injection USP) within eight hours of vial entry to minimize the risk of bacterial contamination. 
11.3 
The total administered dose: 
Of injectable antineoplastic agents may be rounded up or down within a range of 5% of the 
actual calculated dose.  
11.4 
Changes in weight:  
It is not necessary to change the dose of bevacizumab due to changes in weight unless the 
calculated dose changes by ≥ 10%. 
11.5 
Bevacizumab (NSC #704865, IND #113911) 
Questions about drug orders, transfers, returns, or accountability should be addressed to 
the PMB by calling 240-276-6575 Monday through Friday between 8:30 am and 4:30 pm 
Eastern 
Time. 
You 
may 
also 
contact 
the 
PMB 
via 
e-mail 
at 
pmbafterhours@mail.nih.gov.   
All investigators who receive a copy of the protocol should also obtain a copy of the 
Investigator’s Brochure (IB). IB’s are available from the Pharmaceutical Management Branch, 
CTEP, 
DCTD, 
NCI 
and 
may 
be 
obtained 
by 
emailing 
the 
IB 
Coordinator 
(ibcoordinator@mail.nih.gov) or by calling the IB Coordinator at 240-276-6570. 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody, consisting of 93% 
human and 7% murine amino acid sequences. The agent is composed of human IgG 
framework and murine antigen-binding complementarity-determining regions. Bevacizumab 
blocks the binding of vascular endothelial growth factor (VEGF) to its receptors resulting in 
inhibition of angiogenesis. 
Availability 
Bevacizumab (NSC 704865) will be provided free of charge by Genentech and distributed by 
the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), 
Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).  
Once this study has converted to the open label design, (Update #3) a supply of bevacizumab 
may be ordered by using the PMB Online Agent Order Processing (OAOP) application 
(https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the 
establishment of a CTEP Identitiy and Access Management (IAM) account (http://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a “current” 
password. 
Prior to the conversion to the open label design, continue to order patient specific supplies per 
the original blinded study design. 


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Open label bevacizumab will be supplied as a clear to slightly opalescent, sterile liquid ready 
for parenteral administration. Each 400 mg (25 mg/mL – 16 mL fill) glass vial contains 
bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP.  
Drug Returns: Only unopened clinical supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed vials remaining when a patient permanently 
discontinues protocol treatment or expired vials recalled by the PMB), investigators should 
return the study drug to the PMB using the NCI Return Drug List available on the CTEP home 
page (http://ctep.cancer.gov).  
Drug Accountability: The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, disposition, and return of all drugs received from 
the PMB using the NCI Drug Accountability Record Form (DARF) available on the CTEP 
home page (http://ctep.cancer.gov) or by calling the PMB at 240-276-6575.  
Note: Supplies for the open label study design are study specific (one DARF for the study). 
Supplies for the blinded study design continue to be patient specific, requiring a separate 
DARF for each patient as long as the blinded design is in effect. 
Storage and Stability 
Bevacizumab is shipped on blue ice for next day delivery. On receipt, bevacizumab should be 
stored in a refrigerator (2o to 8o C) and should remain refrigerated until just prior to use. Do not 
freeze. Do not shake. Shelf-life studies of bevacizumab are continuing. Investigators will be 
notified when lots have expired. The sterile single use vials contain no antibacterial 
preservatives; therefore, vials should be discarded eight hours after initial entry. Solutions 
diluted for infusion may be stored in the refrigerator for up to 8 hours. 
Preparation 
Vials contain no preservative and are intended for single use only. Place the calculated dose 
in 100 mL of 0.9% Sodium Chloride for Injection. Once diluted in 0.9% Sodium Chloride 
for Injection, the bevacizumab solution must be administered within 8 hours. 
Administration 
Bevacizumab is administered as an intravenous infusion. The initial dose should be 
administered over a minimum of 90 minutes. If no adverse reactions occur after the initial 
dose, the second dose should be administered over a minimum of 60 minutes. If no adverse 
reactions occur after the second dose, all subsequent doses should be administered over a 
minimum of 30 minutes. If infusion-related adverse reactions occur, all subsequent infusions 
should be administered over the shortest period that was well tolerated. 
Toxicities 
Hypertension: Hypertension has been commonly seen in bevacizumab clinical trials to date 
and oral medications have been used to manage the hypertension when indicated. Grade 4 and 
5 hypertensive events are rare. Clinical sequelae of hypertension are rare but have included 
hypertensive 
crisis, 
hypertensive 
encephalopathy, 
and 
reversible 
posterior 
leukoencephalopathy syndrome (RPLS). RPLS may include signs and symptoms of headache, 
altered mental function, seizures, and visual disturbances/ cortical blindness and requires 
treatment, which should include control of hypertension, management of specific symptoms, 
and discontinuation of bevacizumab. 
Reversible posterior leukoencephalopathy syndrome (RPLS) or similar leukoencephalopathy 
syndrome: RPLS or clinical syndromes related to vasogenic edema of the white matter have 


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been recently reported in association with bevacizumab therapy. These syndromes have been 
seen in < 1% of patients to date. Clinical presentations are variable and may include altered 
mental status, seizure and cortical visual deficit. HTN is a common risk factor and was present 
in most (though not all) patients on bevacizumab who developed RPLS. MRI scans are key to 
diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images 
and hypointensity in T1 images) predominantly in the white matter of the posterior parietal 
and occipital lobes; less frequently, the anterior distributions and the gray matter may also be 
involved. RPLS should be in the differential diagnosis in patients presenting with unexplained 
mental status change, visual disturbance, seizure or other CNS findings. RPLS is potentially 
reversible, but timely correction of the underlying causes, including control of BP and 
interruption of the offending drug, is important in order to prevent progression to irreversible 
tissue damage. 
Neutropenia: When combined with chemotherapy, bevacizumab is reported to increase the risk 
of neutropenia over that of chemotherapy alone. Grade 3 – 4 neutropenia, febrile neutropenia, 
or increased rate of infection were increased in studies in which bevacizumab with 
chemotherapy (IFL, paclitaxel and carboplatin) was compared to chemotherapy alone. 
Proteinuria: Proteinuria ranging from asymptomatic abnormal urinalysis to nephrotic 
syndrome, has been described in 10% or more of patients receiving bevacizumab. Proteinuria 
is managed with dose modifications as described in Section 9.12. 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, ranging in 
severity from catheter-associated phlebitis to fatal, have been reported in patients treated with 
bevacizumab in the colorectal cancer (CRC) trials and, to a lesser extent, in patients treated 
with bevacizumab in NSCLC and breast cancer trials. In the phase III pivotal trial in metastatic 
CRC, there was a slightly higher rate of venous TE events that was not statistically significant 
in patients treated with bevacizumab plus chemotherapy compared with chemotherapy alone 
(19% vs. 16%). There was also a higher rate of arterial TE events (3% vs. 1%) such as 
myocardial infarction, transient ischemia attack, cerebrovascular accident/stroke and 
angina/unstable angina. A pooled analysis of the rate of arterial TE events from 5 randomized 
studies (1745 patients) showed that treatment with chemotherapy plus bevacizumab increased 
the risk of having an arterial TE event compared with chemotherapy alone (3.8% vs. 1.7%, 
respectively). Furthermore, subjects with certain baseline characteristics (age ≥ 65 years and/or 
a history of a prior arterial TE event) may be at higher risk of experiencing such an event.  
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial 
thromboembolic events in patients at high risk of such events, and the use of aspirin ≤ 325 mg 
daily was allowed in the five randomized studies discussed above. Use of aspirin was assessed 
routinely as a baseline or concomitant medication in these trials, though safety analyses 
specifically regarding aspirin use were not preplanned. Due to the relatively small numbers of 
aspirin users and arterial thromboembolic events, retrospective analyses of the ability of 
aspirin to affect the risk of such events were inconclusive. However, similar retrospective 
analyses suggested that the use of up to 325 mg of aspirin daily does not increase the risk of 
grade 1-2 or grade 3-4 bleeding events, and similar data with respect to metastatic colorectal 
cancer patients were presented at ASCO 2005. Further analyses of the effects of concomitant 
use of bevacizumab and aspirin in colorectal and other tumor types are ongoing.  
Gastrointestinal perforation: Patients with metastatic carcinoma may be at increased risk for 
the development of gastrointestinal perforation when treated with bevacizumab and 
chemotherapy. Bevacizumab should be permanently discontinued in patients who develop 
gastrointestinal perforation. A causal association of intra-abdominal inflammatory process and 
gastrointestinal perforation to bevacizumab has not been established. Nevertheless, caution 
should be exercised when treating patients with intra-abdominal inflammatory processes with 


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bevacizumab. Gastrointestinal perforation has been reported in trials in non-colorectal cancer 
populations (e.g., ovarian, renal cell, pancreas, and breast) and may be higher in incidence in 
some tumor types. 
Wound healing complications: Wound healing complications such as wound dehiscence have 
been reported in patients receiving bevacizumab. In an analysis of pooled data from two trials 
in metastatic colorectal cancer, patients undergoing surgery 28-60 days before study treatment 
with 5-FU/LV plus bevacizumab did not appear to have an increased risk of wound healing 
complications compared to those treated with chemotherapy alone. No definitive data are 
available to define a safe interval after bevacizumab exposure with respect to wound healing 
risk in patients receiving elective surgery; however, the estimated half life of bevacizumab is 
21 days. Bevacizumab should be discontinued in patients with severe wound healing 
complications. 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 4.0% of 1132 patients 
treated with bevacizumab in a pooled database from eight phase I, II, and III clinical trials in 
multiple tumor types (Bevacizumab Investigator Brochure, October 2005). The hemorrhagic 
events that have been observed in bevacizumab clinical studies were predominantly tumor-
associated hemorrhage (see below) and minor mucocutaneous hemorrhage.  
Tumor-associated hemorrhage was observed in phase I and phase II bevacizumab studies. Six 
serious events, of which four had fatal outcome, were observed in a phase II trial of patients 
with non-small cell lung cancer receiving bevacizumab. These events occurred suddenly and 
presented as major or massive hemoptysis in patients with either squamous cell histology 
and/or tumors located in the center of the chest in close proximity to major blood vessels. In 
five of these cases, these hemorrhages were preceded by cavitation and/or necrosis of the 
tumor. Tumor-associated hemorrhage was also seen rarely in other tumor types and locations, 
including central nervous system (CNS) bleeding in a patient with hepatoma with occult CNS 
metastases and continuous oozing of blood from a thigh sarcoma with necrosis.  
Across all bevacizumab clinical trials, mucocutaneous hemorrhage has been seen in 20%-40% 
of patients treated with bevacizumab. These were most commonly grade 1 epistaxis that lasted 
less than 5 minutes, resolved without medical intervention and did not require any changes in 
bevacizumab treatment regimen. There have also been less common events of minor 
mucocutaneous hemorrhage in other locations, such as gingival bleeding and vaginal bleeding.  
Congestive heart failure: CHF has been reported in bevacizumab clinical trials and may be 
increased in incidence in patients with prior exposure to anthracyclines or prior irradiation to 
the chest wall. In a phase III trial (AVF2119g) of capecitabine with or without bevacizumab 
for metastatic breast cancer, 7 subjects (3.1%) who received capecitabine plus bevacizumab 
developed clinically significant CHF compared with 2 subjects (0.9%) treated with 
capecitabine alone; of note, all subjects in this trial had had prior anthracycline treatment. In 
addition, 2 subjects had a left ventricular ejection fraction < 50% at baseline and 2 others had 
prior left chest wall irradiation. A recently published phase II study in subjects with refractory 
acute myelogenous leukemia reported 5 cases of cardiac dysfunction (CHF or decreases to 
<40% in left ventricular ejection fraction) of 48 subjects treated with sequential cytarabine, 
mitoxantrone, and bevacizumab. All but one of these subjects had significant prior exposure to 
anthracyclines as well. Other studies are ongoing in this patient population. 
Osteonecrosis of the jaw: There are several reports in the literature suggesting that 
bevacizumab increases the likelihood of osteonecrosis of the jaw in patients receiving 
bisphosphonates, and that bevacizumab may cause osteonecrosis of the jaw in patients not 
receiving bisphosphonates. This effect is thought to be related to inhibition of angiogenesis. 


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For a comprehensive list of adverse events and potential risks (CAEPR), see Section 16.3. 
Also refer to the bevacizumab Investigator’s Brochure for additional information about 
toxicities. 
11.6 
Everolimus (RAD-001, NSC #733504) 
Please refer to the FDA-approved package insert for everolimus for complete product 
information. 
Availability  
Everolimus is commercially available, supplied as 5 mg and 10 mg tablets in cartons 
containing four blister packs with 7 tablets per pack. 
Administration 
Everolimus will be administered orally by the patient once daily. The dose may be 
administered with or without food.  
Storage and Stability 
Everolimus tablets should be stored and dispensed in the original container. Blister packs 
should be protected from light and moisture. Commercial preparations are labeled with an 
expiration date. 
Toxicities 
Adverse events most frequently observed with everolimus are rash, stomatitis/oral mucositis, 
fatigue, headache, anorexia, nausea, vomiting, and diarrhea. Non-infectious pneumonitis has 
also been observed. The majority of these AEs have been of mild to moderate severity (CTC 
grade 1-2). Overall, the most frequently observed laboratory abnormalities include reduced 
blood 
counts, 
hyperlipidemia 
mostly 
reported 
as 
hypercholesterolemia 
and/or 
hypertriglyceridemia.  
Stomatitis: The principal DLT in Phase 1 trials has been Grade 3 stomatitis. For guidance on 
management of stomatitis refer to Section 12.5. 
Hyperlipidemia was reported as a serious adverse reaction. It is a recognized side-effect of 
rapamycins. Use of lipid-lowering drugs should be associated with dietary recommendations. 
Monitoring of blood lipid levels requires patients to be fasting so that this aspect must be 
verified when interpreting results. For guidance on management of hyperlipidemia refer to 
Section 12.6. 
Hyperglycemia was reported as a serious adverse reaction. Similarly, the fasting state of 
patients should be verified when interpreting results. For guidance on management of 
hyperglycemia refer to Section 12.7. 
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. 
In oncology studies with everolimus, severe pneumonitis suspected as drug-related has been 
reported as a serious adverse event on 13 occasions and additionally in the following 
associated preferred terms including acute respiratory distress syndrome (n=2), alveolitis (n=1) 
and allergic alveolitis (n=1), interstitial lung disease (n=10), lung infiltration (n=23), 
cryptogenic organizing pneumonia, lung consolidation, pulmonary alvealoar haemorrhage, 
pulmonary toxicity and pulmonary fibrosis (n=1, each). One fatal case of drug-related 


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pneumonitis was reported for a patient with metastatic infiltrating ductal carcinoma of the 
breast treated with 10 mg/day, which developed approximately two months after starting 
everolimus. Cytology for both the pleural and pericardial fluids was positive for malignancy. 
The death was considered possibly related to the underlying late stage tumor and study drug. 
Additionally, one patient treated with 10 mg/day died due to severe acute respiratory distress 
syndrome and septic shock. Thoracic CT scan demonstrated condensation in the majority of 
the left lower lobe and frosted glass appearance in the left upper lobe, lingula, and right lung. 
Along with the cases of non-infectious pneumonitis, serious opportunistic infections have also 
been reported in cancer patients treated with everolimus: mycobactrium, aspergillus, and fatal 
candidal sepsis, and fatal pneumocystis carnii in particular. Because everolimus, as other 
rapamycins, inhibits proliferation of activated lymphocytes and reduces neutrophil counts, 
treatment with everolimus must be considered as predisposing patients to the risk of infection. 
This risk will be higher in patients severely immunocompromised because of their underlying 
disease and/or co-medications. Outcome may be fatal in case of serious infections.  
Hematologic toxicity: A reduction in blood cell counts is frequent when everolimus therapy is 
initiated. Without clinical significance and infrequently, anemia and thrombocytopenia have 
been reported. In heavily pretreated patients with aggressive lymphoma, the incidence of grade 
3 anemia, neutropenia, and thrombocytopenia was reported to be 11%, 16%, and 30%, 
respectively. Serious, suspected drug-related hemorrhages have been exceptional. 
Nevertheless, everolimus should be considered as predisposing patients to hemorrhage, 
potentially fatal, should they develop severe drug-related thrombocytopenia. 
Hepatic toxicity: Discrete, reversible changes in liver enzymes have been seen in patients in 
oncology trials, and in patients with rheumatoid arthritis. As noted above, opportunistic 
infections have been associated with everolimus. Opportunistic infections result from the 
immunosuppressive activity of everolimus. Among these opportunistic infections, reactivation 
of hepatitis B virus has been described. Hepatitis B reactivation may lead to hepatic failure, 
which can be fatal. Antiviral prophylaxis with lamivudine (or other HBV-suppressive therapy) 
is required as described in Section 4.11.  
Renal failure: Renal failure has been reported in oncology patients, as well as in transplant 
patients. In the transplant setting, mTOR inhibitors such as everolimus potentiates the 
nephrotoxicity seen with calineurin inhibitors. In the oncology patients, additional factors may 
have contributed to the development of renal failure. 
Hypophosphatemia, 
hypomagnesemia, 
hyponatremia 
and 
hypocalcemia: 
Laboratory 
abnormalities including hypophosphatemia, hypomagnesmia, hyponatremia and hypocalcemia 
have been reported in patients receiving everolimus as a single agent, in combination with 
cytotoxic chemotherapy, and in patients previously treated with agents also known to cause 
these abnormalities. Occasionally, severity grade 3 or 4 abnormalities have been seen. 
Drug Interactions 
Everolimus is metabolized by CYP3A4. Strong inhibitors of CYP3A4 may increase 
everolimus exposure with the potential for toxicity. Several studies have documented 
increased exposure of everolimus in the presence of CYP3A4 inhibitors, but no adverse effects 
as a result of the combination were seen in healthy subjects. Rifampin, a potent inducer of 
CYP3A4 resulted in increased clearance, but highly variable changes in AUC of everolimus. It 
is recommended that both strong inducers (e.g., rifampin, phenobarbital, phenytoin) and strong 
inhibitors (e.g., itraconazole, ketoconazole) be avoided. 


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12.0 ANCILLARY THERAPY 
12.1 
Patients should receive full supportive care: 
Including transfusions of blood and blood products, antibiotics, antiemetics, etc., when 
appropriate. The reason(s) for treatment, dosage, and the dates of treatment should be recorded 
on Form C-260. 
12.2 
Treatment with hormones or other chemotherapeutic agents:  
May not be administered except for steroids given for adrenal failure, suspected drug induced 
pneumonitis or other allergic reactions; hormones administered for non-disease-related 
conditions (e.g., insulin for diabetes); and intermittent use of dexamethasone as an antiemetic, 
or to treat cough associated with everolimus pneumonitis. See also Section 4.14. 
12.3 
Palliative radiation therapy may not be administered while the patient is on study treatment.  
A symptomatic lesion or one which may produce disability (e.g., unstable femur) may be 
irradiated before study initiation, provided other measurable or evaluable disease is present 
and radiation therapy is completed ≥ 2 weeks before start of therapy. All eligibility criteria 
must still be met. Any other indications for radiotherapy after protocol treatment has begun 
will constitute disease progression, and the patient will stop protocol treatment. 
12.4 
CALGB Policy Concerning the Use of Growth Factors 
12.4.1 Epoetin (EPO) 
The use of EPO is permitted; however, its use is discouraged according to the current 
guidelines. 
12.4.2 Filgrastim (G-CSF) and sargramostim (GM-CSF) 
1. Filgrastim (G-CSF), pegfilgrastim and sargramostim (GM-CSF) treatment for patients is 
discouraged. 
2. Filgrastim/pegfilgrastim and sargramostim may not be used: 
a. to avoid dose reductions, delays or to allow for dose escalations specified in the 
protocol, 
b. prophylactically because of concern about myelosuppression  
3. For the treatment of febrile neutropenia the use of CSFs should not be routinely instituted 
as an adjunct to appropriate antibiotic therapy. However, the use of CSFs may be indicated 
in patients who have prognostic factors that are predictive of clinical deterioration such as 
pneumonia, hypotension, multi-organ dysfunction (sepsis syndrome) or fungal infection, 
as per the ASCO guidelines. Investigators should therefore use their own discretion in 
using the CSFs in this setting. The use of CSF (filgrastim/pegfilgrastim or sargramostim) 
must be documented and reported on Form C-260.  
4. If filgrastim/pegfilgrastim or sargramostim are used, they must be obtained from 
commercial sources. 
12.5 
Recommendations for management of oral mucositis:  
(see also Section 9.5 for recommended dose reductions)  
For grade 1 oral mucositis, the manufacturer recommends the use of alcohol-free mouthwash 
or saline mouthwash 3-4 times daily. For ≥ grade 2 oral mucositis, consider topical anesthetics 
or topical steroids. 


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12.6 
Recommendations for management of hyperlipidemia: 
That is present at baseline or developing during treatment include a statin or other lipid-
lowering agent as well as diet.  
12.7 
Recommendations for management of hyperglycemia:  
Grade 3 hyperglycemia has been observed in patients receiving everolimus therapy, 
particularly in patients with an abnormal fasting glucose at baseline. Optimal glucose control 
should preferably be achieved before starting a patient on everolimus and should be monitored 
and treated promptly during everolimus therapy. Everolimus dose reduction or interruption is 
not required. 
13.0 CRITERIA FOR RESPONSE AND PROGRESSION  
For the purposes of this study, disease should be reevaluated every 4 weeks by physical 
examination and every 8 weeks by imaging studies. In addition to a baseline scan, confirmatory 
scans should also be obtained at least 4 weeks following initial documentation of objective 
response. This study uses RECIST criteria version 1.1. 
13.1 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, and should be 
chosen based on their suitability for accurate repetitive measurements. It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible repeated measurements in 
which case the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum LD will 
be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease. 
13.1.1 Complete Response: Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
13.1.2 Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.  
13.1.3 Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
13.1.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest sum diameters while on study. 
13.2 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. 


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13.2.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
13.2.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or 
more non-target lesion(s) and/or maintenance of tumor marker level above the normal 
limits. 
13.2.3 Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of non-target lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed later on by the review panel (or Study Chair). 
13.3 
Cytology and Histology 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
These techniques can be used to differentiate between PR and CR in rare cases (for example, 
residual lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
13.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient’s best response assignment 
will depend on the achievement of both measurement and confirmation criteria (see Section 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required 
CR 
CR 
No 
CR 
≥ 4 wks confirmation* 
CR 
Non-CR/Non-PD 
No 
PR 
≥ 4 wks confirmation* 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once 
≥ 4 wks from baseline* 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
Only for non-randomized trials with response as the primary endpoint. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration” on the Off-treatment Form (C-300) under “other.” Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
For Patients with Non-measurable Disease (i.e., Non-target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised. 
 
13.5 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
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13.5.1 Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers (e.g., 
skin nodules). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
13.5.2 Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
13.5.3 Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for 
body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition variables involved in 
MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is 
performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the 
modality used at follow-up should be the same as was used at baseline and the lesions 
should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, 
body parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
13.5.4 Ultrasound (US): Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is advised. If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances. 
13.5.5 Endoscopy and Laporascopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
13.5.6 Tumor markers alone cannot be used to assess response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  
13.6 
Confirmation Measurement/Duration of Response 
13.6.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat studies that should be performed at least 4 weeks after the criteria for response 
are first met. In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval of 8 weeks. 
13.6.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 


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disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is objectively 
documented. 
13.6.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements. 
14.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
14.1 
Duration of Treatment 
14.1.1 CR, PR, or SD: Continue treatment at the highest tolerable dose until the appearance of 
disease progression or unacceptable toxicity per Section 9.0. 
14.1.2 Disease Progression: Give a minimum of 2 cycles of therapy. Remove from protocol 
therapy any patient with rapid disease progression. Document details, including tumor 
measurements, on data forms. 
14.2 
Extraordinary Medical Circumstances: If, at any time the constraints of this protocol are 
detrimental to the patient's health and/or the patient no longer wishes to continue protocol 
therapy, protocol therapy shall be discontinued. In this event: 
• 
Notify the Study Chair. 
• 
Document the reason(s) for discontinuation of therapy on Form C-1934. 
• 
Follow the patient for survival or secondary malignancy and new primaries for a minimum 
of 5 1/2 years following registration. 
15.0 STATISTICAL CONSIDERATIONS 
15.1 
Endpoints 
The primary endpoint is overall survival (OS). Secondary endpoints will be progression-free 
survival (PFS), objective response rate (defined as confirmed CR plus PR), and toxicity. OS 
will be measured from date of randomization to date of death due to any cause. PFS will be 
measured from the date of randomization to date of progression or death due to any cause, 
whichever occurs first. Progression and response will be defined using the RECIST criteria. 
15.2 
Randomization and Stratification 
Randomization will be stratified on the number of negative prognostic features (0, 1, 2-3) 
based on the variables: Karnofsky performance status < 80%, corrected serum calcium ≥ 10 
mg/dl and hemoglobin levels ≤ 13 for males and ≤ 11.5 for females and prior VEGFR-TKI 
therapy (< 12 weeks of therapy, ≥ 12 weeks of therapy). Assignment to treatment arm will be 
performed centrally at the CALGB Statistical Center following determination of eligibility. 
The CALGB Statistical Center will use a randomized permuted block randomization method.  
15.3 
Power Considerations 
This is a randomized, prospective phase III trial in which 700 patients will be randomized with 
equal probability to one of two possible treatment regimens: everolimus alone or everolimus 
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The following calculations assume a monthly accrual rate of about 23 patients/month accrued 
over a 30-month period, post accrual period of 34 months after study closure and a two-sided 
alpha level of 0.05. Survival time is assumed to follow an exponential distribution. With 632 
deaths, the power to detect a hazard ratio of 1.30 or a 24% decrease in hazard rate (equivalent 
to an increase in median OS from 12 months to about 15.6 months as was observed by Motzer, 
et al. is 90%.  
15.4 
Interim Analysis 
Efficacy (overall survival) results will be conducted on semiannual basis to coincide with the 
semiannual meetings of the CALGB Data and Safety Monitoring Board (DSMB). Under the 
alternative hypothesis, six hundred thirty two events (deaths) are expected at the end of the 
follow-up period. The first interim analysis for OS will be performed at about 23% of the full 
information (approximately 18 months after study activation). Other interim analyses will be 
performed at 37% of the full information (approximately 24 months), at 54% (approximately 
30 months), at 69% of the total information (approximately 36 months), at 79% 
(approximately 42 months), at 88% (approximately 48 months), and at 100% (approximately 
64 months after study activation). To help insure complete data on which to base the interim 
analyses, institutions will be asked to submit survival status on their patients on a semi-annual 
basis (April 1 and September 1 of each year when the trial is being monitored by the DSMB). 
A Lan-Demets spending function analogue of a one-sided O’Brien-Fleming will be used to 
stop the trial early to reject the null hypothesis. Assuming the above percent information 
available at each look and a one-sided type I error rate = 0.025, the z-score boundaries for 
stopping for superiority for OS endpoint and the z-score boundaries for stopping for futility 
under the alternative hypothesis using Friedlin, et al. (73) futility guidelines presented in the 
table below. Should any boundary be crossed, accrual to the trial may be stopped. These rules 
have a negligible impact on the type I and II error rates of this trial.  
 
 
 
One-sided Boundaries for Interim 
Analysis for the OS endpoint 
 
Percent information 
(Number of deaths) 
For Superiority 
For Futility 
1 
23% (145) 
4.340 
-1.645 
2 
37% (236) 
3.400 
 0.003 
3 
54% (340) 
2.834 
 0.120 
4 
69% (433)  
2.510 
   0.252 
5 
79% (502) 
2.331 
   0.353 
6 
88% (553) 
2.222 
   0.452 
7 (Final) 
100% (632) 
2.077 
   1.960 
Table 2 


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In addition, this trial incorporates a phase II PFS-based decision rule and will be evaluated 
after the first 100 patients have been followed for 4 months. The phase II rule will be 
implemented as follows: the PFS rate at 4-month will be estimated and reported to the CALGB 
DSMB. The trial will remain open if the observed PFS rate at 4-month in the experimental arm 
is at least 6% higher than what is observed in the control arm. The trial will remain open while 
the phase II rule is evaluated. 
15.5 
Data Analysis 
An intent-to-treat approach will be used in this phase III study to analyze OS and PFS. Patients 
who withdraw consent for treatment or withdraw from the study due to toxicity will continue 
to be followed for overall survival, even if they begin another therapy. The stratified log-rank 
statistic will be the primary analysis to compare the two treatment arms on OS and PFS 
adjusting on the stratification factors (number of negative prognostic factors (0, 1, 2-3) and 
prior VEGFR-TKI therapy (< 12 weeks, ≥ 12 weeks).  
PFS will be defined as the time from randomization to disease progression or death from any 
cause. For patients who do not experience disease progression or death at the time of analysis 
their PFS will be censored at the time of the last tumor assessment (or, if no tumor assessments 
were performed after the baseline visit, at the time of randomization plus 1 day). In addition, 
we will perform sensitivity analyses based on the PFS endpoint. For patients who receive non-
protocol-specified anti-cancer therapy prior to experiencing documented disease progression, 
their PFS will be censored at the time of the last tumor assessment prior to receiving the non-
protocol-specified therapy. In addition, for patients who die more than 90 days following their 
last dose of study drug and are not found to have progression prior to death, PFS will be 
censored at the date of their last tumor evaluation. 
The Kaplan-Meier product-limit estimator will be used to estimate the OS, and PFS 
distributions. In addition, the proportional hazards model will be used to assess the importance 
of the treatment arm adjusting on patient characteristics, stratification variables and other 
important covariates in predicting OS and PFS.  
Furthermore, the Cochran-Mantel-Haenszel test will be used to compare the two arms on the 
proportion of patients who experience an objective response (defined as either a confirmed CR 
or a PR) adjusting on the stratification factors (number of negative prognostic features and 
prior VEGFR-TKI therapy. In addition, the Fisher exact test will be used to compare the two 
treatment arms on the proportion of patients with unacceptable treatment related grade 3 or 
higher toxicity. 
15.6 
Accrual Rate  
Based on previous data from patients enrolled on CALGB 90206, the accrual rate was 40 
patients per month. Assuming an accrual rate of 23 patients/month, accrual is expected to be 
completed in about 30 months within study activation. All patients will be followed for a 
maximum period of 5 ½ years after randomization. 
Statistical considerations for correlative sciences studies 
 
 
 
 
 
 
 
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15.7.2 Data Analysis 
The Kaplan-Meier product-limit estimator will be used to estimate the overall and survival 
distribution by the median value of each biomarker. In addition, the log-rank test will be 
used to compare OS between the two groups (low and high levels). Furthermore, the 
proportional hazards model will be used to assess the importance of VEGF levels in 
predicting OS adjusting for important clinical and stratification factors including Memorial 
Sloan Kettering risk factors, which are a stratification factor as well. Moreover, quartiles 
and continuous measures of VEGF levels will be used in the proportional hazards model. 
In addition, exploratory statistical methods will be used to find different (than the median) 
cut points for each biomarker that may identify a biologically significant subgroup.  
For the second objective, we will be testing whether changes in biomarkers at 8 weeks (2 
cycles of treatment) from baseline will predict survival time. Landmark analyses will be 
performed at 8 weeks from randomization to minimize “lead time bias.” Furthermore, the 
Kaplan-Meier product-limit estimator will be used to estimate the overall survival 
distribution by median change in each biomarker level at 8 weeks from baseline. In 
addition, the log-rank test will be used to compare OS between the two groups. Moreover, 
the proportional hazards model will be used to assess the importance of change at 8 weeks 
from baseline in biomarker levels in predicting OS adjusting for important clinical and 
stratification factors. We will test whether change in biomarkers at 8 weeks from baseline 
is a surrogate for OS if the treatment is statistically significant using Prentice’s criteria. 
In addition, exploratory statistical methods will be used to find different (than the median) 
cut points for change in biomarker levels at 8 weeks from baseline. Statistical methods 
based on exact asymptotic distributions will be used to find a cutpoint (other than the 
median) for change in each biomarker at 8 weeks from baseline. 
 
 
15.8.1 Power Justification 
Power computations are computed based on objective 1 (Section 10.2.2) and are presented 
assuming that 80% (n = 560) of the samples will be available and useable. The median 
survival for the control arm is 12 months. The hypothesized median for the experimental 
arm is 15.6 months. Based upon previous analyses we expect approximately 60% of the 
patients to display evidence of a VHL gene inactivation (either a gene mutation or 
methylation).  
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Table 4 below presents the minimum HR that can be detected assuming OS follows 
exponential distribution, 0.80 power, a two-sided test of 0.025, and events rates of 70-90% 
of the 560 patients. 
Proportion of patients 
with VHL levels  
Proportion of events observed among 560 
patients with anticipated plasma 
 
70% events 
80% events 
90% events 
0.60 
1.33 
1.31 
1.29 
Table 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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15.8.3 Data Transfer 
Once the SNPs data analyses have been generated, files with the unadjusted expression 
data (CEL files) will be sent to the CALGB Bioinformatics Unit for Quality control and 
data analysis. 
15.9 
Statistical considerations for pharmacogenetics studies (60901) 
15.9.1 Candidate Gene Analysis 
The primary objective for this candidate marker study is to validate the IL17F SNP 
(rs763780) as a prognostic marker for overall survival.  
A total of 700 patients are to be randomized to the study. It is assumed that 85% of these 
patients will provide consent and usable samples for this pharmacogenomic companion 
study. The analysis population will consist of those self-reported as Caucasian on the CRF 
form. The expected proportion for this population is 0.85. As such, the companion study 
will be powered based on a sample size of 506 (=700*0.85*0.85). According to the 
clinical design, the assumed time to death distributions for the two arms are hypothesized 
to be exponential with medians of 12 and 15.6 months respectively. The follow-up 
distribution is assumed to be uniform on the interval (34,30+34) months. 
Based on the CALGB 80303 genome-wide association study (GWAS), the relative 
genotypic frequencies for this SNP were 0.92, 0.08 and 0 for AA, AG and GG 
respectively. We will power the analyses for the dominant (in the G allele) model 
assuming relative frequencies of 0.92 and 0.08 for the {AA} and {AG, GG} groups, 
respectively. For the power calculations, it will be assumed that the OS distribution for the 
control arm is expressible as a mixture of exponential laws of the form P(T1>t) = 
0.92*exp[-lam1,0*t]+0.08*exp[-lam1,0*D*t] where D ≥ 1 is the hazard ratio. Similarly for 
the experimental arm, the OS distribution will be expressed as P(T2>t)=0.92*exp[-
lam2,0*t]+0.08*exp[-lam2,0*D*t]. In the power calculations, we will set P(T1>t)=0.5 for t = 
12, P(T2>t)=0.5 for t = 15.6 and then solve for lam1,0 and lam2,0. 
Under the above assumptions, the power of the two-sample log-rank test, at the one-sided 
0.05 level, is 0.89 and 0.97 for hazard ratios of 1.6 and 1.8, respectively. The power was 
approximated using B = 10,000 simulation replicates. It is noted that the estimated hazard 
ratio, within a proportional hazards framework, was 3.3 (95%CI = 2.1,5.1) for CALGB 
80303. 
It is also noted that this is a hypothesis of association (gene by outcome) and not a 
hypothesis of interaction (gene by drug with respect to outcome). Any potential interaction 
will be investigated using a log-linear multiplicative logistic model. 
A secondary objective is to investigate if VEGFA variant rs2010963 is a predictive maker 
for OS. Specifically, we will investigate if there is a genotype by bevacizumab interaction 
with respect to OS. To this end, a log-linear multiplicative Cox model will be used. 
The addition of other important clinical and demographic co-variables will be considered. 
Multivariable models, with molecular, clinical and demographic variables, will be 
constructed using conditional inference trees and random forests. The primary objective 
will be tested at the one-sided level of 0.05. All secondary and exploratory objectives will 
be tested at an unadjusted two-sided level of 0.05. Secondary analyses will also look into 
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additional candidate genes of treatment outcomes, including PFS and toxicity of 
chemotherapy. (39) 
In addition to the candidate markers rs763780 and rs2010963, we may consider 
genotyping other markers. We may obtain the genotypes directly or by imputation from 
the platform used for the GWAS (section 15.9.2), or by candidate marker typing (e.g., 
PCR). 
15.9.2 Genome-Wide Association Study 
The primary objective for the Genome-wide Association Study (GWAS) is to identify 
prognostic SNPs for overall survival. Secondary objectives are to correlate SNPs with the 
progression-free survival, as well as the occurrence of toxicity from treatment. 
15.9.3 Computing Environment 
For pre-processing (quality control and genotype calls) the Illumina chips, we will use the 
commercial program Bead Studio, developed by Illumina. Although Illumina does not 
provide a Linux port of Bead Studio, one can run the software on VirtualBox running on a 
Linux host. A two CPU dual core (four cores) AMD Operation Socket F workstation, with 
16GB of RAM, will be available for this purpose. The statistical analyses will be carried 
out on a Linux server with 8 dual core Operation Socket F CPUs (16 cores) with 64GB of 
RAM (expandable to128GB if needed). 
15.9.4 Analyses to assess genotyping quality and population stratifications 
Initial quality studies will be conducted to identify SNPs that have generated sufficiently 
poor quality genotype data that should be removed from analyses. Call rate, patterns of 
missing data, and departures from Hardy-Weinberg equilibrium (HWE) using an exact test 
will all be scrutinized to identify markers that will not be used in analysis.  
The study will be designed with intra- and inter-plate intended duplicates and CEPH trio 
controls. The technical replicates and CEPH controls will be verified by cross-tabulating 
the genotypes. Among each set of technical replicates, the sample with the highest call rate 
will be retained. 
Once the duplicates and controls are removed, we will remove any samples with extremely 
low call rates (< 0.1) and then based on the remaining samples and SNPs with extremely 
low call rate (< 0.1). Next, we determine, based on SNPs on the X chromosome, the 
genetic gender for each sample. Samples for which the genetic genetic differs from the 
self-reported gender, may be removed. In the next, step we exclude SNPs with low minor 
relative allele frequencies (MAF< 0.01), any samples or SNPs with call rates lower than 
0.95. Next we exclude any samples with high autosomal heterozygosity (HET) followed 
by any samples with high IBS (based on 2000 randomly selected autosomes). The latter 
may indicate the presence of unintended duplicates. These could be because of 
mismanagement of the samples or the presence of related samples. Although we do not 
expect to have closely related individuals included in this sample, only one member of any 
set of first-degree relatives will be included in subsequent analysis. We then repeat the 
MAF, call rate, HET and IBS filters iteratively until no samples or SNPs are in need of 
elimination. This procedure can be implemented in by the check.marker function in the R 
extension package GenABEL. 
Population structure that is not appropriately recognized and accommodated can lead to 
both false positive and false negative results in association studies. We will conduct 
studies using structure (41) to estimate ancestry proportions using 10,000 SNPs chosen for 
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CHB+JPT samples used to model the ancestral populations. Substantial previous research 
has shown this to be a rapid and effective approach to defining historical geographic 
ancestry. Although self-identified race/ethnicity is usually highly correlated with estimated 
historical geographic ancestry (this has been confirmed by the GWA studies carried out 
for CALGB 80303, 40101 and 90401), there are often a few individuals who appear to be 
misclassified with self-defined labels, and it is the genetically defined ancestry that is 
critical to correctly accommodate to insure robust results from association studies. 
Each individual will then have estimates of European, African and Asian ancestry. For 
individuals with high ancestry proportion for a single group (>98%), we will conduct 
further analyses with eigenstrat (42) using all SNPs to determine whether there are 
additional important sources of variation among individuals leading to detectable 
stratification by allele frequencies (reflecting, for example, differences in ethnic make-up 
within individuals of European descent from different U.S. cities from which subjects for 
the trial were obtained). Primary analyses, described below, will be conducted within 
groups defined by historical geographic ancestry. Secondary analyses will be conducted 
using logistic regression with ancestry proportions (and any additional stratification 
identified using eigenstrat) as covariates. 
This principal component analysis will be based on the set of SNPs and samples that 
passed the initial set of QC filters. Once the set of genetic European samples has been 
determined, the iterative QC procedure described above, will be repeated restricted to the 
European samples and SNPs that passed the initial filter. At this step, any SNPs with 
significant deviation from HWE (P-value<10-8) will be removed as well. The resulting set 
of samples and SNPs will be used in the association analyses. 
Other QC steps will be carried out as well. Non-random patterns of missing data are 
sometimes encountered in data generated on high-throughput genotyping platforms; the 
most common non-random missing data problem is that heterozygous genotypes are more 
likely to be assigned as missing than either homozygous genotype. We will perform 
analyses using blind duplicates as well as analyses assessing the relationship between 
heterozygous call rates and missing data to identify any SNPs in which data are clearly not 
missing at random. Depending on the number and degree of difficulty observed, we will 
either remove problematic SNPs from analysis, or assign quality scores to reflect the 
extent of the non-random missing data. 
15.9.5 Feature discovery 
The association between the genotype call (say AA, AB or BB) for each autosomal SNP 
and OS will be carried out using a univariable Cox model. Let lam0[t],lam1[t] and lam2[t], 
denote the hazard rate at time t conditional on having 0, 1 or 2 copies of the B allele. 
For the power calculations we will assume that the SNPs satisfy HWE and that the OS 
distribution for the control arm is expressible as a mixture of exponential laws of the form 
P(T1>t)=(1-q)2exp[-lam1,0*t]+2*q*(1-q)exp[-lam1,1*t]+q2exp[-lam1,2*t] where q denotes 
the relative frequency of the B allele and lam1 the exponential hazard rate specified in the 
clinical protocol. Similarly for arm 2, we will assume a mixture distribution of the form 
P(T2>t)=(1-q)2exp[-lam2,0*t]+ 2*q*(1-q)exp[-lam 2,1*t]+q2exp[-lam2,2*t]. In the power 
calculations, we will set P(T1>t)=0.5 for t=12, P(T2>t)=0.5 for t=15.6 and then solve for 
lam1,0 and lam2,0. 
We will power the study for the additive genetic model with no drug interaction. In other 
words, for some D>1, P(T1>t)=(1-q)2exp[-lam1,0*t]+2*q*(1-q)exp[-lam1,0*D*t]+q2exp[-
lam1,0*D2*t] and P(T2>t)=(1-q)2exp[-lam2,0*t]+2*q*(1-q)exp[-lam2,0*D*t]+q2exp [lam2,0* 
D2*t] for some 0<lam2,0 <lam1,0. 


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A total of 700 patients are to be randomized to the study. It is assumed that 85% of these 
patients will provide consent and usable samples for this companion study. The analysis 
population will consist of those determined to be genetically European based on the SNP 
data. The expected proportion for this population is 0.85. As such, the companion study 
will be powered based on a sample size of 506 (=700*0.85*0.85). 
According to the clinical design, the assumed times to death distributions for the two arms 
are hypothesized to be exponential with medians of 12 and 15.6 months respectively. The 
follow-up distribution is assumed to be uniform on the interval (34,30+34) months.  
A feature (SNP) will be considered significant if the corresponding nominal unadjusted 
two-sided P-value is less than 0.05/K, where K is number of features which pass the pre-
processing step. Needless to say, this approach may be conservative. It does however 
guarantee strict type I error control. It is expected that these samples will be genotyped on 
the Illumina 610Quad platform. The power, at the two-sided 0.05/600000 level (i.e., 
assuming K = 600,000 autosomal SNP markers pass through the pre-processing step), is 
illustrated in Table 3. The Cox statistics, coding the genotypes AA, AB and BB as 0, 1 and 
2 is used. Each case is based on 10,000 simulation replicates. In addition to the additive 
model, we provide power calculations for the recessive (i.e., lam0=lam1,lam2=lam0*D) and 
dominant (i.e., lam1=lam2=lam0*D) models if the test based on the additive model is used. 


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Hazard 
Ratio 
(D) 
 
 
 
 
 
 
 
 
 
 
q 
mod 
1.6 
1.8 
2 
2.2 
2.4 
2.6 
2.8 
3 
3.2 
0.1 
additive 
0.1705 
0.5305 
0.8362 
0.9646 
0.9943 
0.9990 
1.0000 
1.0000 
1.0000 
 
dominant 0.0909 
0.3356 
0.6583 
0.8777 
0.9649 
0.9931 
0.9987 
0.9998 
0.9998 
 
recessive 
0.0000 
0.0001 
0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
0.2 
additive 
0.6247 
0.9523 
0.9978 
0.9999 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
 
dominant 0.2207 
0.6260 
0.9052 
0.9847 
0.9983 
0.9998 
1.0000 
1.0000 
1.0000 
 
recessive 
0.0000 
0.0000 
0.0000 
0.0000 
0.0003 
0.0003 
0.0005 
0.0010 
0.0011 
0.3 
additive 
0.8479 
0.9956 
0.9999 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
 
dominant 0.2093 
0.6001 
0.8837 
0.9796 
0.9974 
0.9998 
1.0000 
1.0000 
1.0000 
 
recessive 
0.0002 
0.0010 
0.0021 
0.0060 
0.0119 
0.0187 
0.0323 
0.0443 
0.0587 
0.4 
additive 
0.9195 
0.9985 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
 
dominant 0.1144 
0.4042 
0.7290 
0.9183 
0.9816 
0.9962 
0.9990 
0.9997 
1.0000 
 
recessive 
0.0023 
0.0141 
0.0470 
0.1061 
0.1971 
0.3011 
0.4135 
0.5245 
0.6078 
0.5 
additive 
0.9290 
0.9990 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
 
dominant 0.0366 
0.1670 
0.3901 
0.6434 
0.8270 
0.9255 
0.9702 
0.9890 
0.9960 
 
recessive 
0.0186 
0.1011 
0.2872 
0.5237 
0.7337 
0.8630 
0.9443 
0.9729 
0.9880 
0.6 
additive 
0.8999 
0.9980 
0.9999 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
 
dominant 0.0046 
0.0288 
0.0918 
0.1934 
0.3563 
0.5012 
0.6421 
0.7527 
0.8359 
 
recessive 
0.0783 
0.3277 
0.6721 
0.8865 
0.9724 
0.9936 
0.9983 
0.9999 
1.0000 
0.7 
additive 
0.7853 
0.9874 
0.9995 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
 
dominant 0.0005 
0.0021 
0.0044 
0.0169 
0.0349 
0.0630 
0.1047 
0.1559 
0.2008 
 
recessive 
0.1546 
0.5175 
0.8476 
0.9738 
0.9972 
0.9999 
1.0000 
1.0000 
1.0000 
0.8 
additive 
0.4726 
0.8848 
0.9886 
0.9992 
1.0000 
1.0000 
1.0000 
1.0000 
1.0000 
 
dominant 0.0000 
0.0000 
0.0000 
0.0004 
0.0007 
0.0010 
0.0014 
0.0025 
0.0042 
 
recessive 
0.1402 
0.5046 
0.8254 
0.9646 
0.9947 
0.9994 
1.0000 
1.0000 
1.0000 
0.9 
additive 
0.0647 
0.2949 
0.6079 
0.8282 
0.9420 
0.9818 
0.9954 
0.9987 
0.9996 
 
dominant 0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
0.0000 
 
recessive 
0.0291 
0.1658 
0.4194 
0.6899 
0.8591 
0.9473 
0.9816 
0.9942 
0.9976 
 
Table 5: Power illustration for SNP by OS association testing 
Here q denotes the relative frequency for the risk allele. A log-additive genetic risk model is 
assumed. D denotes the hazard ratio. 
15.9.6 Submission of molecular data 
The laboratory of Dr. Yusuke Nakamura will submit the Illumina*.idat image file using 
secure means to the CALGB Statistical Center. The lab will also submit a table along with 
this transmission, which at the minimum will provide the following information for each 
sample received from the repository. 
The lab ID number provided by the repository. 
• 
The experimental ID, a concatenation of the plate, well and replicate information, 
generated by the lab. 
• 
The idat file names (the file string name will contain Lab ID). 
• 
The md5sum signature of the idat files to ensure data integrity. 


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• 
The date the specimen was received from the repository. 
• 
The date the sample was analyzed by the RIKEN laboratory. 
Additionally, the lab will also provide the complete results from any quality control 
measurers carried out. If a sample had to be redone (e.g., defective or poor quality array), 
the lab will provide all replicate idat files and add an appropriate column to the 
supplementary table. The molecular data generated for this aim may not be shared with 
other investigators or used for any analysis not specified in the protocol until a formal 
approval from the CALGB Statistical Center is obtained. 
15.9.7 Secondary objectives 
Other clinical endpoints such as overall-survival and toxicity are of interest. The 
definitions for these will coincide with those of the clinical protocol. Note that due to 
small sample size, we are primarily focusing on finding prognostic features. From a 
pharmacogenetic point of view, what is of greater interest is to validate existing or find 
novel predictive markers. This will be done in the context of multiplicative two-way 
ANOVA log-linear Cox (logistic) for censored (binary) outcomes. Logisitic regression 
models and conditional inference trees (or more generally conditional random forests) will 
be used to construct multi-variable models basedon the SNPs identified as interesting. 
These models also allow for inclusion of other potentially relevant clinical demographic 
variables.The Illumina HuamaHap610 Quad contains 4,300 SNPs in regions with 
commoncopy number variants (CNVs). Given the complex structure of CNVs, it is 
notalways clear how to define the genotype of a CNV. Instead of categorizing copy 
numbers into genotypes, we will estimate relative genomic abundance probeintensities. 
This approach allows for the consideration of other CNVs beyond deletions, including 
duplications and combinations of both. For notational brevity, we shall refer to these as 
CNV markers. For each objective, the association between each CNV marker and the 
clinical AE endpoint, will be assessed using the Wilcoxon two-sample test. The family-
wise error rate will be controlled at the 0.05 level using permutation resampling (based on 
B=10,000 replicates). 
Regression methods, as in the case of the SNP markers, will be employed to construct 
multivariable models based on the CVN markers. Secondary relevant clinical endpoints 
include other adverse events (e.g., proteinuria, hypertension, and other common side 
effects of study drugs) and overall survival. For censored time-to-event outcomes, the 
stratified log-rank test will be primarily used for assessment of significance. A risk 
analysis will be carried out by comparing the genotypic distributions of the SNPs from the 
CALGB 80802 data to those from controls (thought to not have cancer). The SNP data 
from the controls will be obtained from public databases. In addition to conduction 
analyses on all features directly assessed on the high-throughput platform used in these 
studies, we will also interrogate all additional HapMap SNPs that are not in strong 
pairwise LD with any genotyped SNP, but for which there is sufficient multi-locus LD to 
SNPs on the high-throughput platform. Testing UNtyped Alleles (TUNA) is a robust 
approach for conducting such analyses that provides inexpensive in silico follow up to the 
initial analysis and allows us to more efficient design any follow up genotyping studies 
(43, 44). For example, use of Illumina HumanHap300 enables direct testing of 270K-450K 
SNPs, and indirect testing of 750K-1.5M additional SNPs (i.e., these SNPs are so highly 
correlated with SNPs that are directly tested for association that testing them would 
provide little additional information). The ranges given above, bracket the expectations for 
different human populations, with European populations at the high end of the range, and 
populations of recent African descent at the lower end. Use of TUNA enables 
interrogation of an additional 100K-250K SNPs that are neither on the platform nor highly 


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correlated with any individual SNP on the platform. Note that use of TUNA will facilitate 
comparisons to genome-wide association studies on potentially related phenotypes (e.g., 
clinical trials of the same or related drugs) conducted using other high-throughput 
platforms or candidate gene studies utilizing SNPs not directly genotyped on the high-
throughput platform chosen for our studies. 
Finally, we note that the methodology field for the analysis of genome-wide SNPdata is in 
its infancy. We will consider the employment of “newer” methods if they are deemed to be 
statistically sound and enable us to better interrogate, and more importantly, understand 
the data. 
15.9.8 Statistical software 
The R statistical environment (45) and Bioconductor (46) packages will be used for all of 
the primary statistical analyses relating features to phenotypes. Specialized statistical 
genetics software, including PLINK (47) structure (41), eigenstrat (42) and TUNA (43, 
44) will be used for some of the quality or secondary analyses, and R will be used for 
logistic regression analyses allowing for ancestry covariates. 
 
16.0 ADVERSE EVENT REPORTING (AER) 
Investigators are required by Federal Regulations to report serious adverse events as defined below. 
Investigators are required to notify the CALGB Central Office, the Study Chair, and their 
Institutional Review Board (IRB) if a patient has a reportable serious adverse event. The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of 
the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep .cancer.gov). All 
reactions determined to be “reportable" in an expedited manner must be reported using the CTEP 
Adverse Event Reporting System (CTEP-AERS). 
Reporting of cases of secondary AML/MDS should be done using the NCI/CTEP Secondary 
AML/MDS Report Form. New primary malignancies should be reported using Study Form C-1001. 
In the rare occurrence when Internet connectivity is lost, an adverse event report may be submitted 
using CTEP’s Adverse Event Expedited Report – Single Agent or Multiple Agent paper template 
(available at http://ctep.cancer.gov) and faxed to 301-230-0159. A 24-hour notification is to be 
made to CTEP by telephone at 240-276-6575, only when Internet connectivity is disrupted. Once 
Internet connectivity is restored, an adverse event report submitted on a paper template or a 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter at 
the site. 
CALGB requires investigators to route all adverse event reports (AERs) through the Central 
Office for CALGB-coordinated studies.  
The reporting of adverse events described in the table below is in addition to and does not supplant 
the reporting of adverse events on study-specific adverse event forms (see Section 6.1 for required 
CALGB forms). 
16.1 
CALGB 90802 Reporting Requirements: 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND: CTEP-AERS Expedited 
Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of 
Treatment 


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Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
10 Calendar 
Days 
Not 
Required 
24-Hrs; 
5 Calendar 
Days 
10 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of treatment require 
reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is required as outlined in 
the table. 
March 2005 
Note: All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause should be provided. 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 5 calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
• 
The CTEP-AERS reporting system can be accessed via the CTEP home page: 
https://eapps-ctep.nci.nih.gov/ctepaers. 
16.2 
Additional Instructions or Exclusions from CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent under a CTEP-IND: 
• 
CALGB 90802 uses a drug under a CTEP IND. The reporting requirements for 
investigational agents under a CTEP IND should be followed for all agents (either 
treatment arm) in this trial. 
• 
For the purposes of expedited adverse event reporting, the CAEPR (which includes 
expected adverse events) for bevacizumab may be found in Section 16.3, below. Expected 
adverse events for everolimus may be found in Section 11.6 or in the everolimus product 
literature. Note: The ASAEL column of the CAEPR has been replaced with the specific 


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protocol exceptions to expedited reporting (SPEER) list. This list now includes “expected” 
severity grades in addition to event terms. 
• 
A discussion of the adverse events associated with the agents used in this trial can be 
found in Section 11.0 (Drug Formulation, Availability and Preparation).  
• 
Grade 3 myelosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. 
• 
Grade 3/4 hyperlipidemia hyperglycemia, or mucositis, and hospitalization resulting from 
such do not require CTEP-AERS, but should be submitted as part of study results. 
• 
Deaths occurring greater than 30 days after the last dose of treatment that are due to 
disease progression do not require CTEP-AERS. 
• 
Reporting of cases of secondary AML/MDS is to be done using the NCI/CTEP Secondary 
AML/MDS Report Form. New primary malignancies should be reported using study form 
C-1305. 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
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5) 
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10) 
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11) 
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APPENDIX I: UPC (URINE PROTEIN TO CREATININE) RATIO 
 
The UPC (urine protein to creatinine) ratio directly correlates with the grams of protein found in a 24 hr 
urine. The UPC ratio can be used in the place of a 24-hour urine. 
 
 
Procedure for Obtaining a Urine Protein/Creatinine Ratio: 
 
1. 
Obtain at least 4 mL of a random urine sample in a sterile container (does not have to be a 
24-hour urine sample). 
2. 
Determine protein concentration (mg/dL). 
3. 
Determine creatinine concentration (mg/dL). 
4. 
Divide #2 by #3 above: 
 
 
UPC Ratio = 
 
Protein Concentration (mg/dL) 
Creatinine Concentration (mg/dL) 
 


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APPENDIX II: COLLABORATIVE AGREEMENT PROVISIONS 
 
 
The agents used in this protocol are provided to the NCI under Collaborative Agreements 
(CRADA, CTA) between Genentech Inc. (hereinafter referred to as “Collaborator”) and Novartis 
Pharmaceuticals (hereinafter referred to as “Provider”) and the NCI Division of Cancer Treatment 
and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” (at http://ctep.cancer.gov/industry) contained within 
the terms of award, apply to the use of bevacizumab in this study: 
1. Agents may not be used for any purpose outside the scope of this protocol, nor can it be 
transferred or licensed to any party not participating in the clinical study. Collaborator’s and 
Provider’s data for agents are confidential and proprietary to Collaborator and Provider and 
shall be maintained as such by the investigators. The protocol documents for this study contain 
confidential information and should not be shared or distributed without the permission of the 
NCI. If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol in which there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements, the 
access to and use of data by each Collaborator and Provider shall be as follows (data pertaining 
to such combination use shall hereinafter be referred to as "Multi-Party Data.”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own investigational Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available exclusively to Collaborator, the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order. Additionally, all Clinical Data and 
Results and Raw Data will be collected, used and disclosed consistent with all applicable 
federal statutes and regulations for the protection of human subjects, including, if applicable, 
the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. 
Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator or Provider for this phase III study must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for the clinical trial. 


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6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group Office for immediate delivery to Collaborator for advisory review and comment prior to 
submission for publication. Collaborator will have 30 days from the date of receipt for review. 
Collaborator shall have the right to request that publication be delayed for up to an additional 
30 days in order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator’s intellectual property rights, are protected. Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the meeting 
or publication in the proceedings. Press releases and other media presentations must also be 
forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland 20892 
FAX 301-402-1584 
Email: anshers@ctep.nci.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator. No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/proprietary information. 


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APPENDIX III: INHIBITORS AND INDUCERS OF CYP3A4