Clinical trial NCT01661283
Conditions: Malignant Peripheral Nerve Sheath Tumors MPNST Sarcoma
Keywords: MPNST malignant peripheral nerve sheath tumors RAD001 Everolimus Bevacizumab Sarcoma Avastin mTOR inhibitor
Sponsor: Sarcoma Alliance for Research through Collaboration
Start date: 2012-09-01; Completion date: 2017-12-01
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To determine the clinical response rate of everolimus in combination with bevacizumab for patients with chemotherapy refractory sporadic or neurofibromatosis type 1 (NF1) associated malignant peripheral nerve sheath tumor (MPNST). To evaluate the toxicity and safety of everolimus in combination with bevacizumab in individuals with MPNST

Detailed description:

Arms: arm 1: All patients with MPNST will continue everolimus 10 mg daily and bevacizumab 10 mg/kg dose every 14 days
Interventions: intervention 1: everolimus intervention 2: bevacizumab
Intervention descriptions: intervention 1: 10 mg tablet once daily intervention 2: 10 mg/kg dose every 14 days

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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SARC Protocol #: 
SARC016 
 
 
TITLE:  SARC016 Phase 2 study of the mTOR inhibitor everolimus in combination 
with bevacizumab in patients with sporadic and neurofibromatosis type 1 (NF1) related 
refractory malignant peripheral nerve sheath tumors 
 
 
Sponsor: 
 
SARC (Sarcoma Alliance for Research through 
Collaboration) 
 
Funding: 
 
Department of Defense 
 
Supporters: 
 
Novartis and Genentech 
 
 
 
 
Confidentiality Statement 
The information contained in this document, especially the unpublished data, 
has been generated by SARC and the National Cancer Institute and 
therefore provided to you in confidence as an investigator, potential 
investigator or consultant, for review by you, your staff and applicable 
Independent Ethics Committee/Institutional Review Board.  It is understood 
that this information will not be disclosed to others without written 
authorization from SARC except to the extent necessary to obtain informed 
consent from those persons to whom the drug may be administered. 
 
 


 
 
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Principal Investigator Clinical: 
Brigitte C. Widemann, MD 
National Cancer Institute 
Pediatric Oncology Branch 
10 Center Drive, room 1-5750 
Bethesda, MD 20892-1101 
Phone: 301-496-7387 
Fax: 301-480-8871 
E-mail: widemanb@mail.nih.gov 
 
Medical Monitor/DoD Independent 
Research Monitor:  
SARC Medical Officer 
Scott Okuno, MD 
Mayo Clinic 
200 1st St SW 
Rochester, MN  55905 
Phone: 507-284-4849 
Email: okuno.scott@mayo.edu 
 
Database: 
Medidata RAVE 
 
 
 
 
Statistician:  
Seth Steinberg, PhD 
Head, Biostatistics and Data Management 
Section, Office of the Clinical Director 
Center for Cancer Research, NCI 
6116 Executive Blvd., Room 702 
Bethesda, Maryland 20892  
Phone: 301-496-9502 
E-mail: steinbes@mail.nih.gov  
 
 
 
 
 
Participating sites: SARC institutions, Department of Defense sponsored 
Neurofibromatosis Consortium institutions (full listing in Operations Manual) 
   
 
IND #:  IND Exempt (FDA acknowledgement and agreement on IND status received by 
SARC, March 18, 2011) 
 
 
 
Protocol Type/Version # / Version Date: Phase 2 trial, version 3, 9 July, 2015  


 
 
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Roles and responsibility of study personnel: 
Brigitte Widemann, MD: Principal investigator for the study 
Scott Okuno, MD: SARC Medical Officer, providing SARC oversight to the conduct of 
this trial and ongoing medical monitoring; Independent Research Monitor for study 
Denise Reinke, MS, NP, MBA: President and CEO, SARC 
Vesna Milacic, PhD: Director of Research Project Management, SARC 
Ndidi Onwudiwe, MS: Research Project Manager 
Eva Dombi, MD: Volumetric MRI analysis of MPNSTs on protocol 
Nalini Jayaprakash, MS, and Chand Khanna, DVM, PhD: Analysis of PD correlative 
studies 
John Perentesis, MD: Investigator overseeing PD analysis of correlative studies 
Seth Steinberg, PhD: Study Statistician 
Karen Cichowski, PhD: Preclinical collaborator 
Ludwine Messiaen, PhD: Genotyping 
David Viskochil, MD: Serve as interface between NF1 centers and sarcoma centers; 
facilitate referral of patients not affiliated with NF1 centers 
Lee Helman, MD, Brigitte Widemann, MD, Christina Annunziata, MD, Melinda 
Merchant, MD, PhD, John Glod, MD, PhD,: Enrollment of patients and patient care 
responsibilities at the NIH 
Donna Bernstein, RN, Andy Gillespie, RN: Research nurses for study at the NIH 
Joanne Derdak, C.R.N.P.: Clinical care of patients enrolled on this study at the NCI 
 
 
 


 
 
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GLOSSARY OF ABBREVIATIONS 
4E-BP1 
4E-binding protein 
ADR 
Adverse Drug Reaction 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase/glutamic pyruvic transaminase/Serum glutamic-
pyruvic transaminase 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/Serum 
glutamic-oxaloacetic transaminase 
ATC 
Anatomical Therapeutic Chemical classification system 
AUC 
Area under the plasma-concentration time curve 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CGH 
Comparative Genomic Hybridization 
CR 
Complete Response or clinical research 
CRF 
Case report/Record form 
CRO 
Contract Research Organization 
CT 
Computer tomography 
CTC 
Common toxicity criteria 
CV 
Coefficient of Variation 
CYP3A4 
CytochromeP450 3A4 isoenzyme 
DLT 
Dose Limiting Toxicity 
EC50 
plasma concentration associated with half-maximal effect 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGF 
Epidermal Growth Factor 
EGFR 
Epidermal Growth Factor Receptor 
eIF-4E 
Eucariotic Initiation Factor 4E 
eIF2 alpha 
Eucariotic translation initiation factor 2 alpha 
ESFT 
Ewing Sarcoma Family of Tumors 
FDG-PET 
Fluorine-18-2-fluoro-Deoxy-D-Glucose Positron Emission Tomography 


 
 
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FISH 
Fluorescence in situ hybridization 
FKBP-12 
FK506-binding protein 12 
G-CSF 
Granulocyte colony-stimulating factor 
GF 
Growth factor 
HBV 
Hepatitis B virus 
HBcAb 
Hepatitis B core antibodies 
HBsAb 
Hepatitis B surface antibodies 
HBsAg 
Hepatitis B surface antigen 
HBC 
Hepatitis C Virus 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
HDL 
High-density lypoproteins 
HER 
Human Epidermal Receptor 
HSCT 
Hematopoietic Stem Cell Transplant 
huMAb IGF-1R 
Human monoclonal antibody against the human insulin-like growth factor 1 
receptor; RO4858696 
HUVECS 
human umbilical endothelial cells 
IEC 
Independent Ethics Committee 
IGF1-R 
Insulin-like Growth Factor 1 Receptor 
IHC 
Immunohistochemistry 
INN 
International Non-proprietary Name 
INR 
International Normal Ratio 
IR 
Insulin receptor 
IRB 
Institutional Review Board 
keo 
Equilibration rate constant 
LC-MS 
liquid chromatography method with mass spectrometry 
LDL 
Low-density lypoproteins 
LFT 
Liver function tests 
LLN 
lower limit of normal 
LLQ/LLOQ 
Lower limit of quantification 
LVEF 
Left Ventricular Ejection Fraction 
MAPK 
Mitogen Activated Protein Kinase 
mRNA 
messenger Ribonucleic acid 


 
 
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MPNST 
Malignant peripheral nerve sheath tumor 
mTOR 
mammalian Target of Rapamycin 
NCI-CTC 
National Cancer Institute-Common toxicity Criteria 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NF1 
Neurofibromatosis type 1 
NIH/NCI 
National Institutes of Health/National Cancer Institute 
nM 
nano-molar 
NOAEL 
No observed adverse event level 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
overall survival, osteosarcoma 
P-AKT 
phosphor-AKT, a human oncogenic protein 
PCR 
Polymerase Chain Reaction 
PD 
Progressive disease or Pharmacodynamics 
PET 
Proton emission tomography 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetics 
PK/PD model 
Pharmacokinetic/pharmacodynamic model 
PR 
Partial response 
PS 
Performance Status 
PT/PTT 
prothrombin time 
PTEN 
Phosphatase and Tensin homolog deleted on chromosome 10 
p-PTEN 
Phosphorylated form of PTEN, a human tumor suppressor 
RBC 
red blood cell count 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
response rate 
S6K1 
S6 kinase 1 
SAE 
serious adverse event 


 
 
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SCLC 
Small cell lung cancer 
SD 
Stable disease 
SF 
Shortening Fraction 
STAT3 
Signal Transducer and Activator of Transcription 3 
STS 
Soft tissue sarcoma 
TGI 
Tumor growth inhibition 
TK 
Tyrosine kinase 
TNM 
primary tumor/regional lymph nodes/distant metastasis 
TSC2 
Tuberous Sclerosis Complex 2 
TTP 
Time to Tumor Progression 
TUNNEL 
Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin Nick 
End Labeling 
ULN 
upper limit of normal 
UPC ratio 
Urine Protein Creatinine ratio 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
total white blood cell count 
WHO 
World Health Organization 
 
 


 
 
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TREATMENT OUTLINE: 
 
Patients with NF1 related or sporadic refractory MPNST will receive 28 day cycles of 
everolimus + bevacizumab until disease progression or unacceptable toxicity for a 
maximum of 2 years. 
 
Everolimus will be administered at a dose of 10 mg/dose once daily on a continuous 
dosing schedule.  
 
Bevacizumab will be administered at a dose of 10 mg/kg IV every 2 weeks (day 1 and 
15). 
 
Response evaluation (WHO criteria) will be performed before every other treatment 
cycle (3, 5, 7, 9, etc). 


 
 
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SYNOPSIS: 
 
Primary objective:  
 To determine the clinical benefit rate (complete response, partial response, and stable 
disease at ≥ 4 months using WHO criteria) of everolimus in combination with 
bevacizumab for patients with chemotherapy refractory sporadic or neurofibromatosis 
type 1 (NF1) associated malignant peripheral nerve sheath tumor (MPNST) 
 To evaluate the toxicity and safety of everolimus in combination with bevacizumab in 
individuals with MPNST 
 
Secondary objectives: 
 To evaluate the spectrum of germline NF1 mutations in individuals with NF1 
associated MPNSTs 
 To explore the relationship between response to everolimus in combination with 
bevacizumab and the presence of NF1 mutations or NF1 inactivation in MPNST 
tumor samples 
 To explore differences in the response rate to everolimus in combination with 
bevacizumab in individuals with sporadic and NF1 associated MPNST 
 To assess preliminary correlations of radiographic response and progression with 
changes in pharmacodynamic parameters including S6K1 (p70 S6 kinase 1), eIF4E, 
eIF2 alpha VEGF, VEGFR, Akt phosphorylation, and markers of cell metabolism in 
peripheral blood specimens 
 To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in comparison to 
1-dimensional and 2-dimensional measurements to more sensitively monitor response 
to everolimus in combination with bevacizumab 
 
Hypothesis and rationale: 
The NF1 tumor suppressor regulates mammalian target of rapamycin (mTOR) pathway 
activation, which appears to be critical for the progression of MPNSTs. The mTOR 
inhibitor sirolimus halts progression of MPNSTs for prolonged time periods in a murine 
genetically engineered NF1 MPNST model and in a NF1 and sporadic mouse MPNST 
xenograft model. Angiogenesis contributes to the progression of MPNST, and in the 
transgenic mouse model MPNSTs become ultimately resistant to treatment with 
rapamycin. The development of resistance is associated with re-vascularization and 
upregulation of vascular endothelial growth factor (VEGF). Preliminary preclinical data 
in the transgenic NF1 MPNST mouse model demonstrate prolonged survival for mice 
treated with rapamycin plus sunitinib, which in part, mediates anti-tumor activity by 
inhibition of angiogenesis, compared to mice treated with rapamycin or sunitinib alone 
(unpublished data K. Cichowski). These findings provide the rationale for our proposed 
phase 2 trial of the mTOR inhibitor everolimus in combination with the angiogenesis 
inhibitor bevacizumab.  This trial will determine the activity of everolimus in 
combination with bevacizumab in refractory MPNST and allow validation of the 
genetically engineered MPNST mouse model by preliminarily evaluating pathways 


 
 
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associated with response and disease progression. In addition, this trial will serve as a 
model for future combination trials of targeted agents for MPNST. 
 
Trial design: 
This is a two-stage phase 2 clinical trial with the objective to assess activity of the mTOR 
inhibitor everolimus in combination with the angiogenesis inhibitor bevacizumab in 
patients with sporadic and NF1 associated MPNSTs refractory after ≥ 1 prior cytotoxic 
chemotherapy regimen. The diagnosis of NF1 will be made based on clinical criteria. The 
primary endpoint is clinical benefit rate (PR, CR or stable disease at ≥ 4 months). All 
patients meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for response. Everolimus will be administered at a dose of 10 
mg po once daily on a continuous dosing schedule (28 days = 1 cycle). Bevacizumab will 
be administered IV at a dose of 10 mg/kg/dose every 14 days.  
 
Initially enrollment will be limited to patients ≥ 18 years old. Patients will be regularly 
monitored for everolimus and bevacizumab toxicity and response. Success will be 
defined as PR, CR, and SD at ≥ 4 months using WHO response criteria. A two-stage 
design will be used, and a clinical benefit rate of ≥ 25% will be defined as success ruling 
out a < 5% clinical benefit rate.  
 
Numbers of subjects: 
Fifteen patients will be enrolled on the first stage, with no further accrual if no successes 
(PR, CR, and SD at ≥ 4 months) are observed within the first 15 patients. If at least one 
success is observed, accrual will continue until a total of 25 evaluable patients have been 
enrolled. If at least four successes are observed in the 25 patients everolimus in 
combination with bevacizumab will be considered active in that it would be consistent 
with a 25% success rate.  
 
Target population: 
Individuals ≥ 18 years of age with adequate organ function and unresectable or metastatic 
MPNST who experienced progression after ≥ one prior cytotoxic chemotherapy regimen 
will be eligible. Patients have to be able to swallow tablets. The protocol will be amended 
to allow enrollment of pediatric patients as soon as an ongoing pediatric phase I trial of 
everolimus and bevacizumab has determined the pediatric phase II dose. 
 
Length of study: 
Patients will be able to remain on treatment for a maximum of 2 years as long as they do 
not experience progressive disease or unacceptable toxicity. It is expected that 10-15 
patients per year will be enrolled, and enrollment is expected to complete within 
approximately 1 to 2 years depending on the number of responses observed in the initial 
stage.  
 
Study drugs: 
 Everolimus as 2.5 mg, 5 mg, and 10 mg tablets  
 Bevacizumab: Supplied in vials containing 400 mg bevacizumab 


 
 
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Dosing and administration: 
 Everolimus will be administered once daily at a dose of 10 mg on a continuous 
dosing schedule (1 cycle = 28 days) 
 Bevacizumab will be administered every 14 days at a dose of 10 mg/kg IV (1 
treatment cycle =28 days) 
 
Efficacy evaluations: 
Response evaluations (WHO) with appropriate imaging studies (MRI/CT) will be 
performed before the beginning of every other treatment cycle (3, 5, 7, 9, etc.).  
 
Safety: 
History and physical examination including vital signs will be regularly performed during 
treatment with everolimus and bevacizumab. Laboratory studies will include CBC with 
differential, fasting glucose and lipid panel, and a comprehensive chemistry panel.  
 
Molecular analysis: 
 Frozen tumor samples, if available, will be evaluated for NF1 mutation/inactivation. 
 Blood samples will be obtained for NF1 genotyping in patients with a clinical 
diagnosis of NF1. 
 
Pharmacodynamics: 
Peripheral blood samples will be collected prior to and serially during treatment with 
everolimus for S6K1 (p70 S6 kinase 1), eIF4E, eIF2 alpha, VEGF, VEGFR, Akt 
phosphorylation, and markers of cell metabolism. 
 
Statistical Analysis: 
An evaluable patient will be classified a responder (success) for the primary endpoint if 
the patient achieves a PR, CR or stable disease at ≥ 4 months. The target clinical benefit 
rate will be 25%, and a clinical benefit rate < 5% will be considered uninteresting. Using 
a two-stage phase 2 design with 5.0% as the value for a one-sided alpha, the first stage 
will require 15 patients, with no further accrual if 0 of 15 respond. If > 1/15 patients 
respond accrual will continue until a total of 25 patients have been enrolled. If > 4/25 
patients respond, everolimus with addition of bevacizumab will be considered active in 
that it would be consistent with a 25% clinical benefit rate. Assuming the number of 
successes is binomially distributed, this design has a one sided alpha of 5.0% and a power 
of 90% for detecting a true success probability of at least 25% versus the null hypothesis 
success rate of 5% or less.  


 
 
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Table of Contents 
Treatment Outline: ..................................................................................................................... 8 
Synopsis: ....................................................................................................................................... 9 
1. OBJECTIVES: ..................................................................................................................... 15 
1.1 
Primary objectives: ............................................................................................................... 15 
1.2 
Secondary objectives: ........................................................................................................... 15 
2. BACKGROUND: ................................................................................................................ 15 
2.1 
Malignant peripheral nerve sheath tumors ................................................................. 15 
2.2 
Study agents: everolimus (Afinitor®/Votubia®) and bevacizumab (Avastin®)
 
19 
2.3 
Rationale ................................................................................................................................... 37 
2.4  
Study Design............................................................................................................................. 40 
2.5 
Correlative studies ................................................................................................................ 42 
3. PATIENT SELECTION ........................................................................................................ 43 
3.1 
Eligibility criteria ................................................................................................................... 43 
3.2 
Exclusion criteria ................................................................................................................... 46 
3.3 
Inclusion of Women and Minorities ................................................................................ 48 
4. REGISTRATION PROCEDURES ................................................................................. 48 
4.1 
General guidelines ................................................................................................................. 48 
4.2 
Patient registration ............................................................................................................... 49 
5. TREATMENT PLAN ............................................................................................................ 49 
5.1 
Agent administration ............................................................................................................ 49 
5.2 
General Concomitant Medication and Supportive Care Guidelines ..................... 50 
5.2.1  
Concomitant Cancer and other Therapy ................................................................... 51 
5.2.2  
Supportive Care ................................................................................................................. 51 
5.3 
Duration of therapy ............................................................................................................... 52 
5.4 
Duration of follow up ............................................................................................................ 53 
5.5 
Criteria for removal from study ........................................................................................ 53 
6. DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 53 
6.1 
Interruption or discontinuation of treatment with everolimus ........................... 53 
6.1.1   
Management of stomatitis/oral mucositis/mouth ulcers .................................. 55 
6.1.2  
Management of hyperlipidemia and hyperglycemia ............................................ 56 
6.1.3  
Management of non-infectious pneumonitis .......................................................... 56 
6.1.4  
Management of Selected Toxicities............................................................................. 57 
6.2 
Interruption or discontinuation of treatment with bevacizumab ....................... 58 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ............................... 62 
7.1  
Definition of Adverse Event (AE) ...................................................................................... 63 
7.2  
CTCAE term (AE description) ............................................................................................. 63 
7.3  
Drug-Adverse Event relationship ..................................................................................... 63 
7.4  
Definition of Serious Adverse Events (SAE).................................................................. 64 
7.5   
Progression of Underlying Malignancy and Hospitalization .................................. 64 
7.6 
Guidelines for Reporting of Laboratory Abnormalities as AEs /SAEs................. 65 
7.7 
Serious Adverse Event Reporting ..................................................................................... 65 
7.8  
Pregnancy ................................................................................................................................. 66 


 
 
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7.9 
Follow-up of AEs ..................................................................................................................... 66 
7.10  
Reporting of all Unanticipated Problems Involving Risk to Subjects or Others 
(UPIRTSOs) to the HRPO .................................................................................................................... 66 
8. PHARMACEUTICAL INFORMATION ............................................................................. 67 
8.1 
Everolimus (Afinitor®, Votubia®) .................................................................................. 67 
8.1.1 
Preparation and administration ...................................................................................... 68 
8.1.2 
Formulation, packaging and labeling ............................................................................. 68 
8.1.3 
Availability ............................................................................................................................... 68 
8.1.4 
Agent ordering ........................................................................................................................ 68 
8.1.5 
Agent accountability ............................................................................................................. 68 
8.1.6 
Everolimus toxicities ............................................................................................................ 69 
8.2 
Bevacizumab ............................................................................................................................ 74 
8.2.1 
How Supplied:.......................................................................................................................... 74 
8.2.2 
Agent Ordering: ...................................................................................................................... 75 
8.2.3 
Agent Accountability ............................................................................................................. 75 
8.2.4 
Preparation .............................................................................................................................. 75 
8.2.5 
Storage ....................................................................................................................................... 75 
8.2.6 
Preparation .............................................................................................................................. 75 
8.2.7 
Method of Administration: ................................................................................................. 76 
8.2.8 
Bevacizumab toxicities: ....................................................................................................... 76 
9. CORRELATIVE STUDIES................................................................................................... 81 
9.1 
Laboratory correlative studies ......................................................................................... 81 
9.1.1 
Proangiogenic factors ........................................................................................................... 82 
9.1.2  
Pharmacodynamic of everolimus ................................................................................ 82 
9.1.3  
Germline NF1 ...................................................................................................................... 82 
9.1.4  
MRI 3-dimentional analysis ........................................................................................... 82 
10. STUDY EVALUATIONS AND STUDY CALENDAR .................................................... 82 
10.1 
Screening studies ................................................................................................................... 82 
10.2 
On study evaluations ............................................................................................................ 84 
10.3 
End of treatment/off study evaluations ......................................................................... 86 
10.4      Schedule of Evaluations ....................................................................................................... 88 
11. MEASUREMENT OF EFFECT ......................................................................................... 90 
11.1 
Antitumor effect – solid tumor .......................................................................................... 90 
11.1.1  
Definitions ........................................................................................................................... 90 
11.1.2  
Disease Parameters .......................................................................................................... 90 
11.1.3  
Methods for Evaluation of Measurable Disease ..................................................... 91 
11.1.4 
WHO Response Criteria ................................................................................................... 91 
11.1.4.1 
Evaluation of Index Lesions ...................................................................................... 91 
11.1.4.2 
Evaluation of Non-Index Lesions ............................................................................ 92 
11.1.5 
Duration of Response ....................................................................................................... 93 
11.1.6 
Progression-Free Survival ............................................................................................. 93 
12. DATA REPORTING/REGULATORY CONSIDERATIONS ............................... 93 
12.1 
Data Reporting ........................................................................................................................ 93 
12.2 
Multi-institutional guidelines ............................................................................................ 95 
12.3 
Data and Participating Institution Monitoring............................................................ 97 
12.4  
Human Subjects Protection ................................................................................................ 98 


 
 
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13. STATISTICAL CONSIDERATIONS ....................................................................... 100 
13.1 
Primary objectives ............................................................................................................... 100 
13.2 
Secondary objectives .......................................................................................................... 101 
REFERENCES: ......................................................................................................................... 104 
Appendix I: Performance Status Criteria ........................................................................ 112 
Appendix II: P450 Drug Interaction Table .................................................................. 113 
Appendix III: CLINICALLY RELEVANT DRUG INTERACTIONS: SUBSTRATES, 
INDUCERS INHIBITORS OF PGP AND PGP/CYP3A DUAL INHIBITORS ............... 117 
Appendix IV: Patient Diary ............................................................................................... 118 
Appendix V: Hepatitis Screening/Monitoring/Treatment ........................................... 122 
APPENDIX VI: DOCUMENTATION OF FINDINGS OF NF1 ......................................... 125 
 


 
 
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1. OBJECTIVES: 
 
1.1 
Primary objectives: 
 
To determine the clinical benefit rate (complete response, partial response, 
and stable disease at ≥ 4 months using WHO criteria) of everolimus in 
combination with bevacizumab for patients with chemotherapy-refractory 
sporadic or neurofibromatosis type 1 (NF1) associated malignant peripheral 
nerve sheath tumor (MPNST) 
 
To evaluate the toxicity and safety of this everolimus in combination with 
bevacizumab in individuals with MPNST 
 
1.2 
Secondary objectives: 
 
To evaluate the spectrum of germline NF1 mutations in individuals with NF1 
associated MPNSTs  
 
To explore the relationship between response to everolimus in combination 
with bevacizumab and the presence of NF1 mutations or NF1 inactivation in 
MPNST tumor samples 
 
To explore differences in the response rate to everolimus in combination with 
bevacizumab in individuals with sporadic and NF1 associated MPNST 
 
To assess preliminary correlations of radiographic response and progression 
with changes in pharmacodynamic parameters including S6K1 (p70 S6 kinase 
1), eIF4E, eIF2 alpha VEGF, VEGFR, Akt phosphorylation, and markers of 
cell metabolism in peripheral blood specimens 
 
To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in 
comparison to 1-dimensional and 2-dimensional measurements to more 
sensitively monitor response to everolimus in combination with bevacizumab  
 
 
2. BACKGROUND: 
 
2.1 
Malignant peripheral nerve sheath tumors 
Malignant peripheral nerve sheath tumors (MPNSTs), (also called neurogenic 
sarcomas, malignant schwannomas, neurofibrosarcomas) are soft tissue sarcomas, 
which show nerve sheath differentiation and are associated with a high risk of 
local recurrence and hematogenous metastasis1. They account for 10% of all soft 
tissue sarcomas, and half of these malignancies arise in patients with 
neurofibromatosis type 1 (NF1)2.  
Neurofibromatosis 1 (NF1) is a common autosomal dominant, progressive genetic 
disorder with an incidence of 1:3000 (> 80,000 persons affected in The United 
States).  Neurofibromin, the NF1 gene product, contains a domain with significant 
homology to ras GTPase-activating proteins (GAP)3. The ras proteins are integral 
in cell signaling pathways, and activation of ras leads to cell proliferation.  GAPs 
catalyze the hydrolysis of ras-GTP (the active form of ras) to ras-GDP and lead 
to ras inactivation.  Patients with NF1 have decreased levels of neurofibromin, 


 
 
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which is associated with an activated ras-GTP status. Lack of functional 
neurofibromin can lead to dysregulated ras and tumorigenesis. NF1 is 
characterized by diverse, progressive cutaneous, neurological, skeletal and 
neoplastic manifestations.  Patients with NF1 have an increased risk of developing 
tumors of the central and peripheral nervous system including plexiform 
neurofibromas (27%) optic gliomas (15-20%), pheochromocytomas (1%), and 
MPNSTs (5%)4,5.  
 
MPNSTs occur in about 2-5% of patients with NF1 compared with an incidence 
of 0.001% in the general population1,6. However, in a large population based 
longitudinal study the lifetime risk of developing a MPNST in NF1 was 8-13%4. 
In patients with NF1, the majority of MPNSTs arise in a previously clinically 
detectable plexiform neurofibroma, but they may develop in absence of 
preexisting tumors6-8. Early diagnosis of MPNSTs is crucial, as only complete 
surgical resection has been shown to be curative. However, the diagnosis of 
MPNSTs in patients with NF1 is difficult to establish, because clinical indicators 
of malignancy (mass and pain) may also be features of benign plexiform 
neurofibromas. Contrast enhanced MRI9, and new imaging modalities like 
18FDG-PET10 are being evaluated for their potential to differentiate benign 
plexiform neurofibromas from MPNSTs.  The most frequent sites of metastasis of 
MPNSTs are lung, liver, brain, soft tissue, bone, regional lymph nodes, and 
retroperitoneum6. 
 
Staging of MPNST: As other soft tissue sarcomas (STS), MPNSTs are most 
commonly staged using the American Joint Committee on Cancer staging 
system11. In this system, four tumor grades are designated: Well differentiated 
(G1), moderately differentiated (G2), poorly differentiated (G3), and 
undifferentiated (G4). Poor prognostic factors for MPNST include: Tumor size > 
5 cm, deep location, high grade (G3, G4), presence of distant metastases at time 
of diagnosis, and radiation induced MPNST. In addition, based on a postoperative 
nomogram for the 12-year sarcoma specific death, the presence of MPNSTs 
carries the highest risk for sarcoma specific death compared to other histologic 
types of STS12.  
 
Epidemiology and outcome: The epidemiology and outcome of NF1 associated 
MPNSTs may be different from sporadic MPNSTs, in that several studies report a 
younger age at diagnosis and worse prognosis for NF1 associated MPNSTs4,13. 
Reasons for the potentially worse outcome of NF1 associated MPNSTs are 
unknown.  Two studies indicate that NF1 associated MPNSTs may develop more 
frequently as central, non-extremity lesions, which could impact on outcome, as 
central lesions are less amenable to surgery6,14. A recently published large 
retrospective review of 126 individuals with MPNST treated on Italian and 
German studies between 1975 and 1998 described that response to chemotherapy 
was lower in NF1-associated MPNSTs (3 of 17 individuals responded, = 17.6%), 
compared to sporadic MPNSTs (26 of 47 responded = 55.3%). Details regarding 


 
 
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the chemotherapy agents used were not provided13. Similarly, in a more recent 
study Ferrari et al reported described a 5-year overall survival of 11% for 27 
children with NF1 associated MPNST compared to 48% for 44 patients with 
sporadic MPNST2. However, it is not clear that NF1-related MPNSTs have a 
worse prognosis when adjusted for the known prognostic features. A recently 
published study, for example, describes excellent survival in MPNSTs with no 
difference between sporadic and NF1 associated tumors15. Potential reasons for 
the favorable survival compared to other reports are not discussed in this 
manuscript, but 70% of the MPNSTs described were extremity lesions compared 
to 30% in central location.  Recently completed gene expression profiling of NF1-
associated (n=25) and sporadic (n=17) MPNSTs did not identify a molecular 
signature that could reliably distinguish between both groups16. 
 
Molecular biology of MPNSTs: Surgical specimens and cell lines from patients 
with MPNSTs and NF1 demonstrate complete inactivation of NF1 and high levels 
of ras activity17-19. Benign plexiform neurofibromas also demonstrate complete 
inactivation of NF1 with evidence suggesting that the Schwann cells represent the 
neoplastic element20-22, therefore additional genetic alterations and abnormalities 
of other biochemical pathways likely contribute to progression to malignancy. 
Immunohistochemical analysis and molecular studies have implicated p53, 
EGFR, p16, and p27 as potential contributors to malignant transformation in 
peripheral nerve sheath tumors. Gene expression profiling of human MPNSTs 
showed expression of EGFR in 16 of 42 (38%) of human16. Further highlighting 
the unique pathogenesis of this tumor type, both NF1 deletions and homozygous 
p16 deletions appear to be relatively restricted to MPNSTs in comparison to other 
spindle cell sarcomas with overlapping morphologic features22. In addition, 
microarray analysis of MPNSTs recently identified topoisomerase II (TOP2A) 
as the most overexpressed gene in MPNSTs compared to benign neurofibromas, 
and TOP2A expressing tumors were associated with poor cancer specific survival 
and presence of metastasis23.  
 
Treatment of adult soft tissue sarcomas (STS) and MPNSTs: Treatment of 
MPNST follows the treatment of other adult soft tissue sarcomas. Only complete 
surgical resection has been shown to be curative, and it remains the cornerstone of 
therapy11,24. The goal of surgery is to resect the MPNST with wide negative 
margins. However, the local recurrence rate of MPNST is high, and ranges from 
32-65%25. Radiotherapy is used in situations where the sarcoma is not amenable 
to surgical resection, but, when used as primary treatment, large doses are needed 
and the control rate is only 30-60%. Clinical trials have demonstrated that 
external beam radiation or brachytherapy in addition to limb sparing surgery 
improve local control in patients with soft tissue sarcomas26,27. Adjuvant 
radiotherapy is thus recommended to improve local control for intermediate to 
high grade lesions > 5 cm after a marginal excision1,26,28. 
 


 
 
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The role of chemotherapy for MPNSTs has not been defined to date. Only 
doxorubicin, dacarbazine, and ifosfamide were consistently associated with 
response rates of 20% or more in  adults with soft tissue sarcomas and the 
combination of ifosfamide and doxorubicin has produced response rates as high 
as 46%29. However, adjuvant doxorubicin-based chemotherapy did not 
demonstrate statistically significant improvement in overall survival 29.  In 
patients with advanced, metastatic soft tissue sarcomas doxorubicin and 
ifosfamide have the highest activity.  The overall response rate for single agent 
doxorubicin was 19% (range 16-27%), and for ifosfamide response rates of 36% 
and 28% have been reported29,30.  
 
Responses to chemotherapy have been described in children and adults with 
MPNSTs31-33, but the response rate of MPNSTs to chemotherapy is unknown. 
They are thought to have intermediate chemosensitivity, less responsive than 
synovial sarcoma, but more responsive than refractory diseases such as alveolar 
soft part sarcoma34.  
 
A recent retrospective review of individuals with MPNSTs described less 
response to chemotherapy for individuals with NF1 associated MPNSTs 
compared to sporadic MPNSTs13. 
 
Currently a Department of Defense sponsored, SARC coordinated, phase 2 
clinical trial is ongoing with the primary objective to prospectively determine the 
response rate of high grade unresectable chemotherapy naïve MPNST to standard 
chemotherapy agents (doxorubicin, ifosfamide, and etoposide) used to treat 
pediatric and adult patients. As the response to chemotherapy may differ between 
sporadic and NF1 associated tumors, this trial stratifies for the presence of 
sporadic versus NF1 associated MPNST.  Depending on its outcome this trial may 
serve in the future as a model for the addition of targeted therapies for MPNST. In 
addition Children’s Oncology Group study ARST0332 (Risk-based treatment for 
non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in patients under 30 years 
of age, PI Sheri Spunt) is ongoing, and enrolls patients with newly diagnosed NF1 
and sporadic MPNST. Treatment on this protocol includes, depending on the 
treatment arm, surgery, radiation, and chemotherapy with doxorubicin and 
ifosfamide. This study will thus also provide additional information regarding 
treatment and outcome of sporadic and NF1 associated MPNST. 
 
With increasing knowledge of the molecular biology of MPNST there is a strong 
rationale for the development of targeted treatment approaches for MPNST35.  A 
recently completed trial of the EGFR inhibitor erlotinib for individuals with 
refractory MPNST based on EGFR expression in MPNSTs demonstrated lack of 
activity with 19/20 evaluable patients developing progressive disease at the time 
of the first response evaluation after completion of 2 treatment cycles36. This trial 
demonstrated the feasibility of conducting histology specific phase 2 trials for 
MPNSTs. Similarly sorafenib, a raf kinase and RTK inhibitor, recently completed 


 
 
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evaluation in several sarcoma strata including refractory and metastatic 
MPNSTsma37. Sixteen patients with MPNST were enrolled. No partial or 
complete responses were observed, and progression free survival (PFS) was 1.7 
months (range, 1.3 to infinity), overall survival was 4.9 months (range 3 months 
to infinity), and the Kaplan-Meier estimates for percent PFS at 3 and 6 months 
were 25% and 8%, respectively.  In another recently reported phase II trial of 
dasatinib (SARC009), which included a refractory MPNST stratum, none of 12 
evaluable patients had a PR or CR, or stable disease at 4 months, and the median 
time to progression was 35 days38. Finally, in a phase II trial of imatinib for 
refractory sarcomas, including an MPNST stratum, of 6 patients with MPNST, 
who received imatinib, 4 had progressive disease at 2 months, 1 was removed 
from the trial for toxicity early, and one withdrew from the study early39.  These 
studies highlight the need for the development of more effective targeted 
treatments for MPNST and provide justification for inclusion of stable disease at 
4 months as a criterion for success. 
 
Recently, NF1was identified as a regulator of the mTOR pathway, and based on 
the data described in Section 2.3, we are proposing a phase 2 trial of the mTOR 
inhibitor everolimus in combination with the angiogenesis inhibitor bevacizumab 
for refractory MPNST.  
 
2.2 
Study agents: everolimus (Afinitor®/Votubia®) and bevacizumab 
(Avastin®) 
Everolimus is a novel oral derivative of rapamycin. Everolimus has been in 
clinical development since 1996 as an immunosuppressant in solid organ 
transplantation and has obtained marketing authorization (Certican®) for 
prophylaxis of rejection in renal and cardiac transplantation in a number of 
countries, including the majority of the European Union.  Everolimus has been in 
development for patients with various malignancies since 2002.  Everolimus was 
first approved under the trade Afinitor® for patients with advanced renal cell 
carcinoma (RCC) and is now approved in the EU and several other countries, as 
well as by the US Food and Drug Administration (FDA).  The FDA granted 
accelerated approval in November 2010 for patients with subependymal giant cell 
astrocytoma (SEGA) associated with tuberous sclerosis (TSC) who require 
therapeutic intervention but are not candidates for curative surgical resection.  
Approval in patients with SEGA was based on a Phase II open label study in 
which 75% of patients experienced reductions of ≥ 30%, and 32.1% experienced 
reductions of ≥ 50%.  Range of time on study was reported as 4.7 to 47.1 months.  
It is noteworthy in the TSC setting in patients with angiomyolipoma (AML) that 
an international multicentre Phase III placebo controlled study demonstrated a 
41.8% AML response rate among everolimus treated patients versus a 0% 
response rate among the placebo treated patients (p < 0.0001).  Median time to 
angiomyolipmoma progression was 11.4 months in the placebo arm and was not 
reached in the everolimus arm, leading to regulatory approval in patients with 
AML.  Everolimus was later approved in 2011 for patients with advanced 


 
 
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neuroendocrine tumors of the pancreas (pNET) based on the results of a 
randomized, double-blind, multi-centre phase III study that showed a statistically 
significant clinical benefit over placebo with a median PFS of 11.0 months vs 4.6 
months, resulting in a 65% risk reduction in PFS.   
 
Everolimus is being investigated as an anticancer agent based on its potential to 
act: 
 
 Directly on the tumor cells by inhibiting tumor cell growth and proliferation 
 Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via  
potent inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-
induced proliferation of endothelial cells). The role of angiogenesis in the 
maintenance of solid tumor growth is well established, and the mTOR 
pathway has been implicated in the regulation of tumor production of 
proangiogenic factors as well as modulation of VEGFR signaling in 
endothelial cells. 
 
At weekly and daily schedules and at various doses explored, everolimus is 
generally well tolerated.  The most frequent adverse events (incidence ≥ 10% and 
suspected to be related to treatment by the investigator) were infections, 
stomatitis, 
pyrexia, 
acneiform 
dermatitis, 
diarrhea, 
acne, 
cough, 
hypertriglyceridemia, and decreased white blood cell count.   The only grade 3 
adverse reactions were infections (single cases of sinusitis, pneumonia, tooth 
infection, and viral bronchitis), and single cases of stomatitis and decreased white 
blood cell count.  No Grade 4 adverse events were reported.  
 
mTOR pathway and mechanism of action 
At a cellular and molecular level everolimus acts as a signal transduction 
inhibitor. Everolimus selectively inhibits mTOR (mammalian target of 
rapamycin), a key and a highly conservative serine-threonine kinase, which is 
present in all cells and is a central regulator of protein synthesis and ultimately 
cell growth, cell proliferation, angiogenesis and cell survival. mTOR is the only 
currently known target of everolimus40.  
 
mTOR is downstream of PI3K/AKT pathway, a pathway known to be 
dysregulated in a wide spectrum of human cancers (e.g. through loss/mutation of 
the PTEN negative regulator; through PI3K mutation/amplification; through 
AKT/PKB overexpression/overactivation; through modulation of TSC1/TSC2 
tumor suppressors). In addition, activation of the PI3K/AKT/mTOR pathway is 
frequently a 
characteristic of worsening 
prognosis 
through increased 
aggressiveness, resistance to treatment and progression.  
The main known functions of mTOR include the following40,41: 


 
 
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 mTOR functions as a sensor of mitogens, growth factors and energy and 
nutrient levels, facilitating cell-cycle progression from G1 to S phase in 
appropriate growth conditions. 
 The PI3K-mTOR pathway itself is frequently activated in many human 
cancers, and oncogenic transformation may sensitize tumor cells to mTOR 
inhibitors.  
 Through inactivating eukaryotic initiation factor 4E binding proteins (4E-
BP1) and activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR 
regulates translation of important massages, including those encoding the 
HIF-1 proteins, c-myc, ornithine decarboxylase, and cyclin D1, as well as 
ribosomal proteins themselves.  
 The activation of mTOR pathway leads to the increased production of pro-
angiogenic factors (i.e., VEGF) in tumors and to tumor, endothelial and 
smooth muscle cell growth and proliferation. 
 The regulation of mTOR signaling is complex and involves positive 
regulators, such as AKT that phosphorylate and inactivate negative regulators 
such as the Tuberous Sclerosis Complex (TSC1/TSC2). 
 
mTOR is represented by two structurally and functionally distinct multiprotein 
signaling complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and 
mTORC2 (mTOR complex 2, rapamycin insensitive). 
 
mTORC1 is mainly activated via the PI3 kinase pathway through AKT (also 
known as PKB, protein kinase B) and the tuberous sclerosis complex 
(TSC1/TSC2)41. Activated AKT phosphorylates TSC2, which lead to the 
dissociation of TSC1/TSC2 complex, thus inhibiting the ability of TSC2 to act as 
a GTPase activating protein.  This allows Rheb, a small G-protein, to remain in a 
GTP bound state and to activate mTORC1. AKT can also activate mTORC1 by 
PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of 
mTORC142.  
 
mTORC2 (mTOR complex 2) is activated through a currently unknown 
mechanism, possibly by receptor tyrosine kinase (RTK) signaling42.  It has been 
suggested that mTORC2 phosphorylates and activates a different pool of AKT 
that is not upstream of mTORC1. PHLPP phosphatase plays a role of a negative 
regulator. mTORC2 is rapamycin insensitive and is required for the organization 
of the actin cytoskeleton43. 
 
mTORC1-mediated signaling is subject to modulation by the macrocyclic lactone 
rapamycin and its derivatives, such as everolimus.  Once these agents bind to the 
12 kDa cytosolic FK506-binding protein immunophilin FKBP12, the resulting 
rapamycin-FKBP12 complexes bind to a specific site near the catalytic domain of 
mTORC1 and inhibit phosphorylation of mTOR substrates. As a consequence, 
downstream signaling events involved in regulation of the G1 to S-phase 


 
 
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transition are inhibited. This mechanism is thought to be responsible for the 
immunosuppressive effects of rapamycin as well as its putative antineoplastic 
activity44. As many cancers are characterized by dysregulation of G1 transit (for 
example, overexpression of cyclin or cyclin-dependent kinases), inhibition of 
mTOR becomes an intriguing target for inducing cytostasis41. 
 
Preclinical studies  
Preclinical investigations have demonstrated that everolimus is a potent inhibitor 
of the proliferation of a broad range of human tumor cell lines in-vitro with IC50s 
ranging from sub/low nM to μM concentrations, concentrations capable of being 
reached in patients at the doses used in clinical trials.   
 
Everolimus was shown to have activity in human tumor cell lines originating from 
lung, breast, prostate, colon, kidney, melanoma and glioblastoma. Everolimus was 
also shown to have activity in human pancreatic neuroendocrine cells, where 
induction of apoptosis was reported45, as well as in acute myeloid leukemia cell46, 
adult T-cell leukemia cells47, diffuse large B cell lymphoma cells48, pancreatic 
tumor cells49, ovarian cancer cells50 and hepatocellular carcinoma cells51.  
 
As a single agent, everolimus inhibited proliferation in three mantle cell 
lymphoma cell lines (Jeko1, SP49 and NCEB1) approximately 40–65% compared 
to control cells. This was associated with G1 cell-cycle arrest and reduced 
phosphorylation of the mTOR downstream target, 4E-BP152.  
 
In a clonogenic assay using cells derived from 81 patient-derived tumor 
xenografts never cultured in vitro (11 human tumor types with 3 to 24 tumors 
each: bladder, colon, gastric, NSCLC [adeno, squamous epithelium and large 
cell], 
SCLC, 
breast, 
ovary, 
pancreatic, 
renal, 
melanoma, 
and 
pleuramesothelioma), everolimus inhibited colony formation in a concentration-
dependent manner. In addition, normal hematopoetic stem cells were insensitive 
to everolimus, with an IC50 about 15 fold higher than the tumor lines.  
 
Everolimus also inhibits the proliferation of human umbilical vein endothelial 
cells (HUVECS), with particular potency against VEGF-induced proliferation. 
The inhibition of endothelial proliferation and antiangiogenic activity of 
everolimus was confirmed in vivo, as everolimus selectively inhibited VEGF-
dependent angiogenic response.  Mice with primary and metastatic tumors treated 
with everolimus showed a significant reduction in blood vessel density when 
compared to controls at well tolerated doses. Additionally, activity in a VEGF-
impregnated s.c. implant model of angiogenesis and reduced vascularity (vessel 
density) of everolimus-treated tumors (murine melanoma) provided evidence of in 
vivo effects of angiogenesis. 
 
Everolimus also inhibits tumor growth in-vivo in xenografted, syngeneic and 
orthotopic animal models, residing longer in tumor tissue than in plasma and 


 
 
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demonstrating high tumor penetration in a rat pancreatic tumor model. These 
effects occurred within the dose range of 2.5 to 10 mg/kg p.o. daily. Typically, the 
antitumor activity of everolimus monotherapy was that of reduction of tumor 
growth rates rather than producing regressions or stable disease. 
 
Everolimus, administered p.o., was a potent inhibitor of tumor growth and well 
tolerated in: 
 s.c. mouse xenograft model, established from a variety of tumor cell lines of 
diverse histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), 
including a Pgp170 overexpressing multi-drug resistant tumor line  
 in a series of low-passage tumor xenografts established directly from human 
tumor material, maintained only in vivo and considered highly predictive of 
therapeutic outcome in patients. These included breast (5 lines), colorectal (9 
lines), gastric (3 lines), lung (22 lines including adenocarcinomas, epidermoid 
cell, large cell and small cell histotypes), melanoma (6 lines), ovarian (4 
lines), pancreatic (3 lines) and renal (6 lines) 
 in two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic 
melanoma) 
Taken together, these data indicate the broad antiproliferative potential of 
everolimus. 
 
It is not clear which molecular determinants predict responsiveness of tumor cells 
to everolimus. Molecular analysis has revealed that relative sensitivity to 
everolimus in vitro correlates with the degree of phosphorylation (activation) of 
the AKT/PKB protein kinase and the S6 ribosomal protein. PTEN status alone 
may not be predictive of everolimus relative in vitro sensitivity, however in some 
cases (i.e., GBM) there is also a correlation with PTEN status.   
 
In preclinical models, the administration of everolimus is associated with 
reduction of protein phosphorylation in target proteins downstream of mTOR, 
notably phosphorylated S6 (pS6) and p4E-BP1, and occasionally with an increase 
in phosphorylation AKT (pAKT).  
 
Preclinical safety 
In safety pharmacology studies, everolimus was devoid of relevant effects on vital 
functions including the cardiovascular, respiratory and nervous systems. 
Everolimus had no influence on QT interval prolongation. Furthermore, 
everolimus showed no antigenic potential. Although everolimus passes the blood-
brain barrier, there was no indication of relevant changes in the behavior of 
rodents, even after single oral doses up to 2000 mg/kg or after repeated 
administration at up to 40 mg/kg/day. Based on these findings, the potential of 
everolimus to affect vital functions in patients is considered to be low.   
 
Everolimus is considered to have no genotoxicity or carcinogenicity potential.  


 
 
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All significant adverse events observed in preclinical toxicology studies with 
everolimus in mice, rats, monkeys and minipigs were consistent with its 
anticipated pharmacologic action as an antiproliferative and immunosuppressant 
and at least in part reversible after a 2 or 4-week recovery period with the 
exception of the changes in male reproductive organs, most notably testes. Ocular 
effects (lenticular disorders) observed in rats were not observed in any other 
species and are considered to be a species-specific disorder. 
 
More pre-clinical information is provided in the Investigator Brochure53. 
 
Clinical experience  
Everolimus Pharmacokinetics: everolimus is rapidly absorbed with a median 
Tmax of 1-2 hours. The bioavailability of the drug is believed to be 11% or greater. 
The AUC0-τ is dose-proportional over the dose range between 5 to 70 mg in the 
weekly regimen and 5 and 10 mg in the daily regimen. Cmax is dose-proportional 
between 5 and 10 mg for both the weekly and daily regimens. At doses of 20 
mg/week and higher, the increase in Cmax is less than dose-proportional. The 
coefficient of variation between patients is approximately 50%. 
 
Trough levels (24 hour post-dose) correlate well with AUC0-τ at steady-state 
during daily administration.   
 
In whole blood, at a daily dose of 10 mg, about 20% of everolimus is confined in 
plasma with 26% being unbound. The remaining 80% is sequestered in blood 
cells.   
 
Everolimus is extensively metabolized in the liver and eliminated in the bile. 
Major metabolites are inactive. Elimination half-life is approximately 30 hours. 
The clearance of everolimus is approximately halved in patients with mild-
moderate hepatic impairment (Child-Pugh Class A or B), while renal impairment 
has little or no impact on the pharmacokinetics of everolimus.   
 
Age, weight and gender in the adult population do not affect the pharmacokinetics 
of everolimus to a clinically relevant extent. The clearance of everolimus is 
reduced in children.  
 
Pharmacokinetic characteristics are not notably different between Caucasian and 
Japanese subjects, whereas in Black patients population pharmacokinetic studies 
have shown an average 20% higher clearance. 
 
A high-fat meal altered the absorption of everolimus with 1.3 hour delay in Tmax, 
a 60% reduction in Cmax and a 16% reduction in AUC.  
 
Everolimus is a substrate of CYP3A4 and a substrate and a moderate inhibitor of 
the multi-drug efflux pump P-glycoprotein (P-gP, MDR1, ABCB1). Hence, its 


 
 
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metabolism is sensitive to drugs which modify these enzymes (substrates, 
inducers, or inhibitors of these enzymes).  Competitive inhibition could occur 
when everolimus is combined with drugs which are also CYP3A4 or P-
glycoprotein substrates.  
 
Appendix II lists examples of clinically relevant CYP3A inhibitors and inducers. 
 
Please refer to section 3.2.14 for more information on the concomitant use of 
CYP3A4 inhibitors/inducers and other medications.   
 
More information on everolimus pharmacokinetics is provided in the Investigator 
Brochure53. 
 
Everolimus Pharmacodynamic studies  
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the 
biomarker p70S6 kinase 1 [S6K1]54 in peripheral blood mononuclear cells 
suggests that 5-10 mg daily should be an adequate dose to produce a high-degree 
of sustained target inhibition55.  Furthermore, molecular pharmacodynamic 
(MPD) studies, using immunocytochemistry (IHC) in biopsied tumor tissue, 
assessed the degree of inhibition and its duration for pS6, p4E-BP1 and pAKT 
expression with the daily and weekly dosing. There was high inhibition of the 
downstream markers S6K1 and 4E-BP1 at 5 mg/day, which was complete at 10 
mg/day, while preliminary results suggest increase in pAKT expression with 
maximal effect at 10 mg daily56.   
 
More information is provided in the Investigator Brochure53. 
 
Clinical studies with everolimus  
Everolimus 
has 
been 
investigated 
as 
a 
component 
of 
multi-drug 
immunosuppression in solid organ transplantation since 1996 and was approved 
for the indication of prophylaxis of organ rejection in adult patients receiving an 
allogeneic renal or cardiac transplant on 8 Jul 2003 by the European Union under 
the trade name of Certican®. The most frequent adverse drug reactions in this 
context are highly specific to the transplant context.  However, certain events are 
generalizable, most notably myelosuppression, skin disorders and increases in 
blood lipid levels.  
Everolimus (everolimus) was approved by the FDA in March 2009 for the 
treatment of advanced renal cell carcinoma for patients with advanced renal cell 
carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.  It was also 
approved as previously noted in 2010 for patients with SEGA with TC who 
require therapeutic intervention but are not candidates for curative surgical 
resection and in 2011 for patients with pNET.  It is also FDA approved for lung 
neuroendocrine 
tumors 
and 
Waldenström’s 
macroglobulinemia/ 
lymphoplasmacytic lymphoma. 


 
 
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Everolimus has been in development for patients with cancer since 2002. 
Everolimus 5 mg and 10 mg tablets were recently approved under the trade name 
Afinitor® for patients with advanced renal cell carcinoma in the US, EU and 
several other countries and is undergoing registration in other regions worldwide. 
Phase I dose escalating studies, exploratory Phase I/II studies with everolimus as 
single agent or in combination with other anti-cancer agents, Phase II/III studies 
of everolimus in indications, and Phase III double-blind studies are contributing to 
the extensive database.  Approximately 18,730 patients have been treated with 
everolimus as of 30-September 2011: 
• 
9,528 patients in Novartis-sponsored clinical trials 
• 
2,559 patients in the single patients use IND program  
• 
6,638 patients in investigator-sponsored studies 
• 
In addition, healthy volunteer subjects and hepatically impaired non-oncology 
subjects have participated in the clinical pharmacology studies 
 
As of 23 Nov 2011, there are a total of 8 Phase III trials ongoing in the indications 
mRCC (1), advanced GEP-NET (3), breast cancer (1), DLBCL (1) and, 
Hepatocellular carcinoma (1). 
 
Recent approvals of everolimus were based upon a Phase III, international, 
multicenter randomized, double-blind, placebo-controlled study [C2240] in 
patients with metastatic renal cell carcinoma (mRCC) whose disease had 
progressed despite prior treatment with VEGFR-TKI (vascular endothelial growth 
factor receptor tyrosine kinase inhibitor) therapy. Progression-free survival (PFS) 
assessed via a blinded, independent central review, was the primary endpoint. 
Secondary endpoints included safety, objective tumor response 
 
In the pivotal, Phase III study, which included patients with advanced renal cell 
carcinoma, the most common adverse reactions (incidence ≥ 10%) were 
stomatitis, rash, fatigue, asthenia, diarrhea, anorexia, nausea, mucosal 
inflammation, vomiting, pneumonitis, cough, peripheral edema, infections, dry 
skin, epistaxis, pruritus, and dyspnea. The most common grade 3-4 adverse 
reactions (incidence ≥ 2%) were infections, stomatitis, fatigue, and pneumonitis. 
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including 
everolimus and some of these cases have been severe and on rare occasions, fatal 
outcomes have been observed. Everolimus has immunosuppressive properties and 
may predispose patients to bacterial, fungal, viral or protozoan infections, 
including infections with opportunistic pathogens.  Localized and systemic 
infections, including pneumonia, other bacterial infections, invasive fungal 
infections, such as aspergillosis or candidiasis and viral infections including 
reactivation of hepatitis B virus, have been described in patients taking 


 
 
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everolimus.  Some of these infections have been severe (e.g. leading to respiratory 
or hepatic failure) and occasionally have had a fatal outcome. 
The most common laboratory abnormalities (incidence ≥ 50%) were anemia, 
hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and 
increased creatinine. The most common grade 3/4 laboratory abnormalities 
(incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, 
and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), 
infection (0.7%), and acute renal failure (0.4%) were observed on the everolimus 
arm. The rates of treatment-emergent adverse reactions resulting in permanent 
discontinuation were 7% and 0% for the everolimus and placebo treatment 
groups, respectively.  
Overall, safety data available from completed, controlled and uncontrolled studies 
are consistent with the aforementioned findings of the Phase III trial. Everolimus 
is generally well tolerated at weekly and daily dose schedules. The safety profile 
is characterized by manageable adverse events (AEs). These AEs are generally 
reversible and non-cumulative. 
For more information on known undesirable effects of everolimus refer to Section 
8.1.6.  
 
A phase 1 study of everolimus in pediatric patients with refractory cancers was 
recently performed, and determined a dose of 5 mg/m2/dose once daily on a 
continuous dosing schedule as the recommended phase 2 dose57. Of 26 patients 
enrolled, 18 were assessable for toxicity, and the toxicity profile was similar to 
that in adults. Dose-limiting toxicities at the 6.5 mg/m2 dose level were mucositis 
(n=1), diarrhea (n=1), and LALT elevation (n=1). The pharmacokinetics of 
everolimus in children were similar to those in adults. For more information on 
known undesirable effects of everolimus refer to Section 8.1.6.  
 
Impaired renal function is not expected to influence everolimus pharmacokinetics 
based on the fact that ≤ t percent of radioactivity was excreted in urine in the mass 
balance study in maintenance renal transplant patients CP Study.  According to 
the IB, no dose adjustment is necessary for patients with renal impairment.  
Further detailed information regarding everolimus clinical development, safety 
and efficacy is provided in the Investigator Brochure53. 
 
Bevacizumab (rhuMAb) is a recombinant humanized anti-VEGF monoclonal 
antibody composed of human IgG1 framework regions and antigen-binding 
complementarily-determining regions from a murine monoclonal antibody 
(muMAb VEGF A.4.6.1) which blocks the binding of human VEGF to its 
receptors. Approximately 93% of the amino acid sequence, including most of the 
antibody framework, is derived from human IgG1, and ~7% of the sequence is 
derived from the murine antibody.  
 


 
 
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Bevacizumab has been approved by the FDA as first line therapy in combination 
with chemotherapy for treatment of patients with metastatic colorectal cancer or 
unresectable, locally advanced, recurrent or metastatic, non-squamous non-small 
cell lung cancer because of improved overall survival in the patients receiving 
combination therapy as compared to receiving chemotherapy alone. These lines 
of evidence demonstrate that bevacizumab is clinically effective when combined 
with chemotherapy.  
 
Preclinical studies: In cynomolgus monkeys, twice weekly IV treatments with 
bevacizumab (doses of 2, 10 and 50 mg/kg) for 4, 13 or 26 weeks were well 
tolerated, with no overt signs of acute toxicity58.  Animals with open growth 
plates showed physeal dysplasia as well as focal to diffuse chondroid necrosis and 
linear fissuring of the cartilaginous growth plate. Females treated with 10-
50mg/kg twice weekly had decreased ovarian and uterine weights, which were 
associated with absence of corpora lutea. These findings were expected, 
considering the known role of VEGF in formation of the corpora lutea and of the 
growing bone59.  A further study using a similar treatment regimen, in the 
recovery period the physeal dysplasia and ovarian and uterine changes induced by 
rhuMAb VEGF were partially reversible. No antibodies against bevacizumab 
were detected. 
 
Clinical studies in adults: Two phase-1 studies have been performed. Study 
AVF0737g was a dose escalation trial of single and multiple intravenous (IV) 
administration of rhuMAb in patients with advanced malignancies. Five dose 
levels were evaluated (0.1, 0.3, 1.0, 3.0, and 10mg/kg). rhuMAb VEGF was 
administered as a 90-minute infusion on days 0, 28, 35 and 4260. Study 
AVF0761g evaluated multiple doses of rhuMAb VEGF 3 mg/kg weekly for up to 
8 weeks in combination with one of three cytotoxic chemotherapy regimens (5-
fluorouracil/leucovorin, carboplatin/paclitaxel, or doxorubicin) in subjects with 
advanced solid malignancies61. rhuMAb VEGF was administered as eight weekly 
doses of 3mg/kg. 
 
In both studies, rhuMAb VEGF appeared to be well tolerated. In study 
AVF0737g, 3 of 25 patients treated experienced tumor-related hemorrhagic 
events, possibly related to the administration of rhuMAb VEGF. In two cases the 
event was considered serious: an intracranial hemorrhage (at an occult cerebral 
metastasis) in a patient with hepatocellular carcinoma and bleeding at the tumor 
site in a 38-year-old woman with a slowly progressing sarcoma of the thigh. No 
patient in AVF0761g reported serious bleeding. No dose limiting toxicity was 
reached in either study. No antibodies to rhuMAb VEGF were detected after 
therapy in either study. Three subjects from each study subsequently enrolled in 
the extension study.  
 
Pharmacokinetics: In study AVF0737g, the pharmacokinetics of rhuMAb VEGF 
appeared to be linear for doses  1mg/kg with a half-life of approximately 15 


 
 
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days. Comparable pharmacokinetic data was seen in study AVF0761g. Co-
administration of rhuMAb and cytotoxic chemotherapy did not appear to result in 
a change in the systemic concentration of the cytotoxic agents. 
 
Phase 2 Clinical Studies:   
 
Study 
Population 
Study 
Treatment 
rhuMAb 
VEGF 
Dosing 
Regimen 
AVF0757g 
Stage IIIB or 
IV non-
small cell 
lung cancer 
Carboplatin/
paclitaxel  
rhuMAb 
VEGF 
7.5mg or 
15mg/kg 
every 3 
weeks until 
disease 
progression 
AVF0780g 
Metastatic 
colorectal 
cancer 
5-
FU/leucovor
in 
 rhuMAb 
VEGF 
5mg or 
10mg/kg 
every other 
week until 
disease 
progression 
AVF0776g 
Relapsed 
metastatic 
breast 
cancer 
Single-agent 
rhuMAb 
VEGF 
3, 10 or 20 
mg/kg every 
other week 
over a 168-
day 
treatment 
period or 
until disease 
progression 
AVF0775g 
Hormone-
refractory 
prostate 
cancer 
Single-agent 
rhuMAb 
VEGF 
10mg/kg 
every other 
week over a 
168-day 
treatment 
period or 
until disease 
progression 
In Study AVF0780g, patients with metastatic colon cancer were treated with 
either 5-FU/leucovorin (500mg/m2 5-FU and 500mg/m2 leucovorin administered 
weekly for six weeks, with courses repeated every eight weeks) alone or in 
combination with rhuMAb VEGF 5mg/kg or 10mg/kg every two weeks.  


 
 
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Response rates were 17%, 40% (p=.03) and 24% (p=.23), respectively.  A 
prolonged time to disease progression was seen in patients treated with rhuMAb 
VEGF 5mg/kg in combination with chemotherapy (9.0 months p=.005) compared 
with those who received rhuMAb VEGF 10mg/kg (7.2 months p= .217), or 
chemotherapy alone (5.2 months)62.  
The anti-VEGF antibody Bevacizumab (rhuMAb) was evaluated as a single agent 
in several malignancies including CRPC61. In a Phase 2 trial 15 patients with 
CRPC were treated with 10 mg/kg every 14 days. Results of the study showed 
that though the drug was tolerated well, there were no significant objective 
responses.  
Toxicities: The following are the important toxicities. The detailed information 
can be seen in Section 8.2.8.  
 Infusion-Related Reactions: Infusion reactions with bevacizumab were 
uncommon (< 3%) and rarely severe (0.2%).  Infusion reactions may 
include rash, urticaria, fever, rigors, hypertension, hypotension, wheezing, 
or hypoxia. Currently, there is no adequate information on the safety of 
retreatment with bevacizumab in patients who have experienced severe 
infusion-related reactions.  
 
 Hemorrhage: Life threatening hemorrhage was seen in a Phase 1 trial 
(AVF0737g) in the form of an intracranial hemorrhage (at a cerebral 
metastasis) in a patient with hepatocellular carcinoma and in the Phase 2 
study (AVF0757g) in the form of massive hemoptysis or hematemesis. 
There were 6 life-threatening hemorrhages among 66 patients receiving 
rhuMAb VEGF-treated patients of which four of these events were fatal. 
An analysis of possible risk factors for life-threatening bleeding identified 
squamous cell histology as a risk factor (4 of 6 bleeds occurred in patients 
with squamous cell histology whereas only 13 of 66 rhuMAb VEGF-
treated patients had squamous histology). A number of investigations were 
performed on two of the patients with pulmonary hemorrhage and in eight 
patients in AVF0780g receiving rhuMAb VEGF including platelet count, 
prothrombin time, activated prothrombin time, fibrinogen, bleeding time, 
euglobulin clot lysis, d-dimer, alpha2-antiplasmin, PFA-100 (a platelet 
function assay) and these were all within normal range (Novotny,W. 
Genentech Inc. personal communication).  
 
Overall, grade 3 and 4 bleeding events were observed in 4.0% of 1,132 
patients treated with bevacizumab in a pooled database from eight phase 1, 
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. 


 
 
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Mucocutaneus hemorrhage: Across all bevacizumab clinical trials, 
mucocutaneous hemorrhage has been seen in 20%-40% of patients treated 
with bevacizumab. These were most commonly NCI-CTC 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. 
Tumor-associated hemorrhage:  Major or massive pulmonary 
hemorrhage/hemoptysis has been observed primarily in patients with 
NSCLC.  In a phase 2 study in NSCLC, 6 cases of life-threatening (4 fatal) 
hemoptysis were reported among 66 patients treated with bevacizumab 
and chemotherapy63; squamous cell histology was identified as the risk 
factor. In the phase III trial in non-squamous NSCLC (E4599), the rate of 
Grade ≥ 3 pulmonary hemorrhage was <1% in the control arm 
(carboplatin/paclitaxel) versus 2.3% in the chemotherapy plus 
bevacizumab arm (10/427 patients, including 7 deaths). 
Gastrointestinal hemorrhages, including rectal bleeding and melaena have 
been reported in patients with colorectal cancer, and have been assessed as 
tumor-associated hemorrhages. In the pivotal phase 3 trial in advanced 
colorectal cancer, the rate of GI hemorrhage (all grades) was 24% in the 
IFL/bevacizumab arm compared to 6% in the IFL arm; grade 3-4 
hemorrhage was 3.1% for IFL/bevacizumab and 2.5% for IFL.   
Serious tumor associated bleedings have also been observed in patients 
with pancreatic cancer, gastric cancer, CNS metastases, hepatoma, or 
varices treated with bevacizumab.  
 
 Thrombosis: 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 
trials and, to a lesser extent, in patients treated with bevacizumab in 
NSCLC and breast cancer trials.  
The risk of arterial thromboembolic events (ATE) is increased with 
bevacizumab therapy; such events included cerebral infarction, transient 
ischemic attack (TIA), myocardial infarction (MI) and other peripheral or 
visceral arterial thrombosis. A pooled analysis of five randomized studies 
showed a two-fold increase in these events (3.8% vs. 1.7%). ATE led to a 
fatal outcome in 0.8% patients with bevacizumab (vs. 0.5% without 
bevacizumab). The rate of cerebrovascular accidents (including TIA) was 
2.3% vs. 0.5%, and the rates of MI 1.7% vs. 0.7%. Certain baseline 
characteristics, such as age and prior arterial ischemic events, appear to 
confer additional risk64.  In patients > 65 years treated with bevacizumab 
and chemotherapy, the rate of ATE was approximately 8.5%.  


 
 
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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, similarly 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. Further analyses of the 
effects of concomitant use of bevacizumab and aspirin in colorectal and 
other tumor types are ongoing. 
Venous thromboembolism (VTE), including deep venous thrombosis, 
pulmonary embolism and thrombophlebitis:  In the Phase III pivotal trial 
in metastatic CRC, there was a slightly higher rate of venous 
thromboembolism (VTE) in patients treated with 
chemotherapy + bevacizumab compared with chemotherapy alone (19% 
vs. 16%).  The incidence of NCI-CTC Grade ≥ 3 VTEs in one NSCLC 
trial (E4599) was higher in the bevacizumab-containing arm compared to 
the chemotherapy control arm (5.6% vs. 3.2%).  
In clinical trials across all indications, the overall incidence of VTEs 
ranged from 2.8% to 17.3% in the bevacizumab-containing arms 
compared to 3.2% to 15.6% in the chemotherapy control arms. The use of 
bevacizumab with chemotherapy does not substantially increase the risk of 
VTE compared with chemotherapy alone.  However, patients with mCRC 
who receive bevacizumab and experienced VTE may be at higher risk for 
recurrence of VTE. 
 
 Hypertension: Hypertension is common in patients treated with 
bevacizumab. The incidence of hypertension (all grade) is 20-30% across 
trials, with a mean increase of +5.5mmHg to +8.4mmHg for systolic 
pressure, or +4.1mmHg to +5.4mmHg for diastolic pressure. Incidence of 
grade 3 (hypertension requiring initiation of, or increase in, hypertensive 
medications) ranges from 7.8 to 17.9%. Grade 4 hypertension 
(hypertensive crisis) occurred in up to 0.5% of bevacizumab-treated 
patients. 
Hypertension associated with bevacizumab can generally be controlled 
with routine oral drugs while bevacizumab is continued.  However, 
incidents of hypertensive crisis with encephalopathy, including reversible 
posterior leukoencephalopathy syndrome (RPLS, see below), or 
cardiovascular sequelae have been rarely reported.  Blood pressure (BP) 
should be closely monitored during bevacizumab therapy and the goal of 


 
 
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BP control should be consistent with standard medical practice65.  
Bevacizumab therapy should be suspended in the event of uncontrolled 
hypertension. 
 Gastrointestinal Perforation: GI perforations and/or fistula were rare but 
occurred at an increased rate in bevacizumab-containing therapies. The 
majority of such events required surgical intervention and some were 
associated with a fatal outcome. In the pivotal phase III trial in CRC 
(AVF2107), the incidence of bowel perforation was 2% in patients 
receiving 
IFL/bevacizumab 
and 
4% 
in 
patients 
receiving 
5-
FU/bevacizumab compared to 0.3% in patients receiving IFL alone. GI 
perforation has also been reported in non-CRC tumors (e.g. 
gastric/esophageal, pancreatic and ovarian cancers) or nonmalignant 
conditions such as diverticulitis and gastric ulcer.  GI perforation should 
be included in the differential diagnosis of patients on bevacizumab 
therapy presenting with abdominal pain or rectal/abdominal abscess. 
 Fistula: Fistula formations, including events resulting in death, have been 
observed in patients receiving bevacizumab in clinical studies and post-
marketing reports. Fistulae in the GI tract are common (1-10% incidence) 
in patients with certain metastatic tumors such as colorectal cancer or 
cervical, but uncommon (0.1-1%) or rare (0.01-0.1%) in other indications. 
In addition, fistulae that involve areas other than the GI tract have also 
been observed (e.g. tracheoesophageal, bronchopleural, urogenital, 
biliary). Events were reported at various time points during treatment, 
ranging from 1 week to > 1 year following initiation of bevacizumab, with 
most events occurring within the first 6 months of therapy. 
 Wound Healing Complications:  Bevacizumab delays wound healing in 
rabbits, and it may also compromise or delay wound healing in patients. 
Bowel anastomotic dehiscence and skin wound dehiscence have been 
reported in clinical trials with bevacizumab.   
The appropriate interval between surgery and initiation of bevacizumab 
required to avoid the risk of impaired wound healing has not been 
determined.  Across metastatic CRC trials, at least 28 days must have 
elapsed following major surgery before bevacizumab could be initiated; 
data suggested initiation of bevacizumab 29-60 days following surgery did 
not appear to increase the risk of wound healing complications compared 
to those treated with chemotherapy alone.   
The optimal interval between termination of bevacizumab and subsequent 
elective surgery has not been determined. In the pivotal study in CRC, 
among patients who underwent major surgery while on study therapy, 
there was an increased rate of significant post-operative bleeding or 
wound healing complications in the IFL + bevacizumab arms vs. IFL 
alone -10% (4/40) vs. 0% (0/25)-66. 


 
 
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Decisions on the timing of elective surgery should take into consideration 
the half-life of bevacizumab (average 21 days, range 11-50 days). 
If patients receiving treatment with bevacizumab require elective major 
surgery, it is recommended that bevacizumab be held for 4–8 weeks prior 
to the surgical procedure. Patients undergoing a major surgical procedure 
should not begin/restart bevacizumab until 4 weeks after that procedure (in 
the case of high-risk procedures such as liver resection, thoracotomy, or 
neurosurgery, it is recommended that chemotherapy be restarted no earlier 
than 6 weeks and bevacizumab no earlier than 8 weeks after surgery). 
 
 Proteinuria: Proteinuria has been seen in all bevacizumab studies to date, 
ranging in severity from mild asymptomatic increase in urine protein 
(incidence of about 38%) to rare instances of either grade 3 proteinuria (> 
3.5gm/24 hour urine) (3%) or nephrotic syndrome (1.4%). Pathologic 
findings on renal biopsies in two patients showed proliferative 
glomerulonephritis. The risk of proteinuria may be higher in patients with 
advanced RCC or history of hypertension. There is also evidence from 
dose-finding trials that the rate of proteinuria may be dose related. 
Proteinuria will be monitored by urine protein level using urine analysis 
dipstick, or the urine may be sent to the institution’s lab for processing. 
 Congestive Heart Failure (CHF): The risk of left ventricular dysfunction 
may be increased in patients with prior or concurrent anthracycline 
treatment. In phase III trials in metastatic breast cancer (AVF 2119g) in 
which all patients had received prior anthracyclines, CHF or 
cardiomyopathy were reported in 3% in the bevacizumab + capecitabine 
arm compared to 1% in the capecitabine-only arm67. In a phase III trial of 
patients with previously untreated metastatic breast cancer (E2100), the 
incidence of LVEF decrease (defined as NCICTC Grade 3 or 4) in the 
paclitaxel + bevacizumab arm was 0.3% versus 0% for the paclitaxel alone 
arm.  
In phase II study of 48 patients with refractory acute myelogenous 
leukemia treated with cytarabine, mitoxantrone, and bevacizumab, 5 cases 
of cardiac dysfunction (CHF or decreases to < 40% in left ventricular 
ejection fraction, including AML trial) were reported.  All but one of these 
subjects had significant prior exposure to anthracyclines as well.  
Two additional studies investigated concurrent administration of 
anthracyclines and bevacizumab. In 21 patients with inflammatory breast 
cancer treated with neoadjuvant docetaxel, doxorubicin (cumulative doses 
at 240 mg/m2), and bevacizumab, no patients developed clinically 
apparent CHF; however, patients had asymptomatic decreases in LVEF to 
< 40% (78).  In a small phase II study in patients with soft tissue sarcoma, 
2/17 patients treated with bevacizumab and high-dose doxorubicin (75 
mg/m2) developed CHF (one Grade 3 event after a cumulative doxorubicin 


 
 
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dose of 591 mg/m2, one Grade 4 event after a cumulative doxorubicin 
dose of 420 mg/m2); an additional 4 patients had asymptomatic decreases 
in LVEF68. 
Patients receiving anthracyclines or with prior exposure to anthracyclines 
should have a baseline MUGA or ECHO with a normal ejection fraction.   
 Reversible Posterior Leukoencephalopathy Syndrome (RPLS), Posterior 
Reversible 
Encephalopathy 
Syndrome 
(PRES), 
or 
similar 
leukoencephalopathy syndrome:  RPLS/PRES are clinical syndromes 
related to vasogenic edema of the white matter and have rarely reported in 
association with bevacizumab therapy   (< 1%).  Clinical presentations 
may include altered mental status, seizure, visual disturbance or cortical 
blindness, with or without associated hypertension. MRI scans are 
required for diagnosis. Typical findings are vasogenic edema (enhanced 
intensity in T2 and FLAIR sequences on non-contrast MRI) 
predominantly in the white matter of the posterior parietal and occipital 
lobes, and less frequently, in the anterior distributions and the gray matter. 
RPLS/PRES 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 irreversible tissue damage.  
The safety of reinitiating bevacizumab therapy in patients previously 
experiencing RPLS is not known69.   
 Neutropenia:  In the phase III trial with IFL +/- bevacizumab in colorectal 
cancer, grade 3-4 neutropenia was 21% with bevacizumab + IFL vs. 14% 
with IFL (grade 4 neutropenia was 3% vs. 2%). Increased rates of severe 
neutropenia, febrile neutropenia, or infection with severe neutropenia 
(including some fatalities) have been observed in patients treated with 
some myelotoxic chemotherapy regimens plus bevacizumab.  In a phase 
III in NSCLC, carboplatin and paclitaxel + bevacizumab arm was 
associated with increased rate of grade 4 neutropenia (27% vs. 17%), 
febrile neutropenia (5.4% vs. 1.8%), and infection with neutropenia (4.4% 
vs. 2.0%) with three fatal cases70. 
 Fertility and Pregnancy: Clinical data are lacking regarding the 
immediate or long-term effect of bevacizumab on fertility and pregnancy. 
However, bevacizumab is known to be teratogenic and detrimental to fetal 
development in animal models. In addition, bevacizumab may alter corpus 
luteum development and endometrial proliferation, thereby having a 
negative effect on fertility. As an IgG1, it may also be secreted in human 
milk. Therefore, fertile men and women on bevacizumab studies must use 
adequate contraceptive measures and women should avoid breast feeding. 
The duration of such precautions after discontinuation of bevacizumab 
should take into consideration the half-life of the agent (average 21 days, 
ranging from 11 to 50 days). 


 
 
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 Immunogenicity: As a therapeutic protein, there is a potential for 
immunogenicity with bevacizumab. With the currently available assay 
with limited sensitivity, high titer human anti-bevacizumab antibodies 
have not been detected in approximately 500 patients treated with 
bevacizumab.    
Reference should be made to the product labeling of bevacizumab. Specific 
caution and clinical alertness should be exercised for patients receiving the agent. 
 
Clinical Studies in Children: A phase 1 trial of bevacizumab as single agent has 
been completed for children with refractory solid tumors.  In this study, doses 
from 5 mg/kg to 15 mg/kg every 2 weeks were well tolerated71.  Eighteen of 21 
children completed ≥ 1 treatment cycle (median cycle #3, range 1-16 cycles). 
Interestingly, the typical adverse events seen in adults; hypertension, proteinuria, 
arterial thromboembolic events, hemorrhage, congestive heart failure (CHF), 
gastrointestinal perforations, wound healing complications, reversible posterior 
leukoencephalopathy syndrome and fistula formation, were not seen in children.  
Bony toxicity was not observed, but cumulative toxicity could not be evaluated 
given the fairly short treatment duration with bevacizumab. Based on these 
results, phase 2 studies at doses similar to adults were recommended. 
 
Combination studies of everolimus and bevacizumab: Multiple clinical trials 
combining 
everolimus 
with 
bevacizumab 
are 
ongoing 
in 
adults 
(clinicaltrials.gov).  In these studies everolimus is typically administered at a dose 
of 10 mg po/day on a continuous doing schedule, and bevacizumab is 
administered at a dose of 10 mg/kg IV every 14 days or 15 mg/kg IV every 21 
days.  
 
On a phase II trial of bevacizumab (10 mg IV every 2 weeks) and everolimus (10 
mg orally once daily) in patients with advanced renal cell carcinoma 80 patients 
were enrolled (50 untreated, 30 previously treated). Bevacizumab/everolimus 
showed activity in both groups. The median PFS in previously untreated and 
previously treated patients were 9.1 and 7.1 months, respectively. ORR (30% and 
23%). The combination was well-tolerated by most patients, with a toxicity 
profile as expected based on the known toxicities of both agents. Grade-3/4 
proteinuria was more frequent than expected (25%) and led to treatment 
discontinuation in 6 patients (unpublished, information provided by Novartis). 
 
In another phase II trial of bevacizumab 15 mg/kg Q 21 days + everolimus 10 mg 
daily for patients with metastatic melanoma, 57 patients enrolled received a 
median of 4 cycles (range: 1-14+). Seven patients (13%) had major responses, 30 
patients (53%) had objective decrease in the size of measurable lesions. The 
median PFS and OS were 4 months and 8.6 months, respectively.  The regimen 
was well tolerated, and 43% were alive after 12 months follow-up (unpublished 
data, information provided by Novartis). 
 


 
 
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One pediatric phase 1 trial combining bevacizumab 10 mg/kg IV every 14 days 
with everolimus 4 mg/m2/dose (starting dose level 1) and 5 mg/m2/dose (dose 
level 2) once daily po on a continuous dosing schedule is ongoing. The 
recommended phase 2 dose on this trial has not been determined yet (personal 
communication Lisa McGregor, study PI).  Therefore pediatric patients will not 
be initially eligible for trial participation.  
 
2.3 
Rationale 
Role of Mammalian target of rapamycin (mTOR) in cell proliferation:  
Mammalian Target of rapamycin (mTOR) is a serine/threonine kinase which is 
regulated by the phosphoinositol 3 kinase (PI3K)/Akt signaling pathway.  
Evidence suggests mTOR acts as a master switch of numerous cellular processes, 
including cellular catabolism and anabolism, cell motility, angiogenesis, and cell 
growth72. mTOR integrates two of the most important signals involved in the 
regulation of cell growth:  growth factors and nutrients. Growth factors, such as 
insulin and insulin-like growth factor, and nutrients, such as amino acids and 
glucose, enhance mTOR function.  mTOR controls translation in part by 
regulating ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E binding 
protein (4E-BP1), but may also regulate ribosomal biogenesis through 
nucleophosmin (NPM)73. Phosphorylation of the S6 protein by S6K selectively 
increases the ribosomal biogenesis, 4E-BP1 acts as a translation repressor by 
binding and inhibiting the eukaryotic translation initiation factor 4E (eIF4E).  
 
mTOR and cancer:   Preclinical studies have demonstrated efficacy of sirolimus 
analogs and parent compound in multiple tumor types.  In the NCI 60 tumor cell 
line panel, mTOR inhibitors demonstrated growth inhibitory activity against a 
broad spectrum of tumors including leukemia, brain, renal, breast and 
melanoma72,73 with an average IC50 of 8.2 nM.  Subsequent xenograft studies 
have confirmed the cytostatic properties of the mTOR inhibitors. Single agent 
mTOR inhibition has resulted in objective radiographic responses to a variety of 
mTOR inhibitors in patients with low-grade astrocytomas74, glioblastoma 
multiforme75, renal cell carcinoma76, mantle cell lymphoma44, breast cancer77 and 
sarcomas78. Patients with Tuberous Sclerosis Complex (TSC) also exhibit similar 
deregulation of mTOR/S6K signaling.  A recent clinical series has demonstrated 
clinical responses to single agent sirolimus in subependymal giant cell 
astrocytomas and a low grade glioma in 5 pediatric patients with TSC74.  In 
addition, a recent North Central Cancer Treatment Group phase 2 trial of the 
sirolimus ester temsirolimus (CCI-779) in 65 adult patients with recurrent 
glioblastoma multiforme revealed radiographic improvement in 36% of the 
temsirolimus-treated patients, and was associated with significantly longer time to 
progression75. The most common grade 3 or higher toxicities encountered were 
hypercholesterolemia (13% of patients), hypertriglyceridemia (11%) and 
hyperglycemia (8%).  Chan and colleagues treated 109 patients with relapsed, 
progressive advanced-stage breast cancer in a randomized trial with temsirolimus 
(CCI-779) at either 75 mg or 250 mg weekly by vein77.  He found that 9% of 


 
 
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patients had a response (all PR); while these responses were divided equally 
between the low and high dose of CCI-779, toxicity was less common in the 
lower dose.  The most common clinically important grade 3 or 4 adverse events 
were mucositis (9%), leucopenia (7%), hyperglycemia (7%), somnolence (6%), 
thrombocytopenia (5%), and depression (5%).  Others have treated patients with 
advanced refractory renal cell carcinoma with single agent CCI-779 and reported 
objective response and minor response rates of 7% and 26%, respectively76. 
Grade 3 or 4 toxicities in this group of 111 patients included hyperglycemia 
(17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%).  
MTOR inhibitors such as CCI-779, sirolimus, and everolimus have proven safe at 
a range of doses. 
 
Available mTOR Inhibitors: Sirolimus and three analogs, CCI-779 
(temsirolimus), everolimus (everolimus), and AP23573, have been developed for 
human use.  Among these, only sirolimus, everolimus, and temsirolimus are 
currently FDA approved.  Sirolimus is approved for prevention of kidney allograft 
rejection in adults and children at least 13 years old.  In this patient population, 
the typical starting dose is 2 mg once daily with a single loading dose of 6 mg.  
Sirolimus is also approved for use in drug-eluting stents to reduce the incidence of 
re-stenosis following coronary artery angioplasty79.  Temsirolimus (Wyeth) is an 
ester of sirolimus and is available for intravenous infusion. Temsirolimus was 
approved by the FDA for adults with advanced renal cell cancer on May 30, 2007 
using a weekly intravenous schedule.  Everolimus (Afinitor®/Votubia®) 
(Novartis) is an orally available hydroxyethyl derivative of sirolimus, and is 
currently FDA approved for advanced RCC, advanced PNET, lung 
neuroendocrine tumor, SEGA with TS in an individuate who is not a candidate for 
curative surgical resection and in Waldenström’s 
macroglobulinemia/lymphoplasmacytic lymphoma.  Additionally, in adults three 
Phase 3 trials are ongoing, four Phase 2 trials (alone or in combination with other 
agents), and in a limited number of pediatric trials.  Finally AP23573 (Ariad 
Pharmaceuticals) is an analog of sirolimus currently in Phase 2 trials in adults.   
At this time, it is unclear whether one compound will have an advantage over the 
others in a particular tumor type. 
 
mTOR and NF1: The NF1 gene encodes a protein, termed neurofibromin, which 
functions partly as a Ras-GTPase activating protein (RasGAP). Accordingly, 
neurofibromin loss in tumor cells leads to Ras hyperactivation. Signaling 
intermediates downstream of Ras are hyperactivated as a result of NF1 gene 
inactivation and these specific proteins are critical for transmitting the Ras growth 
signal and for the development of neoplasia in patients with NF1. One of these 
downstream proteins is the mammalian target of rapamycin (mTOR) molecule.  
Recent studies have demonstrated that the NF1 tumor suppressor regulates mTOR 
pathway activation. MTOR was found to be activated in both NF1 deficient 
primary human and mouse cells as well as in human and genetically-engineered 
Nf1 mouse tumor models. This aberrant activation was dependent on Ras and PI3 


 
 
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kinase/AKT signaling80,81. In this regard, Nf1 loss in mouse embryonic 
fibroblasts81 and primary mouse astrocytes80 was shown to result in Ras- and 
PI3K-dependent mTOR pathway activation, which could be inhibited with 
sirolimus. Moreover, Nf1-/- astrocytes are highly sensitive to sirolimus treatments 
that have no effect on normal astrocyte growth. In addition, the increased 
proliferation associated with loss of neurofibromin expression in human MPNST 
cell lines was dramatically reduced by treatment with sirolimus. Using a genetic 
mouse model of NF1-deficient malignant peripheral nerve sheath tumors 
(MPNST) development, sirolimus completely inhibited the growth of these 
tumors in vivo82. In addition, sirolimus treatment of optic gliomas developing in a 
genetically-engineered Nf1 mouse model resulted in attenuated mTOR signaling 
in vivo83 as well as tumor growth in vivo.  While tumors rapidly ceased to 
proliferate, there was no evidence of apoptosis or senescence, and sirolimus had 
no early effect on microvasculature in either preclinical model. Similarly, the 
mTOR inhibitor everolimus decreased growth in five MPNST cell lines, and 
prevented growth of subcutaneously implanted MPNST in mice82.  
 
Details describing studies performed by Dr. Karen Cichowski’s group81,84 in a 
transgenic mouse model are described below: 
In this model mice carrying compound mutations in the Nf1 and p53 tumor 
suppressors on the same chromosome (referred to as NP cis animals) develop 
aggressive MPNSTs that are histologically indistinguishable from human 
MPNSTs. Tumors grow with consistent and rapid kinetics, and on average mice 
only survive 10.7 days after the tumor is detected. Importantly, lesions develop as 
a result of somatic loss of the wild-type Nf1 and p53 alleles, and therefore are also 
genetically similar to human MPNST. This model was used to test the 
requirement for mTOR in tumorigenesis in vivo and assess the therapeutic utility 
of rapamycin. Animals with palpable tumors (approximately 300 mm3) were 
injected I.P. with 5 mg/kg rapamycin per day. Control NP cis mice died on 
average in 12.2 days, and tumors grew 9.7-fold. In contrast, rapamycin potently 
suppressed MPNST growth, resulting in only a .04 fold increase in size, and 
allowed the animals to survive. In no case did a rapamycin-treated animal die, but 
rather animals were sacrificed for interim analysis. Thus, rapamycin has potent 
cytostatic effects on these highly aggressive malignancies. Inhibition of S6 
phosphorylation was observed in tumor and non-tumor tissue, demonstrating that 
rapamcyin was effectively suppressing the mTOR pathway in vivo.  Moreover 
rapamycin mediated its anti-tumor effects within 24 hours by potently suppressing 
proliferation, as assessed by BrDU incorporation in control and rapamycin treated 
tumors. Consistent with in vitro observations, apoptotic and senescent cells were 
not detected.  As such, tumor growth was dependent on continued exposure to 
rapamycin, as tumors re-exhibited S6 phosphorylation and resumed growing at a 
rate comparable to control treated tumors following rapamycin removal. These 
data demonstrate that these aggressive tumors could be completely contained by 
an mTOR inhibitor. mTOR inhibition through treatment with everolimus also 
provided benefit in a mouse xenograft model of sporadic and NF1 associated82.  


 
 
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mTOR Inhibition and AKT activation: Several investigators have recently 
reported a negative feedback loop between mTOR and Akt in cancer cell lines85. 
Since Akt activation is associated with signaling down cell survival pathways, the 
effect of mTOR inhibition may be attenuated. However, in two independent NF1-
associated preclinical mouse tumor models treated with sirolimus (optic glioma 
and malignant peripheral nerve sheath models), no evidence was found for 
changes in Akt activation following rapamycin treatment81,83,84. 
 
These findings described above identify the NF1 tumor suppressor as a negative 
regulator of mTOR, and demonstrate that sirolimus blocks the growth of several 
NF1-deficient cells and tumor cell types in vitro and in vivo. The combination of 
cell culture and preclinical mouse modeling data provides a strong rationale for 
the use of sirolimus in treating human NF1-associated tumors. 
 
However, ultimately MPNSTs become resistant to treatment with rapamycin in 
this model, which is associated with re-vascularization and upregulation of 
VEGF. Preliminary preclinical data in the transgenic NF1 MPNST mouse model 
demonstrate prolonged survival for mice treated with rapamycin plus sunitinib, 
which in part, mediates anti-tumor activity by inhibition of angiogenesis, 
compared to mice treated with rapamycin or sunitinib alone (unpublished data K. 
Cichowski). Other studies demonstrate a role of angiogenesis in progression of 
MPNST. Angiogenesis has also been implied in the progression of MPNST. Ras 
mutations can upregulate VEGF expression86,87 and vascular endothelial growth 
factor (VEGF) and basic fibroblast growth factor (FGF) are also highly expressed 
in neurofibromas from patients with NF1 at the mRNA and protein level88. 
Furthermore, VEGF expression and tumor vascularization significantly increased 
in MPNSTs89. Use of a specific small molecular inhibitor of VEGF-receptor 2 
(VEGFR2) in a mouse explant model of neurogenic sarcomas showed a reduction 
in tumor growth due to decreased tumor angiogenesis with subsequent reduction 
in tumor cell proliferation and an increase in apoptosis89.  
 
Based on these preclinical studies we are proposing a phase 2 clinical trial of 
the mTOR inhibitor everolimus (everolimus) in combination with 
bevacizumab in NF1 related and sporadic MPNST. The primary goal of this 
trial will be to evaluate the activity of everolimus in refractory MPNST, and 
as such this trial will serve to validate the transgenic NF1 MPNST mouse 
model. The intent is that this trial will serve as platform for future studies 
combining targeted agents or standard chemotherapy agents with mTOR 
inhibition based on emerging additional findings from studies in preclinical 
models. 
2.4  
Study Design 
This is a two-stage phase 2 clinical trial with the objective to assess activity of the 
mTOR inhibitor everolimus in combination with the angiogenesis inhibitor 


 
 
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bevacizumab in patients with sporadic and NF1 associated MPNSTs refractory 
after ≥ 1 prior cytotoxic chemotherapy regimen. Novartis will provide everolimus 
and Genentech will provide bevacizumab for the trial.  
 
The primary endpoint is clinical benefit rate (PR, CR or stable disease at ≥ 4 
months). The diagnosis of NF1 will be based on clinical criteria.  
 
Most MPNSTs occur in adults, but MPNSTs in adolescents and children have 
been described and treatment approaches are similar for adults and children with 
MPNST. Initially enrollment will be limited to patients ≥ 18 years old, as the 
phase 2 dose for the combination of everolimus and bevacizumab in children has 
not been defined yet. A pediatric phase 1 trial of everolimus and bevacizumab is 
ongoing. Everolimus will be administered at the recommended phase 2 dose.  
Bevacizumab will also be administered at FDA approved doses. Everolimus will 
be administered orally once daily as tablets at a dose of 10 mg on a continuous 
dosing schedule. Bevacizumab will be administered IV at a dose of 10 
mg/kg/dose every 14 days. One treatment cycle will be defined as 28 days.  
 
Patients will be regularly monitored for everolimus and bevacizumab toxicity and 
response.  Dose modifications and interruptions will be performed as outlined in 
Section 6. Specific guidelines for grading and management of hypertension are 
described in Section 6.  
 
Patients will receive PCP prophylaxis while on everolimus; for example 
trimethoprim/sulfamethoxazole as per institutional guidelines, or inhaled 
pentamidine. 
 
Clinical benefit rate (success) will be defined as PR, CR, and SD at ≥ 4 months 
(WHO response criteria). A two-stage design will be used, and a clinical benefit 
rate of ≥ 25% will be defined as success ruling out a ≤ 5% clinical benefit rate. 
Initially 15 patients will be enrolled. If ≥ 1 of 15 patients respond, enrollment 
continues to 25 evaluable patients. If ≥ 4 of 25 evaluable patients respond; 
everolimus in combination with bevacizumab will be considered active and 
worthy for further exploration. Patients ≥ 18 years old who are able to swallow 
tablets and have adequate organ function and unresectable or metastatic MPNST 
which progressed after ≥ one prior cytotoxic chemotherapy regimen will be 
eligible. Patients will be able to remain on treatment for as long as they do not 
experience progressive disease or unacceptable toxicity up to a maximum of 2 
years. It is expected that 15-25 patients per year will be enrolled, and enrollment 
is expected to complete within approximately 1-2 years depending on the activity 
of everolimus and bevacizumab observed during the initial stage. Response 
evaluations (WHO) with appropriate imaging studies (MRI/CT) will be 
performed before every other treatment cycle (3, 5, 7, 9, etc)..  History and 
physical examination including vital signs will be performed after cycles 1, 2, 3 
and at the time of each evaluation. Laboratory studies will include CBC with 


 
 
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differential, fasting glucose and lipids, comprehensive chemistry panel. Based on 
the preclinical studies in transgenic and subcutaneous murine MPNST models we 
expect to observe predominantly a cytostatic effect. Therefore response will be 
defined as PR, CR, and SD at ≥ 4 months using WHO response criteria. MPNSTs 
are very aggressive tumors. In a recently completed phase 2 trial with the EGFR 
inhibitor erlotinib the median progression free survival was 2 months with 19 of 
20 evaluable patients demonstrating progression at the time of the first disease 
evaluation on treatment36. A subsequent phase 2 trial of sorafenib for different 
refractory sarcoma strata identified MPNST as the sarcoma type with the worst 
PFS (1.7 months) and overall survival (4.9 months) among the sarcomas 
evaluated37. We therefore believe that disease stability at ≥ 4 months indicates 
potential activity of the evaluated treatment. 
 
 
2.5 
Correlative studies 
Correlative studies will not be mandatory, and patients will be able to participate 
in the trial without agreeing to participate in any or all of the following studies. 
 
 To evaluate the spectrum of germline NF1 mutations in individuals with NF1 
associated MPNSTs: Comprehensive NF1 mutation analysis has become 
available within the past few years and allows identification of an NF1 
mutation in 95% of non-founder patients with > 2 neurofibromas or 1 
plexiform and fulfilling the NIH clinical diagnostic criteria in a CLIA-
certified laboratory90. This allows for meaningful analysis of phenotype and 
genotype correlations.  Total NF1 gene deletion has been described to result in 
a greater risk for development of an MPNST91. This finding, if confirmed, 
would have implications for genetic counseling. In addition, obtaining the 
spectrum of germline NF1 mutations in individuals with NF1 and MPNST 
and comparing it with the spectrum of germline NF1 mutations in a cohort of 
adult patients without externally visible plexiform neurofibromas will enhance 
our knowledge. Genotyping will only be performed after genetic counseling 
including the potential risks of genotyping and after obtaining written 
informed consent.  
 To explore the relationship between response to everolimus in combination 
with bevacizumab and presence of NF1 mutations or NF1 inactivation in 
MPNST tumor samples. 
 To explore the response rate to everolimus in combination with bevacizumab 
in individuals with sporadic and NF1 associated MPNST. While NF1 
inactivation has been described in sporadic and NF1 associated MPNST92, 
retrospective studies describe worse survival in individuals with NF1 
associated compared to sporadic MPNST4,13, and two studies describes worse 
response to chemotherapy in NF1 associated versus sporadic MPNST2,13. This 
analysis will only be performed in exploratory fashion and not be powered for 
a statistical comparison.  


 
 
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 To assess preliminary correlations of radiographic response and progression 
with changes in pharmacodynamic parameters including S6K1 (p70 S6 kinase 
1), eIF4E, eIF2 alpha, VEGF, VEGFR, Akt phosphorylation, and markers of 
cell metabolism in peripheral blood mononuclear cells collected prior to and 
serially during treatment with everolimus and bevacizumab: Markers of 
angiogenesis and downstream targets of mTOR will be analyzed to evaluate 
the effect of everolimus and bevacizumab on response and resistance. These 
evaluations can be performed in blood, and will thus be serially performed 
during treatment with everolimus at the same time as response evaluations.  
 To more sensitively monitor response to everolimus and bevacizumab by 
using three-dimensional MRI (3D-MRI) analysis of MPNSTs compared to 
conventional two-dimensional MRI (2-D MRI) and one-dimensional MRI (1-
D MRI) data analysis: Volumetric MRI analysis has become the standard 
method to evaluate the growth rate of plexiform neurofibromas on clinical 
trials93,94. This method may have utility for MPNSTs, which are typically 
large and have a complex shape. Volumetric MRI analysis will therefore be 
performed as a secondary objective and compared to standard response 
evaluation with 1D- and 2D- measurements. MRI studies performed for 
response evaluation will be used for volumetric analysis, and no MRI 
sequence other than STIR MRI (Short T1 inversion recovery), which is 
commonly used in the evaluation of sarcomas and does not require contrast 
administration, will be required.  
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility criteria 
 
Patients must have baseline evaluations performed prior to the first dose of study 
drug and must meet all inclusion and exclusion criteria. Results of all baseline 
evaluations verifying that all inclusion and exclusion criteria have been satisfied 
must be reviewed by the Principal Investigator or his/her designee prior to 
enrollment of that patient. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written 
informed consent must be obtained from the patient or legal representative prior 
to enrollment. The following criteria apply to all patients enrolled onto the study 
unless otherwise specified.  
 
3.1.1 Patients ≥ 18 years old with unresectable or metastatic sporadic or NF1 
associated high-grade MPNST who have experienced progression after one or 
more prior regimens of cytotoxic chemotherapy. Patients who have refused 
cytotoxic chemotherapy, or for whom treatment on this protocol prior to receiving 
cytotoxic chemotherapy is felt to be in the best interest for the patient by the local 
investigator, will also be eligible. 


 
 
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Diagnostic criteria for NF1 are (NIH Consensus Conference 1987): Presence of 2 
or more of the following criteria:   
1. Six or more café-au-lait spots (≥ 0.5 cm in prepubertal subjects or ≥ 1.5 cm in 
postpubertal subjects) 
2. ≥ 2 neurofibromas or 1 plexiform neurofibroma 
3. Freckling in the axilla or groin 
4. Optic glioma 
5. Two or more Lisch nodules 
6. A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or 
thinning of long bone cortex) 
7. A first degree relative with NF1 
The diagnostic criteria leading to the diagnosis of NF1 and other NF1 findings 
will be documented on the eligibility checklist and on the form provided in 
Appendix V. 
 
3.1.2 Patients must be able to swallow tablets. 
 
3.1.3 Patients must have measurable disease, defined as at least one tumor that is 
measurable (defined as those that can be accurately measured in at least two 
dimensions (longest diameter > 20 mm with conventional techniques or > 10 mm 
using spiral CT scan; See Section 11, Measurement of Effect) in two dimensions 
on CT or MRI scan. 
 
3.1.4 Patients who develop a recurrence or progression (WHO criteria) of an 
MPNST in a previously radiated field may be enrolled if it has been at least 4 
weeks since the last dose of radiation therapy. Patients who previously received 
radiation and develop a local or metastatic recurrence outside of the radiation field 
are also eligible. 
 
3.1.5 Serum creatinine ≤ the upper limit of normal  
 
3.1.6 Adequate unsupported hematologic function as shown by: ANC ≥ 1.0 x 
109/L, Platelets ≥ 100,000 x 109/L, Hgb > 9 g/dL (transfusion of packed red blood 
cells allowed). 
 
3.1.7 Adequate liver function as shown by: serum bilirubin ≤ 1.5 x ULN, ALT 
and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases). 
 
3.1.8 Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting 
triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are 
exceeded, the patient can only be included after initiation of appropriate lipid 
lowering medication. 


 
 
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3.1.9 Urine protein should be screened by spot urine analysis for Urine Protein 
Creatinine (UPC) ratio.  For UPC ratio > 0.5, 24-hour urine protein should be 
obtained and the level should be < 1000 mg for patient enrollment.  
Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion – a 
UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm.  UPC 
ratio is calculated using one of the following formulas: 
-- [urine protein]/[urine creatinine] – if both protein and creatinine are reported in 
mg/dL 
-- [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in 
mmol/L 
 
3.1.10 Patients must have recovered from the toxic effects of all prior therapy 
before entering this study. Recovery is defined as a toxicity < grade 1 (CTCAE-
version 4), unless otherwise specified in the inclusion and exclusion criteria. 
These patients must have had the last dose of chemotherapy at least 3 weeks prior 
to trial entry, last biologic agent within 7 days prior to trial entry, and the last dose 
of radiation therapy at least four weeks prior to trial entry. A minimum of 4 weeks 
must have passed from prior major surgical procedures, and a minimum of 7 days 
for core biopsies or other minor surgical procedures excluding placement of a 
vascular access device. 
 
3.1.11 ECOG performance status of 0, 1, or 2 (Appendix I) 
3.1.12 Cardiac function: Patients who received an anthracycline prior to 
enrollment on this study, must have an ejection fraction ≥ 50% documented by 
echocardiogram or MUGA scan. 
3.1.13 Subjects of childbearing or child-fathering potential must be willing to use 
a medically acceptable form of birth control, which includes abstinence, while 
being treated on this study. 
3.1.14 Informed Consent: Diagnostic or laboratory studies performed exclusively 
to determine eligibility for this trial must only be done after obtaining written 
informed consent from all patients. This can be accomplished through an IRB-
approved institutional screening protocol or the study-specific protocol.  
Documentation of the informed consent for screening will be maintained in the 
patient’s research chart. Studies or procedures that were performed for clinical 
indications (not exclusively to determine eligibility) may be used for baseline 
values even if the studies were done before informed consent was obtained. 
 
 


 
 
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3.2 
Exclusion criteria 
3.2.1 Patients currently receiving anticancer therapies or who have received 
anticancer therapies within 3 weeks of the start of study drug (including 
chemotherapy, antibody based therapy, etc.).  
 
3.2.2 At least 7 days since the completion of therapy with a biologic agent.  For 
agents that have known adverse events occurring beyond 7 days after 
administration, this period must be extended beyond the time during which 
adverse events are known to occur.   
  
3.2.3 Patients receiving chronic, systemic treatment with corticosteroids or 
another immunosuppressive agent (for example, cyclosporine).  Topical or 
inhaled corticosteroids are allowed. 
 
3.2.4 Patients should not receive immunization with attenuated live vaccines 
within one week of study entry or during study period. 
 
3.2.5 Uncontrolled brain or leptomeningeal metastases, including patients who 
continue to require glucocorticoids for brain or leptomeningeal metastases.  
 
3.2.6 Other malignancies within the past 3 years except for adequately treated 
carcinoma of the cervix or basal or squamous cell carcinomas of the skin. Stable 
NF1 related tumors, such as optic pathway tumors, which do not require treatment 
at time of study enrollment, will not be considered an exclusion criterion. 
 
3.2.7 Patients who have any known severe and/or uncontrolled medical conditions 
or other conditions that could affect their participation in the study such as: 
 
 Symptomatic congestive heart failure of New York Heart Association 
Class III or IV, unstable angina pectoris, symptomatic congestive heart 
failure, myocardial infarction within 6 months of start of study drug, 
serious uncontrolled cardiac arrhythmia or any other clinically significant 
cardiac disease 
 Severely impaired lung function defined as spirometry and DLCO that is 
50% of the normal predicted value and/or O2 saturation that is 88% or less 
at rest on room air 
 Significant vascular disease (e.g. aortic aneurysm, symptomatic peripheral 
vascular disease) within 6 months prior to enrollment 
 Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN 
 Active (acute or chronic) or uncontrolled severe infectious hepatitis Note: 
A detailed assessment of Hepatitis B/C medical history and risk factors 


 
 
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must be done at screening for all patients.  HBV DNA and HCV RNA 
PCR testing are required at screening for all patients with a positive 
medical history based on risk factors and/or confirmation of prior 
HBV/HCV infection (see Appendix IV). 
 A known history of HIV seropositivity, as immune deficiency increases 
the risk for opportunistic infection. 
 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of everolimus (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small 
bowel resection). 
 Patients with an active, bleeding diathesis or significant coagulopathy (in 
absence of therapeutic anticoagulation). 
 Presence of serious non healing wound, active ulcer, or untreated bone 
fracture including tumor-related pathologic fracture. 
 History of abdominal fistula, gastrointestinal perforation or intraabdominal 
abscess within 6 months prior to day 1. 
 
3.2.8 Female patients who are pregnant or breast feeding, or adults of 
reproductive potential who are not using effective birth control methods. If barrier 
contraceptives are being used, these must be continued throughout the trial by 
both sexes. Adequate contraception must be used throughout the trial and for 8 
weeks after the last dose of study drug, by both sexes. (Women of childbearing 
potential must have a negative urine or serum pregnancy test within 7 days prior 
to administration of study drugs) 
 
3.2.9 Patients who have received prior treatment with an mTOR inhibitor (such as 
sirolimus, temsirolimus, everolimus) for sarcoma and patients who previously 
received bevacizumab. 
 
3.2.10 Patients with a known hypersensitivity to rapamycins (sirolimus, 
temsirolimus, 
everolimus) or to 
its 
excipients 
Excipients: 
 
Tablets: 
butylhyroxytoluene/butylated hydroxytoluene (BHT), magnesium stearate, lactose 
monohydrate, 
hypromellose/hydroxypropyl 
methylcellulose, 
crospovidone, 
lactose anhydrous. The excipients comply with the requirements of the applicable 
compendial monographs (Ph. Eur., USP/NF). 
 
3.2.11 History of noncompliance to medical regimens 
 
3.2.12 Concurrent use of anti-coagulant drugs (not including prophylactic doses), 
history of coagulopathy, or evidence of bleeding diathesis or coagulopathy 
 


 
 
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3.2.13 Patients unwilling or unable to comply with the protocol 
 
3.2.14 CYP3A4 inhibitors: Patients may not be currently receiving strong 
inhibitors of CYP3A4, and may not have received these medications within 1 
week of entry.  See Appendix II. 
 
3.2.15 Patients may not be currently receiving Seville orange, star fruit, grapefruit 
and their juices, and St. John’s Wort affect P450 and PgP activity, and use is not 
allowed while on study. 
 
3.2.16 Enzyme inducing anticonvulsants: Patients may not be taking enzyme –
inducing anticonvulsants, and may not have received these medications within 1 
week of entry, as these patients may experience different drug disposition.  These 
medications include: 
 Carbamazepine (Tegretol) 
 Felbamate (Felbtol) 
 Phenobarbitol 
 Phenytoin (Dilantin) 
 Primidone (Mysoline) 
 Oxcarbazepine (Trileptal) 
 
3.3 
Inclusion of Women and Minorities 
 
Subjects of both genders and from all racial and ethnic groups are eligible for this 
trial if they meet the criteria. To date, there is no information that suggests 
differences in absorption, metabolism, or disposition or disease response among 
racial or ethnic groups or between the genders, indicating that results of the trial 
will be applicable to all groups. Efforts will be made to extend the accrual to a 
representative population, but in a phase 2 trial which will accrue a limited 
number of patients, a balance must be struck between patient safety 
considerations and limitations on the number of individuals exposed to potentially 
toxic or ineffective treatments on the one hand and the need to explore gender, 
racial, and ethnic aspects of clinical research on the other. If differences in 
outcome that correlate to gender, racial, or ethnic identity are noted, accrual may 
be expanded or additional studies may be performed to investigate those 
differences more fully. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General guidelines 
 
After obtaining Informed Consent, eligible patients will be enrolled on this trial. 
Subjects will be registered by local sites through an electronic database, and will 
be issued a subject unique identifying numbers for eligible participants. An 


 
 
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investigator is required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the 
investigation on each subject treated with the investigational product in the study 
or registered to the study. SARC may request faxed copies of selected source 
documents with PHI redacted for verification of records, accuracy of electronic 
submissions and review of data. 
 
While all study evaluations must be performed by the Investigator as described in 
Section 10, Study Evaluations and Study Calendar, only data related to the 
primary and secondary endpoints, as well as safety data, will be captured in the 
eCRFs. 
 
4.2 
Patient registration 
 
The SARC016 study uses a web based data entry system for data submission. All 
subject registrations and Case Report Forms (CRFs) will be submitted 
electronically via the study web site. All subjects must be registered on the study 
website prior to start of treatment.  Data Managers and other authorized users will 
be provided with a unique user identification number and password to access the 
site.  All study case report forms may be accessed online through the study 
website. In case there are problems accessing the website, please contact the 
SARC office directly at: Phone: 734-930-7600, Fax: 734-930-7557. 
 
5. TREATMENT PLAN 
 
5.1 
Agent administration 
 
Everolimus will be provided by Novartis.  Everolimus is formulated as tablets for 
oral administration of 2.5 mg, 5 mg and 10 mg strength.  Tablets are blister-
packed under aluminum foil in units, which should be opened only at the time of 
administration as drug is both hygroscopic and light-sensitive. 
 
The study drug everolimus will be self-administered. The investigator will 
instruct the patient to take the study drug exactly as specified in the protocol.  
Everolimus will be administered orally as a once daily dose of 10 mg. 
 
Patients will be instructed to take everolimus, at the same time each day, 
preferably in the morning. Everolimus should be taken by the patient consistently 
with or without food, and remain as consistent as possible throughout the study, 
and in particular, during those periods when samples are being taken for 
pharmacodynamic analyses (see Section 2.5 and Operations Manual). 
 
If vomiting occurs, no attempt should be made to replace the vomited dose. All 
dosages prescribed and dispensed to the patient and all dose changes during the 
study will be recorded in a patient diary (see Appendix III). Medication labels will 


 
 
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comply with US legal requirements and be printed in English. They will supply 
no information about the patient. The storage conditions for study drug will be 
described on the medication label. 
 
Bevacizumab will be provided by Genentech. The bevacizumab dose will be 
placed into a 100 ml infusion bag. Administration will be as an intravenous 
infusion over 30-90 minutes, or it will be administered per the treating 
institution’s standard policy.  Bevacizumab will be administered every 14 days 
(on days 1 and 15), +/- 2 days.  Everolimus should be given at the same time each 
day, and is not dependent on the time the Bevacizumab is given.  Exception: hold 
everolimus dose until after research labs are obtained (see Appendix 10.4 - 
Schedule of Evaluations).  The initial bevacizumab dose will be delivered as an 
IV infusion over 90  10 minutes. If the first infusion is tolerated without 
infusion-associated adverse events (fevers and/or chills), the second infusion 
maybe delivered over 60  10 minutes.  If the 60 minute infusion is well tolerated, 
all subsequent infusions maybe delivered over 30  10 minutes.  If a patient 
experiences an infusion-associated adverse event, subsequent infusions will be 
given over the shortest period that was well tolerated. The patient may be pre-
medicated for the next bevacizumab infusion. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients must be instructed not to take any additional medications (including over-
the-counter products) during the trial without prior consultation with the 
investigator.  All medications taken at the time of screening should be recorded. If 
concomitant therapy must be added or changed, the reason and name of the 
drug/therapy should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for 
the care of the patient are allowed, including drugs given prophylactically (e.g. 
antiemetics), with the following exceptions: 
 No other investigational therapy should be given to patients 
 No chronic treatment with systemic steroids or another 
immunosuppressive agent (for example, cyclosporine) with the exception 
of patients with endocrine deficiencies who are allowed to received 
physiologic or stress doses of steroids if necessary.  Patients will be 
allowed to receive steroids for the treatment of pneumonitis. 
 The CYP3A4 inhibitors and inducers and enzyme inducing 
anticonvulsants listed in Appendix II are prohibited on this trial. Other 
drugs or substances known to be inhibitors or inducers of the isoenzyme 
CYP3A (listed in Appendix II) should be avoided, if possible, and if 
unavoidable, only be used with caution, in association with everolimus as 
these can alter metabolism. If patient requires co-administration of 
moderate CYP3A4 inhibitors or PgP inhibitors (see Appendix III), reduce 
the dose of everolimus to half the currently used dose. Additional dose 


 
 
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reductions to every other day may be required to manage toxicities. If the 
inhibitor is discontinued the everolimus dose should be returned to the 
dose used prior to initiation of the moderate CYP3A4/PgP inhibitor. 
 Patients should not receive immunization with attenuated live vaccines 
during the study period. Close contact with those who have received 
attenuated live vaccines should be avoided during treatment with 
everolimus. Examples of live vaccines include intranasal influenza, 
measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and 
TY21a typhoid vaccines. 
 
5.2.1  Concomitant Cancer and other Therapy 
 
Concurrent cancer therapy, including chemotherapy, radiation therapy, 
immunotherapy, or biologic therapy may NOT be administered.  
The administration of biphosponates is permitted at investigator discretion. The 
risk for osteonecrosis of the jaw associated with bevacizumab and 
bisphosphonates should be considered (Section 8.2.8). 
The medication history including complementary and alternative medications 
should be reviewed at the initial screening visit and at the time of subsequent 
visits. Patients will be instructed to consult a member of the study team prior to 
introduction of new medications.  No other investigational therapy should be 
given to patients. 
Oral contraceptives in preclinical and clinical data have shown everolimus to have 
CYP3A4 inhibitory activity rather than induction activity, induction of 
metabolism of contraceptive hormones by everolimus is unlikely. Consequently, 
administration of everolimus should not reduce the efficacy of oral 
contraceptives. 
 
5.2.2  Supportive Care 
 
 Appropriate antibiotics, blood products, antiemetics (EXCEPT systemic 
steroids), fluids, electrolytes and general supportive care are to be used as 
necessary.  Platelets should be transfused for thrombocytopenia following 
institutional guidelines.  All blood products will be administered following 
institutional guidelines to prevent graft-versus-host disease.  Corticosteroids 
are permissible as premedication for blood product transfusions, or as 
treatment for an acute allergic reaction. 
 
 Patients must take some form of PCP prophylaxis while on everolimus.  
For example: trimethoprim/sulfamethoxazole as per institutional guidelines, or 
inhaled pentamidine. 
 


 
 
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 Good oral hygiene and mouth care are encouraged, as mucositis is one of the 
toxicities of everolimus. 
 
 Growth Factors that support platelet or white cell number or function can only 
be administered for culture proven bacteremia, clinical sepsis, or invasive 
fungal infection with neutropenia. ASCO guidelines and regulatory authority 
labeling for providing growth factor support are recommended.  
 
 Vaccinations: Patients receiving immunosuppressants, including everolimus, 
should not be administered live vaccines. In addition, the response to vaccines 
(non-live) administered while the patient is immunosuppressed can be 
variable, and clinicians should check titers following for response if a non-live 
vaccine must be administered during this time. 
 
Patients with positive hepatitis screen (See Appendix V):  
 It is highly recommended that patients positive for HBV-DNA or HBsAg are 
treated prophylactically with an antiviral for 1-2 weeks prior to receiving 
study drug.  
 The antiviral treatment should continue throughout the entire study period and 
for at least 4 weeks after the last dose of study drug.  
 Patients on antiviral prophylaxis treatment or positive HBV antibodies should 
be tested for HBV-DNA according to study visit schedule.  
 
5.3 
Duration of therapy 
Treatment may continue for a maximum of 2 years until one of the following 
criteria applies: 
 Disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s), including significant irreversible grade 4 
toxicity attributed to everolimus or bevacizumab 
 Greater than 3 weeks have elapsed since the last dose of everolimus or greater 
than 8 weeks since the last dose of bevacizumab 
 Patient decides to withdraw from the study 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Patient is lost to follow-up 
 Death 
 


 
 
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5.4 
Duration of follow up 
Patients will be followed until 30 days after the last dose of everolimus and 
bevacizumab or longer if patient removed from treatment with everolimus or 
bevacizumab for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event to < grade 1 using the CTCAE v 4 as detailed in 
Section 7.1.2.  
 
5.5 
Criteria for removal from study 
Patients will be removed from study when any of the criteria listed in Section 5.3 
applies and patients have been followed as detailed in section 5.4.  The reason for 
study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dosing changes for everolimus related toxicities are described in Section 6.1, and 
for bevacizumab related toxicities in Section 6.2. If toxicity cannot be clearly 
attributed to either bevacizumab alone or to everolimus alone, the toxicity will be 
attributed to both agents, and modifications made accordingly. Should a patient 
require permanent discontinuation of either everolimus or bevacizumab, this 
patient can continue on study receiving the agent, which is tolerated for as long no 
other off treatment criteria are met. The study PIs should be contacted to discuss 
questions regarding toxicity attribution and to discuss patients who may meet 
criteria to continue treatment with either everolimus or bevacizumab alone.  
 
6.1 
Interruption or discontinuation of treatment with everolimus 
For patients who are unable to tolerate the protocol-specified dosing schedule, 
dose adjustments are permitted in order to keep the patient on study drug. If the 
patient misses a dose of everolimus, they may still take it up to 6 hours after the 
time they would normally take it.  If more than 6 hours have elapsed, the patient 
should skip the dose for that day.  The next day, they should take everolimus at 
the usual time.  The patient should NOT take 2 doses to make up for the one that 
they missed. If administration of everolimus must be interrupted because of 
unacceptable toxicity, drug dosing will be interrupted or modified according to 
rules described in tables 1, 2, and 3 below: Toxicity will be assessed using the 
NIH-NCI Common Terminology Criteria for Adverse Events, version 4.0 
(http://ctep.cancer.gov/forms/CTCAEv4.pdf). 
 
 
 
 
 
Table 1: Everolimus dose level modification guidelines  
 


 
 
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Dose level 
Dose and schedule 
0 (starting dose) 
10 mg daily 
-1 
5 mg daily 
-2 
2.5 mg daily 
 
 
Table 2: Criteria for dose-modifications in case of suspected everolimus toxicity and 
re-initiation of treatment 
 
Toxicity 
Actions 
Non-hematological toxicity 
 
≥ Grade 2  
(except pneumonitis – refer to Table 3) 
 
Any grade 2 non-hematologic toxicity attributable 
to everolimus that persists for ≥ 7 days or is 
considered sufficiently medically significant or 
sufficiently intolerable by patients that it requires 
treatment interruption.  
 
Any Grade 3possibly, probably or definitely 
attributable to everolimus, except the following: 
 
grade 3 nausea or vomiting of less than 3 
days duration; 
 
grade 3 transaminase elevation that returns 
to eligibility criteria within 7 days of study 
drug interruption and that does not recur 
upon study re-challenge with study drug; 
 
grade 3 fasting hypercholesterolemia, 
hyperlipidemia, hyperglycemia; 
 
grade 3 GGT elevation 
 
grade 3 electrolyte abnormalities 
 
Grade 4 possibly, probably or definitely attributable 
to everolimus* 
If the toxicity is tolerable to the patient, maintain the 
same dose. If the toxicity is intolerable to patient, 
interrupt everolimus until recovery to grade ≤ 1. 
Then reintroduce everolimus at same dose.  If event 
returns to grade 2, then interrupt everolimus until 
recovery to grade ≤ 1. Then reintroduce everolimus 
at the next lower dose level (see Table 1 above). 
 
 
Interrupt everolimus until recovery to grade ≤ 1. 
Then reintroduce everolimus at the next lower dose 
level (see Table 1 above). 
 
 
 
 
 
 
 
 
 
 
Discontinue everolimus 
 
Hematological toxicity 
 
ANC < 750 or  
Grade 3 Thrombocytopenia (platelets < 50, ≥ 
25x109/L)    
 
 
 
 
 
 
Grade 3 febrile neutropenia (not life-threatening) 
 
 
 
 
 
 
Interrupt everolimus until recovery to platelets       
(≥ 100,000) and ANC of ≥ 1.0 x 109/L.  Then 
resume at prior dose.  If toxicity recurs after the 
restart of therapy, patients will be dose reduced to 
the next lower dose level (see Table 1above).  Dose 
modifications for hemoglobin and grade 3 
lymphopenia are not required. 
 
 
Interrupt everolimus until resolution of fever and 
neutropenia to grade ≤ 2.  Hold further everolimus 
until the ANC ≥ 1,000/mm3 and fever has resolved. 
Then resume everolimus at the next lower dose 
level (see Table 1 above). If febrile neutropenia 
recurs, discontinue everolimus.  
 


 
 
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Toxicity 
Actions 
Grade 4 febrile neutropenia (life-threatening) 
 
 
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 3 weeks 
Discontinue everolimus 
 
 
Discontinue everolimus 
*Grade 3 or 4 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed using 
medical therapies (see Section 6.1.2) 
 
6.1.1   Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using 
local supportive care. Please note that investigators in earlier trials have described 
the oral toxicities associated with everolimus as mouth ulcers, rather than 
mucositis or stomatitis. If your examination reveals mouth ulcers rather than a 
more general inflammation of the mouth, please classify the adverse event as 
such. Please follow the paradigm below for treatment of stomatitis/oral 
mucositis/mouth ulcers: 
1. For mild toxicity (Grade 1), use conservative measures such as non-alcoholic 
mouth wash or salt water (0.9%) mouth wash several times a day until 
resolution. 
2. For more severe toxicity (Grade 2 in which case patients have pain but are 
able to maintain adequate oral alimentation, or Grade 3 in which case patients 
cannot maintain adequate oral alimentation), the suggested treatments are 
topical analgesic mouth treatments (i.e., local anesthetics such as benzocaine, 
butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or 
without topical corticosteroids, such as triamcinolone oral paste 0.1% 
(Kenalog in Orabase®). For intolerable grade ≥ 2 stomatitis/oral 
mucositis/mouth ulcers, everolimus will be held, and restarted with a dose 
reduction by 1 dose level after recovery from toxicity to grade 1 or less.  If the 
patient is off drug for greater than or equal to 3 weeks for everolimus and 
greater than or equal to 8 weeks for bevacizumab, they will be permanently 
removed from treatment. 
3. Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend 
to worsen mouth ulcers. It is preferable to avoid these agents. 
4. Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong 
inhibition of everolimus metabolism, thereby leading to higher everolimus 
exposures. Therefore, topical antifungal agents are preferred if an infection is 
diagnosed. Similarly, antiviral agents such as acyclovir should be avoided 
unless a viral infection is diagnosed. 
Note: Stomatitis/oral mucositis should be appropriately graded using the 
functional grading given on the NCI-CTC for adverse events, version 4.0. 
 


 
 
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6.1.2  Management of hyperlipidemia and hyperglycemia 
Treatment of hyperlipidemia should take into account the pre-treatment status and 
dietary habits.  Blood tests to monitor hyperlipidemia must be taken in the fasting 
state. Grade 2 hypercholesterolemia (> 300 - 400 mg/dL or 7.75 – 10.34 mmol/L) 
or Grade 2 hypertriglyceridemia (> 300 – 500 mg/dl, or > 3.42 – 5.7 mmol/L) 
should be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase 
inhibitor (e.g., atorvastatin, pravastatin) or appropriate lipid-lowering medication, 
in addition to diet. Patients should be monitored clinically and through serum 
biochemistry for the development of rhabdomyolysis and other adverse events as 
required in the product label/data sheets for HMG-CoA reductase inhibitors. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity 
manifested by rhabdomyolysis, markedly elevated creatine kinase (CPK) levels 
and myoglobinuria, acute renal failure and sometimes death. The risk versus 
benefit of using this therapy should be determined for individual patients based on 
their risk of cardiovascular complications of hyperlipidemia.  Grade 4 
hypercholesterolemia (> 500 mg/dl [12.92 mmol/L], hold everolimus until 
cholesterol is 500 < mg/dl [12.92 mmol/L.  If triglycerides > 700 - 1,000, and 
HDL is low, consider fibrate or niacin. For triglycerides > 10x ULN, hold 
everolimus while instituting fibrate or niacin therapy until triglycerides are < 10x 
ULN. 
 
Grade 3 hyperglycemia has been observed in patients receiving everolimus 
therapy. In many cases the affected patients had an abnormal fasting glucose at 
baseline. Based on this finding, it is suggested that optimal glucose control should 
be achieved before starting a patient on everolimus and should be monitored 
during everolimus therapy. 
 
6.1.3  Management of non-infectious pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of 
non-infectious pneumonitis (including interstitial lung disease) have also been 
described in patients taking everolimus. Some of these have been severe and on 
rare occasions, a fatal outcome was observed.  
A diagnosis of non-infectious pneumonitis should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as hypoxia, 
pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other 
non-medicinal causes have been excluded by means of appropriate investigations. 
Patients should be advised to report promptly any new or worsening respiratory 
symptoms.  
Patients who develop radiological changes suggestive of non-infectious 
pneumonitis and have few or no symptoms may continue everolimus therapy 
without dose alteration.  Dose modifications and retreatment are described in 
Table 3 below. 
 


 
 
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Table 3: Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
Everolimus Dose 
Adjustment 
Grade 1 
CT scans with lung windows and 
pulmonary function testing including: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat chest x-ray/CT 
scan every 2 Cycles until return to 
baseline. 
No specific therapy is 
required 
Administer 100% of 
everolimus dose. 
Grade 2 
CT scan with lung windows and 
pulmonary function testing including: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat each subsequent 
Cycle until return to baseline. Consider 
bronchoscopy *  
Symptomatic only. 
Prescribe 
corticosteroids if 
cough is troublesome. 
Reduce everolimus dose until 
recovery to ≤ Grade 1. 
Everolimus may also be 
interrupted if symptoms are 
troublesome. After recovery to 
< grade 1, resume treatment at 
the next lower dose level (see 
Table 1 above).  Patients will 
be withdrawn from treatment 
if they fail to recover to ≤ 
Grade 1 within 3 weeks. 
Grade 3 
CT scan with lung windows and 
pulmonary function testing including: 
spirometry, DLCO, and room air O2 
saturation at rest; Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is recommended * 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Hold treatment until recovery 
to ≤ Grade 1. May restart 
protocol treatment within 2 
weeks at the next lower dose 
level (see Table 1 above) if 
evidence of clinical benefit. 
Patients will be withdrawn 
from the study if they fail to 
recover to ≤ Grade 1 within 2 
weeks.  
Grade 4 
CT scan with lung windows and required 
pulmonary function testing includes: 
spirometry, DLCO, and room air O2 
saturation at rest. Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is recommended *. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage should be considered (grade 2) or is recommended (grade 3 or 4). 
For any grade infection should be ruled out prior to prescribing corticosteroids. 
 
6.1.4  Management of Selected Toxicities 
Infection - Patients who develop a grade 4 everolimus-related infection, or 
pneumocystis carinii pneumonia will be removed from protocol therapy.  Patients 
with seasonal upper respiratory tract infections are excluded.  
Allergy – Patients with grade 4 allergic reaction, including rash, will be removed 
from protocol treatment.  Patients that come off study for allergy can be replaced.  
Hypertension - Patients who develop grade 4 everolimus-related hypertension will 
be removed from protocol therapy.  
Renal Function - If serum creatinine increases to greater than 1.5 X upper limit of 
normal for age, a creatinine clearance or GFR should be obtained.  If the 


 
 
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creatinine clearance or GFR is <75% of normal for age, the patient will be 
removed from protocol therapy. 
 
All interruptions or changes to study drug administration must be recorded. It will 
be documented whether or not each patient completed the clinical study. If for any 
patient either study treatment or observations were discontinued the reason will be 
recorded.  Reasons that a patient may discontinue participation in a clinical study 
are listed in Section 5.3. 
 
6.2 
Interruption or discontinuation of treatment with bevacizumab 
 
Note:  There will be no dose reduction for bevacizumab.  Treatment should be 
interrupted or discontinued for certain adverse events, as described below 
 
Note:  If bevacizumab is interrupted for ANY reasons for > 8 weeks (unless 
otherwise specified), the patient should discontinue bevacizumab therapy on 
protocol. 
 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Allergic reactions,  
or  
Acute infusion 
reactions/ cytokine 
release syndrome or 
Anaphylaxis 
Grade 1-2 
 
 
Infusion of bevacizumab should be interrupted for subjects who develop 
dyspnea or clinically significant hypotension.  
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.  
Subjects who experience bronchospasm (regardless of the grade) should 
discontinue bevacizumab 
Grade 3-4 
Discontinue bevacizumab 
Thromboembolic 
Event 
(Arterial); 
arterial  
ischemia  
- Cardiac 
ischemia 
- Myocardial 
infarction 
- CNS ischemia 
(TIA, CVA) 
- - any peripheral 
or visceral 
arterial ischemia 
/ thrombosis 
Grade 2 ( if new 
or worsened 
since 
bevacizumab 
therapy) 
Discontinue bevacizumab 
 
Grade 3-4 
 
 


 
 
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Thromboembolic 
event (Venous) 
 
Grade 3 
OR 
asymptomatic 
Grade 4 
 
 Hold bevacizumab treatment.  If the planned duration of full-dose 
anticoagulation is < 2weeks, bevacizumab should be held until the 
full-dose anticoagulation period is over. 
 If the planned duration of full-dose anticoagulation is > 2 weeks, 
bevacizumab may be resumed during full-dose anticoagulation IF all 
of the criteria below are met: 
- 
The subject must not have pathological conditions that carry high 
risk of bleeding (e.g. tumor involving major vessels or other 
conditions) 
- 
The subject must not have had hemorrhagic events while on study 
- 
The subject must on stable dose of heparin or have an in-range 
INR (usually 2-3) on a stable dose of warfarin prior to restarting 
bevacizumab. 
 
 If thromboemboli worsen/recur upon resumption of study therapy, 
discontinue bevacizumab 
 
Grade 4 
(symptomatic) 
Discontinue bevacizumab 
Hypertension (see 
also table below for 
details) 
 
Treat with anti-hypertensive medication as needed.  The goal of BP control should be 
consistent with general medical practice including confirming that BP is elevated across 
three separate measurements on three separate days and all other contributing factors have 
been addressed (i.e. pain, anxiety).] 
Grade 1 
(SBP 120-139 
mmHg or 
DBP80-89 mm 
Hg) 
Consider increased BP monitoring; start anti-hypertensive medication if 
appropriate 
Grade 2 
asymptomatic 
(SBP 140-159 
mmHg or DBP 
90-99 mm Hg) 
Begin anti-hypertensive therapy and continue bevacizumab 
· Grade 2 
symptomatic 
(SBP 140-159 
mmHg or 
DBP 90-99 
mm Hg) 
- Grade 3 
(> SBP 160 
mmHg or > 
DBP 100 
mmHg 
 Start or adjust anti-hypertensive medication 
 Hold bevacizumab until symptoms resolve AND BP < 160/90mmHg* 
 
Grade 4 
Discontinue bevacizumab 
Heart failure of LV 
dysfunction 
Grade 3  
Discontinue bevacizumab  
Grade 4 
Discontinue bevacizumab  
Proteinuria 
 
[Proteinuria should be monitored by urine analysis for urine protein creatinine (UPC) ratio 
prior to every other dose of bevacizumab]  If dipstick shows 2+ proteinuria, 24-hour urine 
protein should be obtained] 
UPC ratio  
< 3.5 or 24-h 
Continue bevacizumab 


 
 
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urine protein < 
2 gm 
UPC ratio  
> 3.5 or 24-h 
urine protein > 
2 gm 
Hold bevacizumab until UPC recovers to < 3.5 or 24-h urine protein < 2 
gm. Discontinue bevacizumab if urine protein does not recover to < 2 
after 8 weeks or bevacizumab interruption.   If proteinuria recurs 
discontinue bevacizumab permanently 
Grade 4 or 
nephrotic 
syndrome 
Discontinue bevacizumab  
Hemorrhage 
(CNS or 
pulmonary) 
Grade 2-4 
Discontinue bevacizumab  
Hemorrhage (any 
other organ 
system) 
Grade 1 
 Patients receiving full-dose anticoagulation should discontinue 
bevacizumab. 
 For patients not on full-dose anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- 
the bleeding has resolved and Hb is stable 
- 
there is no bleeding diathesis that would increase the risk of 
therapy 
there is no anatomic or pathologic condition that could increase the risk of 
hemorrhage recurrence 
Grade 3  
 
 Patients receiving full-dose anticoagulation should discontinue 
bevacizumab. 
 For patients not on full-dose anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- 
the bleeding has resolved and Hb is stable 
- 
there is no bleeding diathesis that would increase the risk of 
therapy 
- 
there is no anatomic or pathologic condition that could increase 
the risk of hemorrhage recurrence. 
 Patients who experience recurrence of grade 3 hemorrhage should 
discontinue study therapy. 
Grade 4 
Discontinue bevacizumab permanently 
Platelet count 
decreased 
Grade 1-2 
Less than lower 
limit of 
institutional 
normal down to 
50,000 
 Hold bevacizumab until resolution of platelet count to greater than or 
equal to 100,000 
 Monitor for bleeding episodes 
 Weekly platelet evaluation until platelet count is greater than 100,000 
Grade 3-4 
Less than 
50,000 
 Discontinue bevacizumab if low platelet count is attributed as 
possibly, probably, or definitely related to study drug 
 Discontinue bevacizumab until recovery to greater than or equal to 
institutional normal if attributed as not related or unlikely to be related 
RPLS (Reversible Posterior 
Leukoencephalopathy syndrome or 
PRES (Posterior Reversible 
Encephalopathy Syndrome) 
Discontinue bevacizumab permanently upon diagnosis of RPLS   
Wound dehiscence requiring medical 
or surgical intervention 
Discontinue bevacizumab  
Perforation (GI, or any other organ) 
Discontinue bevacizumab 
Fistula (GI, pulmonary or any other 
organ) 
Discontinue bevacizumab 


 
 
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Bowel obstruction 
G2 requiring 
medical 
intervention 
 Hold bevacizumab until complete resolution  
 
G3-4 
 Hold bevacizumab until complete resolution 
 If surgery is required, patient may restart bevacizumab after full 
recovery from surgery, and at investigator’s discretion 
Other unspecified 
bevacizumab-
related AEs (except 
controlled 
nausea/vomiting). 
Grade 3 
 Hold bevacizumab until symptoms resolve to < grade 1 
Grade 4 
 Discontinue bevacizumab 
 Upon consultation with the study chair, resumption of bevacizumab 
may be considered if a patient is benefiting from therapy, and the G4 
toxicity is transient, has recovered to < grade 1 and unlikely to recur 
with retreatment. 
+ Patients of childbearing age whom develop grade >2 toxicity based on CTCAE for irregular menstruation attributed to 
bevacizumab as > possible can remain on treatment with consent of the patient regarding long term risk for fertility and under the 
discretion of the study PI.  
 
Specific guidelines for hypertension grading and management are provided below.   
 
Hypertension in adults* 
 
[Treat with anti-hypertensive medication as needed.  The goal of BP control should 
be consistent with general medical practice] including confirming that BP is elevated 
across three separate measurements on three separate days and all other contributing 
factors have been addressed (i.e. pain, anxiety).] 
Grade 1  
Consider increased BP monitoring 
Grade 2 asymptomatic 
but diastolic BP < 100 
mmHg 
Begin anti-hypertensive therapy and continue 
bevacizumab 
-Grade 2-3 
Symptomatic OR 
-Diastolic 
BP 
> 
100 
mmHg  
Hold bevacizumab should until symptoms resolve AND 
BP < 160/90mmHg* 
 
Grade 4 
Discontinue bevacizumab permanently 
*Current CTCAE version 4 definitions used by CTEP: 
 
Grade 1: Prehypertension (systolic BP 120 - 139 mm Hg or diastolic BP 80 - 89 mm Hg); intervention 
not indicated 
 
Grade 2: recurrent or persistent (>24 hrs); symptomatic increase by > 20 mm Hg (diastolic) or to  
 
> 140/90 mm Hg if previously WNL; monotherapy indicated Pediatric: recurrent or persistent (>24 
hrs) BP > ULN; monotherapy  
 
Grade 3: more than one drug or more intensive therapy than previously used indicated 
 
Grade 4: life threatening consequences (e.g. malignant hypertension, transient or permanent neurologic 
deficit, hypertensive crisis); urgent intervention indicated 
 
In addition to the toxicities listed above, bevacizumab will be discontinued 
if it is likely related to a persistent ( 3 weeks) NCI-CTCAE version 4 
Grade 3 or 4 adverse event or any other significant adverse event that 
compromises the subjects’ ability to participate in the study.  
Any toxicity associated or possibly associated with bevacizumab treatment 
should be managed according to standard medical practice.   
Discontinuation of bevacizumab will have no immediate therapeutic effect. 
Bevacizumab has a terminal half-life of 21 days; therefore, its 


 
 
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discontinuation results in slow elimination over several months. There is no 
available antidote for bevacizumab.  
If bevacizumab is held or discontinued due to toxicity, patients should 
continue the rest of the regimen provided that patients have no toxicities that 
require dose interruption or dose modification of other agents of the 
regimen.   
Patients should be assessed clinically for toxicity prior to, during, and after 
each infusion. If severe bevacizumab-related toxicity, such as visceral 
perforation, aortic dissection, or nephritic syndrome, occurs at any time 
during the study, treatment with bevacizumab should be discontinued.  
Bevacizumab will be withheld or discontinued for its related toxicities, but 
not dose-reduced.  
 
Ovarian Failure/Irregular Menstruation: 
Ovarian failure, defined as amenorrhea lasting 3 or more months with 
follicle-stimulating hormone (FSH) elevation (≥ 30 mIU/mL), has recently 
been shown to be associated with the use of bevacizumab in patients with 
various solid tumor receiving bevaciumab in combination with cytotoxic 
chemotherapies.  Specifically, the incidence of ovarian failure was increased 
in patients receiving adjuvant bevacizumab plus mFOLFOX compared to 
mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, 
resumption of menses and an FSH level < 30 mIU/mL was demonstrated in 
22% (7/32) of these women.   
The CTCAE grading of irregular menstruation is: 
 
grade 1: intermittent menses with skipped menses for no more than 1-3 
months,  
 
grade 2: intermittent menses with skipped menses for more than 4-6 
months, and,  
 
grade 3: persistent amenorrhea for more than 6 months.   
All patients enrolled on this study of childbearing potential are notified of 
the risk associated with bevacizumab and the fact that the long term effects 
of bevacizumab exposure on fertility are unknown.  If patients develop > 
grade 2 irregular menstruation that is > possible in its attribution to 
bevacizumab, they are permitted to stay on drug despite this adverse event 
as long as the local investigator and study PI have confirmed with the patient 
the potential short and long term risks to fertility by continuing bevacizumab 
and that the patient wishes to stay on study drug despite these risks. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 


 
 
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For this study, all grade 3 and 4 clinical adverse events which occur after enrollment and 
up to 30 days after the last dose of study medication must be recorded in the appropriate 
case report form (CRF).  Grade 1 and 2 adverse events judged to be clinically significant 
(for example grade ≥1 mucositis, hypertension, pneumonitis) by the treating physician 
should also be recorded in the appropriate CRF.  Guidelines for the reporting of 
laboratory abnormalities are described in section 7.6.  
 
Serious Adverse Events (SAEs), as defined below, should be reported in an expedited 
fashion as per section 7.8.  All SAEs should be reported at the participating sites 
according to their institutional guidelines. 
 
7.1  
Definition of Adverse Event (AE) 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the investigational 
product.  Pre-existing conditions which worsen during a study are to be reported 
as AEs. 
 
7.2  
CTCAE term (AE description) 
 
The descriptions found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  A copy 
of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
 
7.3  
Drug-Adverse Event relationship 
 
The causality relationship of study drug to the adverse event will be assessed by 
the investigator as either:  Definite, Probable, Possible, Unlikely, or Unrelated .  
Attributions can be revised, when further information becomes available.  
Definitions of relationship to study medication are as follows: 
 
Definite – The AE is clearly related to the study treatment.  
Probable – The AE is likely related to the study treatment.  
Possible – The AE may be related to the study treatment.  
Unlikely – The AE is doubtfully related to the study treatment.  
Unrelated – The AE is clearly NOT related to the study treatment.  
 
Additionally, adverse events should be categorized as expected or unexpected 
based on the Clinical Investigator Brochure or package insert.   


 
 
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The following criteria should be considered in order to assess the relationship as  
Yes:  
- Reasonable temporal association with drug administration 
- Known response pattern to suspected drug 
- Disappears or decreases on cessation or reduction in dose 
- Reappears on rechallenge 
 
The following criteria should be considered in order to assess the relationship as  
No: 
- It does not follow a reasonable temporal sequence from administration of the 
drug 
- It may readily have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject 
- It does not follow a known pattern of response to the suspected drug 
- It does not reappear or worsen when the drug is readministered 
 
7.4  
Definition of Serious Adverse Events (SAE) 
 
A serious adverse event is any adverse event that occurs at any dose and fulfils at 
least one of the following criteria: 
- is fatal; (results in death; NOTE: death is an outcome, not an event) 
- is life-threatening; (NOTE: the term "life-threatening" refers to an event in 
which the patient was at immediate risk of death at the time of the event; it 
does not refer to an event which could hypothetically have caused a death had 
it been more severe) 
- required in-patient hospitalization or prolongation of existing hospitalization; 
- results in persistent or significant disability/incapacity; 
- is a congenital anomaly/birth defect; 
- is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
 
Please note: 
 
- Related Serious Adverse Events MUST be collected and reported regardless of 
the time elapsed from the last study drug administration, even if the study has 
been closed.  
- Unrelated Serious Adverse Events must be collected and reported after study 
enrollment and for up to 30 days after the last dose of study medication. 
 
7.5   
Progression of Underlying Malignancy and Hospitalization  
 


 
 
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Progression of underlying malignancy is not reported as an adverse event if it is 
clearly consistent with the suspected progression of the underlying cancer.   
Hospitalization due solely to the progression of underlying malignancy should 
NOT be reported as a serious adverse event.   
If there is any uncertainty about an adverse event being due only to the disease 
under study, it should be reported as an AE or SAE. 
 
7.6 
Guidelines for Reporting of Laboratory Abnormalities as AEs /SAEs 
 
Any treatment-emergent abnormal laboratory result, which is clinically 
significant, i.e., meeting one or more of the following conditions, should be 
recorded as a single diagnosis on the adverse event page in the CRF: 
- Accompanied by clinical symptoms 
- Leading to a change in study medication (e.g. dose modification, interruption 
or permanent discontinuation 
- Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
Please note: any abnormal laboratory result fulfilling the criteria for a serious 
adverse event (SAE) should be reported as such, in addition to being recorded as 
an adverse event in the CRF. 
 
7.7 
Serious Adverse Event Reporting  
All serious adverse events should be submitted to SARC within 1 working day 
from the participating sites as detailed below. SARC is responsible to report the 
events within 1 working day to the trial PI, Novartis, and Genentech.  All SAEs 
should be reported at the participating sites according to their institutional 
guidelines. 
 
The site investigator must assess and record the relationship of each SAE to each 
specific study drug. If only limited information is initially available, follow-up 
reports are required and should be forwarded to SARC. SAEs must be reported on 
the MedWatch Form 3500A along with the completed Fax Coversheet and faxed 
to SARC. (See Operations Manual for SAE Fax coversheet). The original SAE 
Form must be kept on file at the study site. 
 
Complications or progression of the initial SAE must be reported as follow-up to 
the original episode within 24 hours of the investigator receiving the follow-up 
information.   
 


 
 
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7.8  
Pregnancy  
 
Females must be instructed to stop taking the study medication and immediately 
inform the investigator if pregnancy occurs after enrollment to the study. 
Pregnancies occurring up to 120 days after the completion of the study medication 
must also be reported to SARC.  SARC should report all pregnancies within 24 
hours of receipt of notification to Novartis. 
Any pregnancy that occurs during study participation should be reported. The 
pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any 
birth 
defects, 
congenital 
abnormalities, 
or 
maternal 
and/or 
newborn 
complications. 
 
7.9 
Follow-up of AEs   
 
After the discontinuation of therapy with everolimus and/or bevacizumab, 
continue to follow up AEs as follows: 
 
Related AEs:  Follow until one of the following occurs: 
- Resolved or improved to baseline 
- Relationship is reassessed as unrelated 
- Death 
- Start of new anti-cancer regimen 
- Investigator confirms that no further improvement can be expected 
- Clinical or safety data will no longer be collected, or final database closure 
 
Unrelated severe or life threatening AEs:  Follow until one of the following 
occurs: 
- Resolved or improved to baseline 
- Severity improved to grade 2 
-  Death 
-  Start of new anti-cancer regimen 
 
-  Investigator confirms that no further improvement can be expected 
-  Clinical or safety data will no longer be collected, or final database closure 
 
Grade 2 AEs judged to be clinically significant:  Follow as clinically indicated. 
The final outcome of each adverse event must be recorded on the CRF.  
 
7.10  Reporting of all Unanticipated Problems Involving Risk to Subjects or 
Others (UPIRTSOs) to the HRPO 


 
 
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The HRPO Reporting requirements ask only for UPIRTSOs to be reported:  “All 
unanticipated problems involving risk to subjects or others must be promptly 
reported by telephone (301-619-2165), by email (usarmy.detrick.medcom-
usamrmc.other.hrpo@mail.mil), or by facsimile (301-619-7803) to the HRPO.  A 
complete written report will follow the initial notification.  In addition to the 
methods above, the complete report can be sent to the US Army Medical 
Research and Materiel Command, ATTN:  MCMR-RP, 810 Schreider Street, Fort 
Detrick, Maryland  21702-5000.” 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1 
Everolimus (Afinitor®, Votubia®) 
The structural formula and other chemical and physical properties of everolimus 
are summarized below: 
 
 
 
Chemical name: 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-
dihydroxy-12-(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]- 
1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-
aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-
pentaone 
 
International non-proprietary name: Everolimus 
 
Molecular formula: C53H83NO14 
 
Molecular weight: 958.2 
 
Physical form: White to faintly yellow powder. Everolimus stabilized with 
butylated hydroxytoluene (BHT) is amorphous, and contains 0.2% BHT as an 


 
 
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antioxidant. 
 
Clinically: The drug substance, everolimus, contains 15 asymmetric carbon 
atoms and 4 substituted double bonds. The configuration of the asymmetric 
carbon atoms and the double bonds are guaranteed by the microbial origin of 
rapamycin, the starting material of the synthesis, and by the X-ray analysis 
performed on crystalline everolimus. The configuration at carbon 40 is not 
changed by the chemical derivatization that converts rapamycin into everolimus.  
 
8.1.1 Preparation and administration 
 
Tablets: For this trial: 2.5 mg, 5 mg, and 10 mg tablets will be provided. 
 
8.1.2 Formulation, packaging and labeling 
 
All formulations are based on a everolimus solid dispersion intermediate that was 
selected on the basis of the chemical stability of the active ingredient 
and properties allowing for a good in vivo performance. 
 
Everolimus is provided as tablets: 2.5 mg, 5 mg, and 10 mg.  
 
Composition/ excipients: Tablets: butylhyroxytoluene/butylated hydroxytoluene 
(BHT), magnesium stearate, lactose monohydrate, hypromellose/hydroxypropyl 
methylcellulose, crospovidone, lactose anhydrous. The excipients comply with 
the requirements of the applicable compendial monographs (Ph. Eur., USP/NF). 
 
Stability: Immediate release tablets: Current stability data permit a shelf life of 36 
months when stored below 30°C and protected from light and moisture.  
 
8.1.3 Availability 
 
Immediate release:  Tablets: 2.5 mg, 5 mg and 10 mg. 
 
8.1.4 Agent ordering 
 
Everolimus for this trial will be provided by Novartis. Details will be provided in 
the Operations Manual. 
 
8.1.5 Agent accountability 
 
Accountability and patient compliance will be assessed by maintaining adequate 
drug dispensing and return records.  Compliance with individual patient dosing is 
assured as the drug is administered orally and subjects will be asked to keep a 
daily diary of the time and dose of drug ingested (Appendix III).  


 
 
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Accurate records must be kept for each study drug provided by the sponsor. The 
drug dispensing log must be kept current and contain the following information: 
-documentation of drug shipments received from the TBD (date received and 
quantity) 
-disposition of unused study drug not dispensed to patient 
-the identification of the patient to whom the study medication was dispensed 
-the date(s) and quantity of the study medication dispensed to the patient 
All supplies, including partially used or empty containers will be destroyed using 
the site’s local or institutional regulations. 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons e.g., cytotoxicity.  In these cases, it may 
be acceptable for investigational site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document 
verification is performed on the remaining inventory and reconciled against the 
documentation of quantity shipped, dispensed, returned and destroyed.  Written 
authorization must be obtained from SARC at study start up before destruction. 
Written documentation of destruction must contain the following: 
- Identity (batch numbers) of investigational product(s) destroyed 
- Quantity of investigational product(s) destroyed 
- Date of destruction (date discarded in designated hazardous container for 
destruction) 
- Method of destruction (the site must provide the sponsor with documentation 
of their institutional policy and procedures for handling and disposing of 
hazardous drugs) 
- Name and signature of responsible person (or company) who destroyed 
investigational products(s). 
 
8.1.6 Everolimus toxicities: Refer to the current Investigator’s Brochure  
 
Known Undesirable Side Effects of everolimus 
Information about adverse drug reactions is mainly based on data from four 
randomized, double-blind, placebo-controlled phase III trials: 
The most common adverse reactions (incidence ≥ 10% in at least one phase III 
trial and suspected to be related to treatment by the investigator) were in 
decreasing order: Stomatitis, rash, fatigue, diarrhea, infections, nausea, decreased 
appetite, anemia, dysgeusia, pneumonitis, hyperglycemia, weight decreased, 
pruritus, asthenia, peripheral edema, hypercholesterolemia, epistaxis, and 
headache. 


 
 
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The most common grade 3-4 adverse reactions (incidence ≥ 1/100 to <1/10 and 
suspected to be related to treatment by the investigator) were: stomatitis, anemia, 
hyperglycemia, 
fatigue, 
infections, 
pneumonitis, 
diarrhea, 
asthenia, 
thrombocytopenia, neutropenia, dyspnea, lymphopenia, proteinuria, hemorrhage, 
hypophosphatemia, rash, hypertension, aspartate aminotransferase (AST) 
increased, alanine aminotransferase (ALT) increased and pneumonia. 
ADRs are listed according to MedDRA system organ class. Within each system 
organ class, the adverse reactions are ranked by frequency, with the most frequent 
reactions first. In addition, the corresponding frequency category using the 
following convention is also provided for each adverse reaction: very common (≥ 
1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 
1/10,000 to < 1/1,000); very rare (< 1/10,000). 
Adverse reactions reported in oncology trials 
 
System Organ 
Class 
Very common 
Common 
Uncommon 
Rare 
Infections and 
infestations 
Infections1 
 
 
 
 
Blood and 
lymphatic system 
disorders 
Anemia 
Thrombocytopenia, 
neutropenia, 
leukopenia, 
lymphopenia 
Pancytopenia 
Pure red cell 
aplasia 
Immune system 
disorders 
 
 
Hypersensitivity 
 
Metabolism and 
nutrition 
disorders 
Decreased appetite, 
hyperglycemia, 
hypercholesterolemia 
Hypertriglyceridemia, 
hypophosphatemia, 
diabetes mellitus, 
hyperlipidemia, 
hypokalemia, 
dehydration 
 
 
Psychiatric 
disorders 
 
Insomnia 
 
 
Nervous system 
disorders 
Dysgeusia, headache 
Ageusia 
 
 
Cardiac disorders 
 
 
Congestive 
cardiac failure 
 
Vascular 
disorders 
 
Hemorrhage2 , 
hypertension 
Deep vein 
thrombosis 
 
Respiratory, 
thoracic and 
Pneumonitis3, 
epistaxis 
Cough, dyspnea 
Hemoptysis, 
pulmonary 
embolism 
Acute 
respiratory 
distress 


 
 
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mediastinal 
disorders 
syndrome 
Gastrointestinal 
disorders 
Stomatitis4, diarrhea, 
nausea 
Vomiting, dry mouth, 
abdominal pain, oral 
pain, dyspepsia, 
dysphagia 
 
 
Skin and 
subcutaneous 
tissue disorders 
Rash, pruritus 
Dry skin, nail 
disorder, acne, 
erythema, hand-foot 
syndrome 5 
 
Angioedema 
Musculoskeletal 
and connective 
tissue disorders 
 
Arthralgia 
 
 
Renal and urinary 
disorders 
 
Proteinuria, renal 
failure 
Increased 
daytime 
urination, acute 
renal failure 
 
Reproductive 
system and breast 
disorders 
 
Menstruation 
irregular6   
Amenorrhea6 
 
General disorders 
and 
administration 
site conditions 
Fatigue, asthenia, 
peripheral edema  
 
Pyrexia, mucosal 
inflammation 
Non-cardiac 
chest pain 
Impaired 
wound 
healing 
Investigations 
Weight decreased 
Aspartate 
aminotransferase 
increased, alanine 
aminotransferase 
increased, blood 
creatinine increased 
 
 
 
 
Acne 
 
 
1 Includes all reactions within the ‘infections and infestations’ system organ class including common: pneumonia and 
uncommon: herpes zoster, sepsis and isolated cases of opportunistic infections (e.g. aspergillosis, candidiasis, and 
hepatitis B) 
2 Includes different bleeding events not listed individually 
3 Includes common: pneumonitis, interstitial lung disease, lung infiltration; and rare: alveolitis, pulmonary alveolar, 
hemorrhage, and pulmonary toxicity 
4 Includes very common: stomatitis; common: aphthous stomatitis, mouth and tongue ulceration; uncommon: 
glossitis, glossodynia 
5 reported as palmar-plantar erythrodysaesthesia syndrome 
6 frequency is based upon number of women age 10 to 55 years of age in the safety pool 
 
 
Clinically relevant laboratory abnormalities 
In the pooled double-blind phase III safety database, the following new or worsening 
clinically relevant laboratory abnormalities were reported with an incidence of ≥1/10 
(very common, listed in decreasing frequency). 


 
 
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Hematology: hemoglobin decreased, lymphocytes decreased, white blood cells 
decreased, platelets decreased, and neutrophils decreased (or collectively as 
pancytopenia); 
Clinical chemistry: glucose (fasting) increased, cholesterol increased, triglycerides 
increased, AST increased, phosphate decreased, ALT increased, creatinine increased, and 
potassium decreased.  
Most of the observed abnormalities (≥ 1/100) were mild (grade 1) or moderate (grade 2). 
Grade 3/4 hematology and chemistry abnormalities include: 
Hematology: lymphocytes decreased, hemoglobin decreased (very common); neutrophils 
decreased, platelet count decreased, white blood cells decreased (all common). 
 
Clinical chemistry: glucose (fasting) increased (very common); phosphate decreased, 
potassium decreased, AST increased, ALT increased, creatinine increased, cholesterol 
(total) increased, triglycerides increased (all common). 
 
Warnings and Precautions: 
 
Non-infectious Pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including 
everolimus. Cases of non-infectious pneumonitis (including interstitial lung 
disease) have also been described in patients taking everolimus.  Some of these 
have been severe and on rare occasions, fatal outcomes have been observed. 
A diagnosis of non-infectious pneumonitis should be considered in patients 
presenting with non-specific respiratory signs and symptoms such as hypoxia, 
pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other 
non-medicinal causes have been excluded by means of appropriate investigations.  
Patients should be advised to report promptly any new or worsening respiratory 
symptoms. 
Patients who develop radiological changes suggestive of non-infectious 
pneumonitis and have few or no symptoms may continue everolimus therapy 
without dose alteration.  If symptoms are moderate, consideration should be given 
to interruption of therapy until symptoms improve.  The use of corticosteroids 
may be indicated. Everolimus may be reintroduced at 5 mg daily. 
For cases where symptoms of non-infectious pneumonitis are severe, everolimus 
therapy should be discontinued and the use of corticosteroids may be indicated 
until clinical symptoms resolve.  Therapy with everolimus may be re-initiated at a 
reduced dose of 5 mg daily depending on the individual clinical circumstances.  
Pneumonitis has also been reported at a reduced dose of everolimus. 
 
Infections 
Everolimus has immunosuppressive properties and may predispose patients to 
bacterial, fungal, viral or protozoan infections, including infections with 


 
 
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opportunistic pathogens. Localized and systemic infections, including pneumonia, 
other bacterial infections, invasive fungal infections, such as aspergillosis or 
candidiasis and viral infections including reactivation of hepatitis B virus, have 
been described in patients taking everolimus95,96. Some of these infections have 
been severe (e.g. leading to respiratory or hepatic failure) and occasionally have 
had a fatal outcome. 
Physicians and patients should be aware of the increased risk of infection with 
everolimus. Treat pre-existing infections prior to starting treatment with 
everolimus. While taking everolimus, be vigilant for symptoms and signs of 
infection; if a diagnosis of infection is made, institute appropriate treatment 
promptly and consider interruption or discontinuation of everolimus. If a 
diagnosis of invasive systemic fungal infection is made, discontinue everolimus 
and treat with appropriate antifungal therapy. 
Patients with positive results of HBV-DNA and/or HBsAg at screening should 
begin a prophylaxis treatment for 1-2 week prior to beginning everolimus therapy. 
Patients should have HBV-DNA monitored frequently throughout the course of 
everolimus therapy for signs of hepatitis reactivation. 
 
If a diagnosis of invasive systemic fungal infection is made, discontinue 
everolimus and treat with appropriate antifungal therapy. 
 
Hypersensitivity reactions  
Hypersensitivity reactions manifested by symptoms including, but not limited to, 
anaphylaxis, dyspnea, flushing, chest pain or angioedema (e.g. swelling of the 
airways or tongue, with or without respiratory impairment) have been observed 
with everolimus. 
 
Oral ulceration 
Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with 
everolimus. In such cases topical treatments are recommended, but alcohol- or 
peroxide containing mouthwashes should be avoided as they may exacerbate the 
condition. Antifungal agents should not be used unless fungal infection has been 
diagnosed. 
 
Renal Failure Events 
Cases of renal failure (including acute renal failure), some with fatal outcome, 
occurred in patients treated with everolimus. Monitor renal function of patients 
particularly in situations where patients have additional risk factors that may 
further impair renal function.   
Laboratory tests and monitoring 
 
Renal Function 
Elevations of serum creatinine and proteinuria, usually mild, have been reported 
in clinical trials. Monitoring of renal function, including measurement of blood 


 
 
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urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior 
to the start of everolimus therapy and periodically thereafter. 
 
Blood glucose 
Hyperglycemia has been reported in clinical trials. Monitoring of fasting serum 
glucose is recommended prior to the start of everolimus therapy and periodically 
thereafter. Optimal glycemic control should be achieved before starting a patient 
on everolimus.  
 
Hematologic parameters 
Decreased hemoglobin, lymphocytes, platelets and neutrophils have been reported 
in clinical trials. Monitoring of complete blood count is recommended prior to the 
start of everolimus therapy and periodically thereafter. 
 
Hepatic Impairment 
Everolimus exposure was increased in patients with mild (Child-Pugh A), 
moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment.   
Everolimus is not recommended for use in postmenopausal women with hormone 
receptor positive advanced breast cancer, or in patients with advanced 
neuroendocrine tumors of gastrointestinal, lung, or pancreatic origin or advanced 
renal cell carcinoma with severe hepatic impairment (Child-Pugh C) unless the 
potential benefit outweighs the risk.  Everolimus is not recommended in patients 
with SEGA with severe hepatic impairment, (Child-Pugh class C). 
 
Vaccinations 
The use of live vaccines and close contact with those who have received live 
vaccines should be avoided during treatment with everolimus.  Examples of live 
vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella, and TY21a typhoid vaccines. 
 
8.2 
Bevacizumab 
 
Chemical name and identification:  
Recombinant humanized monoclonal anti-VEGF antibody (rhuMAB VEGF) 
Classification: Recombinant humanized monoclonal antibody 
Mechanism of Action:  
Inhibition of vascular endothelial growth factor (VEGF) resulting in 
inhibition of angiogenesis. 
Approximate Solubility: 0.19 mg/100 mL in 0.1 N HCl, 453 mg/100 mL in 
Ethanol, and 2971 mg/100 mL in PEG 400. 
 
8.2.1 How Supplied:  


 
 
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Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid 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. 
 
8.2.2 Agent Ordering: 
 
Bevacizumab for this trial will be provided by Genentech.  For agent ordering, see 
Operations Manual.   
 
8.2.3 Agent Accountability 
See section 8.1.5 
8.2.4 Preparation 
 
Vials contain no preservatives and are intended for single use only.  Do not 
freeze the product. Do not shake bevacizumab during handling or 
preparation for clinical use. 
 
An amount of bevacizumab needed to prepare a dose of 10 mg/kg (patient’s 
body weight) should be withdrawn from one or more vials and diluted in a 
total volume of 0.9% Sodium Chloride Injection, USP, (qs.) 100 mL. 
 
8.2.5 Storage 
 
Bevacizumab must be stored under refrigeration at 2°–8°C (36°–46°F) upon 
receipt and should remain refrigerated until just prior to use.  DO NOT 
FREEZE.  DO NOT SHAKE.    
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE 
USE ONLY.  Vials used for 1 subject may not be used for any other subject.  
Once study drug has been added to a bag of sterile saline, the solution must 
be administered within 8 hours. 
 
8.2.6 Preparation 
 
Intact vials bear the manufacturer’s expiration dating and are stable until 
that date if stored at 2°–8°C.  Partially used vials should be discarded 
because the product does not contain an antimicrobial preservative.  
Bevacizumab should be diluted only with 0.9% Sodium Chloride Injection, 
USP (0.9%NS).  Diluted bevacizumab solutions are stable in both 


 
 
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polyvinylchloride (PVC) and polyolefin containers.  No significant changes 
were observed in protein concentration, pH, turbidity, or potency after 
bevacizumab dilution with 0.9% NS to concentrations of 0.9, 2.25, 3, 6.6, 
7.5, and 16.5 mg/mL and storage for 24 hours in commercial PVC and 
polyolefin containers at 30°C.  No changes were observed with respect to 
protein concentration, turbidity, or potency for the undiluted drug product 
(25 mg/mL) and after bevacizumab dilution with 0.9% NS to 1 mg/mL and 
12.5 mg/mL and storage for 24 hours in non-PVC, polyolefin bags at 5°C 
(41°F) and 30°C (86°F).  
 
8.2.7 Method of Administration:   
 
Bevacizumab will be administered intravenously through a secondary IV set 
piggybacked above the infusion control device (pump) into a primary IV set 
containing 0.9% NS.  When the bevacizumab drug product container is 
empty, 0.9% NS from the primary line should be used to flush the secondary 
set to complete bevacizumab delivery.  0.9% NS infusion should be 
continued to flush the primary IV set with a volume of fluid at least equal to 
the tubing priming volume, thus insuring complete drug delivery.  Note that 
this flush is not included in the infusion times below. The initial dose should 
be administered over a minimum of 90 minutes.  If no adverse reactions 
occur, the second dose should be administered over a minimum of 60 
minutes.  Again, if no adverse reactions occur, the third and subsequent 
doses should be administered over a minimum of 30 minutes.  If infusion-
related adverse reactions occur, subsequent infusions should be administered 
over the shortest period that was well tolerated. 
 
8.2.8 Bevacizumab toxicities:  Refer to current Investigator’s Brochure   
 
Bevacizumab toxicities are listed below and also described in Section 2.2. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 Version 2.3, August 1, 20131 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Blood and lymphatic system 
disorders - Other (renal thrombotic 
microangiopathy) 
  
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 


 
 
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CARDIAC DISORDERS 
  
 
 
Acute coronary syndrome2 
  
 
Cardiac disorders - Other 
(supraventricular 
arrhythmias)3 
 
 Cardiac disorders - Other 
(supraventricular arrhythmias)3 (Gr 3) 
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction2 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Colitis 
 
 Colitis (Gr 3) 
 
Constipation 
 
 Constipation (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula4 
  
 
Gastrointestinal hemorrhage5  
 Gastrointestinal hemorrhage5 (Gr 2) 
 
 Gastrointestinal obstruction6  
  
 
 
Gastrointestinal perforation7 
  
 
 
Gastrointestinal ulcer8 
  
 
Ileus 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Infusion related reaction 
 
 Infusion related reaction (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 3) 
 
Pain 
 
 Pain (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection9 
 
 Infection9 (Gr 3) 
 
 
Infections and infestations - Other 
(necrotizing fasciitis) 
  
 
Infections and infestations - 
Other (peri-rectal abscess) 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Injury, poisoning and procedural 
complications – Other 
(anastomotic leak)10 
  
 
Wound complication 
 
 Wound complication (Gr 2) 
 
Wound dehiscence 
 
 Wound dehiscence (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 3) 


 
 
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Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Cardiac troponin I increased  
  
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 3) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased  
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Musculoskeletal and 
connective tissue disorder -  
Other (bone metaphyseal 
dysplasia)11 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Osteonecrosis of jaw12 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular2 
  
 
Peripheral sensory 
neuropathy13 
 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
Syncope 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Hematuria 
 
 Hematuria (Gr 3) 
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (Nephrotic Syndrome) 
  
 
 
Urinary fistula 
 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
Reproductive system 
and breast disorders - 
Other (ovarian 
failure)14 
 
 
  
 
 
Vaginal fistula 
  
 
Vaginal hemorrhage 
 
 Vaginal hemorrhage (Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 3) 
 
 
Bronchopleural fistula 
  


 
 
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Bronchopulmonary hemorrhage 
  
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 3) 
 
Hoarseness 
 
 Hoarseness (Gr 3) 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 3) 
 
 
Vascular disorders - Other (arterial 
thromboembolic event)2,15 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in 
patients with a history of diabetes. 
 
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and atrial flutter. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-
abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other 
sites under the GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Jejunal perforation, Rectal perforation, Small intestinal perforation, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under 
the GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 


 
 
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10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large 
intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; 
Vaginal anastomotic leak 
 
11Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
12Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with 
bevacizumab treatment, the majority of whom had received prior or concomitant treatment with i.v. 
bisphosphonates. 
 
13Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and 
chemotherapy compared to chemotherapy alone.  
 
14Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone 
(FSH) elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX 
compared to mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses 
and an FSH level <30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term effects of 
bevacizumab exposure on fertility are unknown. 
 
15Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack and stroke. 
 
 
Also reported on bevacizumab (rhuMAb VEGF) trials but with the relationship to bevacizumab 
(rhuMAb VEGF) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(idiopathic thrombocytopenia purpura); Bone marrow hypocellular; Disseminated intravascular 
coagulation; Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac 
arrest; Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane 
perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; 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; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal 
tear; Retinopathy; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Chelitis; Colonic stenosis; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other 
(peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis;Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; 
Edema limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site 
reaction; Localized edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic 
failure; Hepatic necrosis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; 
Dermatitis radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone 
abnormal; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; 
Electrocardiogram QT corrected interval prolonged; Forced expiratory volume decreased; GGT increased; 
INR increased; Lipase increased; Lymphocyte count decreased; Serum amylase increased; Weight gain 


 
 
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METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone 
pain; Chest wall pain; Fibrosis deep connective tissue; Generalized muscle weakness; Head soft tissue 
necrosis; Joint effusion; Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and 
connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal and connective tissue disorder - 
Other (myasthenia gravis); Musculoskeletal and connective tissue disorder - Other (polymyalgia 
rheumatica); Neck pain; Pain in extremity; Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; 
Cerebrospinal fluid leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; 
Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; 
Leukoencephalopathy; Memory impairment; Nervous system disorders - Other (increased intracranial 
pressure); Paresthesia; Peripheral motor neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; 
Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; 
Renal and urinary disorders - Other (dysuria); Renal and urinary disorders - Other (ureterolithiasis); Renal 
hemorrhage; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary 
tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; 
Irregular menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress 
syndrome; Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Pulmonary hypertension; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (dry nares); Respiratory, 
thoracic and mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; 
Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin 
and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and subcutaneous tissue disorders - 
Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin induration; Skin ulceration; 
Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis  
 
 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
9. CORRELATIVE STUDIES 
 
9.1 
Laboratory correlative studies 
 
The following correlative studies are not mandatory for trial participation, and 
will only be performed in patients providing informed consent to all or any of the 
studies.   
After analyses, any remaining correlative samples may be retained in a SARC 
designated specimen bank with the consent of the patient. No personal health 


 
 
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information will be linked to the sample. The specimen will be marked with the 
patient study identification number only. 
 
9.1.1 Proangiogenic factors 
 
Proangiogenic factors will be analyzed in blood.  Blood (5 mL each) samples will 
be collected prior to treatment with everolimus and bevacizumab, and at the time 
of response evaluations prior to cycles 3 and 5, and if feasible, at the time of 
disease progression for determination of pro-angiogenic factors: VEGF1, 2, 
FGF1, 2, ephrin A, angiopoietin 2, IL8, PDGF. Details regarding the timing, 
collection, handling, and shipment of samples to be obtained are provided in the 
Operations Manual. 
 
9.1.2  Pharmacodynamic of everolimus 
 
Markers of the effect of everolimus S6K1 (p70s6 kinase) activity, eIF4E, eIF2, 
and AKT phosphorylation will be analyzed in peripheral blood mononuclear cells 
obtained prior to treatment with everolimus, and at the time of response 
evaluations prior to cycles 3 and 5, and, if feasible, at the time of disease 
progression. Details regarding the timing, collection, handling, and shipment of 
samples to be obtained are provided in The Operations Manual. 
 
9.1.3  Germline NF1  
 
One blood sample will be obtained prior to treatment with everolimus and 
bevacizumab to determine germline NF1 mutations in patients with a clinical 
diagnosis of NF1. This analysis will be performed in a CLIA approved laboratory. 
Details regarding informed consent, sample collection and shipment are provided 
in the Operations Manual.  
 
9.1.4  MRI 3-dimentional analysis 
 
To evaluate the utility of 3-dimentional MRI analysis for MPNST, MRIs obtained 
for disease evaluation at baseline, and as part of the response evaluation will be 
analyzed using 3D MRI in addition to 1D, and 2-D analysis. Details regarding the 
handling and shipment of MRI studies are provided in the Operations Manual. 
 
 
 
10. STUDY EVALUATIONS AND STUDY CALENDAR 
 
10.1 
Screening studies 
 
The following procedures will be performed during the screening period within 7 
days prior to enrollment of this trial unless otherwise specified: 
 
 
Informed consent  


 
 
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 
History/demographics 
 
Physical exam 
 
Vital signs: 
 
Height (first visit), pulse, blood pressure, respiration rate, oxygen 
saturation by pulse oximeter, temperature and weight. Blood pressure, 
pulse and respiration rate should be measured on patients after at least 3 
minutes in the sitting position. 
 
Performance Status (see Appendix I) 
 
Documentation of clinical findings of NF1 (Appendix V) 
 
Hematology:  
  
Hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and 
differential, PT, PTT.  
 
Serum Chemistry:  
 
Must include sodium, potassium, chloride, bicarbonate, calcium, 
phosphorous, FASTING glucose, creatinine, blood urea nitrogen, 
albumin, total protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline 
phosphatase, uric acid, and FASTING serum lipid profile (triglycerides, 
total cholesterol, HDL and LDL) 
 
*FASTING=12 hours prior to glucose testing and lipid testing 
 
Urinalysis:  
 
Standard urinalysis dipstick assessment (pH, protein, glucose, blood, 
ketones, and leukocytes) should be performed.  If the results demonstrate 
any potentially relevant abnormalities, the dipstick assessment must be 
supplemented with laboratory quantification.  If the site does not utilize 
dipsticks for assessment, the urine will be sent to the lab to be processed 
according to the institution's processes. 
 
Urine protein creatinine (UPC) ratio: 
 
 For UPC ratio > 0.5 a 24-hour urine should be obtained and the level 
should be less than 1000 mg for patient enrollment. 
Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion – 
a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm.  UPC 
ratio is calculated using one of the following formulas: 
- [urine protein]/[urine creatinine] – if both protein and creatinine are reported in 
mg/dL 
- [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in 
mmol/L 
 
Serum or urine pregnancy:  
 
Standard pregnancy tests will be given to all females of childbearing age 
within 7 days prior to starting treatment medication. 
 
   Echocardiogram or MUGA scan for patients who received an anthracyline 
prior to evaluation for this study.  
 
   Disease evaluation using appropriate test (CT and/or MRI) must be 
performed within 3 weeks of trial entry 
 
A detailed assessment of hepatitis B/C medical history and risk factors 
must be done for all patients at screening.  


 
 
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Testing for hepatitis B viral load and serologic markers: HBV-DNA, 
HBsAg, HBs Ab, and HBc Ab and HCV RNA PCR are required at 
screening for all patients in the following risk categories:  
o 
All patients who currently live in (or have lived in) Asia, Africa, 
Central and South America, Eastern Europe, Spain, Portugal, and 
Greece.   
o 
Patients with any of the following risk factors:  
 
known or suspected past hepatitis B infection,  
 
blood transfusion(s) prior to 1990,  
 
current or prior IV drug users,  
 
current or prior dialysis,  
 
household contact with hepatitis B infected patient(s),  
 
current or prior high-risk sexual activity,  
 
body piercing or tattoos,  
 
mother known to have hepatitis B 
 
history suggestive of hepatitis B infection, e.g., dark urine, 
jaundice, right upper quadrant pain. 
Patients with positive hepatitis B and/or hepatitis C test results must begin 
a course of antivirals 1-2 weeks prior to the first dose of everolimus (as 
outlined in Appendix IV). 
 
 
10.2 
On study evaluations 
 
The following procedures will be performed during the treatment period within 8 
days of the stated time point:  
 
 
History and physical:  
 
After cycles 1, 2, 3, and at the time of each evaluation (monthly) 
 
     Vital Signs: 
After cycles 1, 2, 3, and at the time of each evaluation (monthly): Height   
(first visit), pulse, blood pressure, respiration rate, oxygen saturation by 
pulse oximeter, temperature and weight. Blood pressure, pulse and 
respiration rate should be measured on patients after at least 3 minutes in 
the sitting position. 
 
Performance Status (see Appendix I): 
 
After cycles 1, 2, 3, and at the time of each evaluation (monthly) 
 
Hematology:  
 
After cycles 1, 2, 3, and at the time of each evaluation (monthly): 
Hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and 
differential, PT, PTT.   
 
Serum Chemistry:  
 
After cycles 1, 2, 3, and at the time of each evaluation (monthly): Must 
include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 


 
 
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FASTING glucose, creatinine, blood urea nitrogen, albumin, total protein, 
SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric 
acid, and FASTING serum lipid profile (triglycerides, total cholesterol, 
HDL and LDL). 
 
Urinalysis:  
 
After cycles 1, 2, 3, and at the time of each evaluation (monthly):  
 
Standard urinalysis dipstick assessment (pH, protein, glucose, blood, 
ketones, and leukocytes) should be performed.  If the results demonstrate 
any potentially relevant abnormalities, the dipstick assessment must be 
supplemented with laboratory quantification.  If the site does not utilize 
dipsticks for assessment, the urine will be sent to the lab to be processed 
according to the institution's processes. 
Urine protein creatinine (UPC) ratio (see Section 10.1). 
 
Echocardiogram or MUGA scan for patients who received an anthracyline 
prior to evaluation for this study, to be performed prior to every other 
treatment cycle (before cycles 3, 5, 7, 9, etc.). 
 
Disease evaluation using appropriate test (CT and/or MRI): Prior to cycles 
3, 5, 7, 9, etc. Tumor imaging should NOT be delayed, if possible, if a 
subject temporarily or permanently suspends study drug treatment for 
toxicity or non-compliance with administration of drug. In patients who 
experience a PR or CR confirmation of the response after 4 weeks should 
be performed, if feasible. 
 
Patients on antiviral prophylaxis treatment or positive HBV antibodies 
should be tested for HBV-DNA prior to every cycle to monitor for re-
activation. Patients with positive HCV RNA-PCR results at screening 
and/or a history of past infection (even if treated and considered ‘cured’) 
should have HCV RNA-PCR testing performed prior to every cycle to 
monitor for reactivation.  
 
Administration of study drug:  
An everolimus diary will be kept by the patient and/or proxy to document 
each dose of drug taken.  The diary will be reviewed after completion of 
cycles 1, 2, and 3, and at the time of each evaluation (monthly). 
 
Recording of adverse events:  
 
After each treatment cycle (monthly) 
 
Correlative studies: 
 
Blood sample for proangiogenic factors: 
Prior to treatment with everolimus and bevacizumab, and at the time of 
response evaluations prior to cycles 3 and 5 (see Operations Manual). 
 
Blood samples as marker for everolimus effect: 
Prior to treatment with everolimus and at the time of response evaluations 
prior to cycles 3 and 5 (see Operations Manual).  


 
 
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 
Blood sample for determination of NF1 mutation in individuals with NF1 
associated MPNSTs: One time point prior to treatment with everolimus 
and bevacizumab. (see Operations Manual).  
 
MRI studies for volumetric analysis: 
MRI studies performed for restaging purposes at the time points of 
response evaluations will be analyzed using volumetric MRI analysis in 
addition to standard 2-dimensional response evaluations (see Operations 
Manual). 
 
10.3 
End of treatment/off study evaluations 
The following studies should be performed, if feasible, at the time a patient is 
removed from the study: 
 
 
History and Physical exam 
 
Vital signs: 
 
Pulse, blood pressure, respiration rate, oxygen saturation by pulse 
oximeter, temperature and weight. Blood pressure, pulse and respiration 
rate should be measured on patients after at least 3 minutes in the sitting 
position. 
 
Performance Status (see Appendix I) 
 
Hematology:  
 
Hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and 
differential, PT, PTT.   
 
Serum Chemistry:  
 
Must include sodium, potassium, chloride, bicarbonate, calcium, 
phosphorous, FASTING glucose, creatinine, blood urea nitrogen, 
albumin, total protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline 
phosphatase, uric acid, and FASTING serum lipid profile (triglycerides, 
total cholesterol, HDL and LDL). 
 
Urinalysis:  
 
Standard urinalysis dipstick assessment (pH, protein, glucose, blood, 
ketones, and leukocytes) should be performed.  If the results demonstrate 
any potentially relevant abnormalities, the dipstick assessment must be 
supplemented with laboratory quantification.  If the site does not utilize 
dipsticks for assessment, the urine will be sent to the lab to be processed 
according to the institution's processes. UPC ratio (see Section 10.1) 
 
Patients on antiviral prophylaxis treatment or positive HBV antibodies 
should be tested for HBV-DNA. Patients with positive HCV RNA-PCR 
results at screening and/or a history of past infection (even if treated and 
considered ‘cured’) should have HCV RNA-PCR testing performed.  
 
Echocardiogram or MUGA scan for patients who received an anthracyline 
prior to evaluation for this study. 
 
Disease evaluation using appropriate test (CT and/or MRI). 
 


 
 
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Correlative studies: 
 Blood sample for proangiogenic factors: 
 If feasible, at the time of disease progression (see Operations Manual). 
 
 Blood samples as marker for everolimus effect: 
If feasible, at the time of disease progression (see Operations Manual).  
 
 
MRI studies for volumetric analysis: 
MRI studies performed for restaging purposes at the time points of 
response evaluations will be analyzed using volumetric MRI analysis in 
addition to standard 2-dimensional response evaluations (see Operations 
Manual). 
 
 
 


 
 
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10.4      Schedule of Evaluations 
 
Treatment Period 
 Off     
Study  
Cycle Number 
 
1(a) 
2(a) 
3(a) 
4(a)  
5(a) 
6 (a) (b) 
Study Week  
Screen 
(c) 
1 
2 
3 
4 
5 
6 
7 8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24  
Everolimus – To be orally 
administered by patient 
 
X X X X X X X X X 
X X X X X X X X X X X X X X X 
 
Bevacizumab  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Informed Consent/Assent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam 
with Vital signs (d) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Documentation of NF1 
Findings (f) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Everolimus Diary Review 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Performance Status (e) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC w/diff., Platelets PT, 
PTT  (g) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Serum Chemistry  (h) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urinalysis, UPC ratio  (i) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Urine or Serum Pregnancy 
Test  (j) 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis labs (k) 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Disease evaluation with 
appropriate radiographic 
studies (l) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA 
scan (m) 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pharmacodynamic Studies: 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X(n) 


 
 
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proangiogenic factors, 
markers of everolimus 
effect 
Genotyping for NF1 
MPNST  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI for 3-D Analysis  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X(n) 
Adverse Events  
 
Continuously throughout the study 
X 
Concomitant Medication  
 
Continuously throughout the study 
X 
a 
Evaluations obtained prior to the next cycle. Evaluations can be performed within 8 days of the requested time. 
b 
Patients who continue on study should have evaluations as shown in cycle 6 performed prior to each cycle 8, 10, 12, 14  etc. 
c 
All studies to determine eligibility must be performed within 1 week prior to enrollment unless otherwise indicated (See section 10.1). 
d 
Vital signs: Height (first visit only), pulse, blood pressure, respiratory rate, oxygen saturation by pulse oximeter, temperature and weight.  
Blood pressure, pulse and respiration rate should be measured on patients after at least 3 minutes in the sitting position.   
e 
See Appendix I for performance status criteria. 
f 
See Appendix V for documentation of findings of NF1. 
g 
Hematology: hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential, PT, PTT. 
h 
Serum Chemistry: must include sodium, potassium, chloride, bicarbonate, calcium, phosphorous, FASTING glucose, creatinine, blood urea 
nitrogen, albumin, total protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase, uric acid, and FASTING serum lipid 
profile (triglycerides, total cholesterol, HDL and LDL). Fasting = 12 hours prior to glucose testing and lipid testing. 
i 
Urinalysis: Standard urinalysis dipstick assessment (pH, protein, glucose, blood, ketones, and leukocytes) should be performed.  If the results 
demonstrate any potentially relevant abnormalities, the dipstick assessment must be supplemented with laboratory quantification.  If the site 
does not utilize dipsticks for assessment, the urine will be sent to the lab to be processed according to the institution's processes. 
j 
Standard pregnancy tests will be given to all females of childbearing age < 7 days prior to starting treatment medication, and subsequently as 
clinically indicated and following institutional guidelines. 
k 
For patients at risk prior to enrollment, and for patients on antiviral hepatitis prophylaxis prior to each subsequent cycle. See Appendix IV 
l 
Performed < 3 weeks prior to trial entry. Disease evaluation using appropriate test (CT and/or MRI) for volumetric analysis must be performed 
within 3 weeks of trial entry and prior to cycles 3, 5, 7, 9, etc. Tumor imaging should NOT be delayed, if possible, if a subject temporarily or 
permanently suspends study drug treatment for toxicity or non-compliance with administration of drug. 
m Required only for patients who received an anthracycline prior to enrollment on this study, performed < 3 weeks prior to trial entry.  
 n   At the time of disease progression (if feasible).


 
 
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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor effect – solid tumor 
 
11.1.1  Definitions  
Evaluable for toxicity:  Patients who have received at least one dose of study drug 
will be considered evaluable for toxicity from the time of their first dose of 
everolimus and bevacizumab until the last evaluation on trial. 
 
Evaluable for objective response:  
 
Measurable disease:  Measurable lesions are defined as those that can be 
accurately measured in at least two dimensions (longest diameter > 20 mm with 
conventional techniques or >10 mm using spiral CT scan). All tumor 
measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Any patient who is enrolled and receives at least one dose of everolimus and 
bevacizumab will be considered evaluable for response provided: (1) the patient 
demonstrates progressive disease or death while on protocol therapy; (2) the 
patient is observed on protocol therapy for at least one cycle and the tumor is not 
removed surgically prior to the time complete response or partial response is 
confirmed; or (3) the patient demonstrates a complete or partial response or stable 
disease as confirmed according to protocol criteria.  Patients who electively 
terminate therapy before receiving all bevacizumab doses and ≥ 70% of the 
required everolimus doses during the first treatment cycle and do not expire 
within 28 days from start of treatment will be replaced.  
 
11.1.2  Disease Parameters 
Measurable, bidimensional:    Malignant disease measurable in two dimensions by 
ruler with surface area determined by multiplying the longest diameter by the 
greatest perpendicular diameter.   
 
Index Lesions: Index lesions should be selected on the basis of their measurability 
in two dimensions and their suitability for accurate repeated measurements (by 
imaging techniques CT or MRI).  A sum of the product(s) of the longest diameter 
(LD) and greatest perpendicular diameter of all index lesions will be calculated 


 
 
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and reported as the baseline sum.   The baseline sum will be used as a reference 
by which to characterize the objective tumor response. 
 
Non-index Lesions: 
All other lesions (or sites of disease) including any 
measurable lesions over and above the index lesions should be identified as non-
index lesions and should also be recorded at baseline.  Measurement of these 
lesions is not required, but the presence or absence of each should be noted 
throughout follow-up. 
 
11.1.3  Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler.  
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 when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Conventional CT and MRI:  These techniques should be performed with cuts of 5 
mm or less in slice thickness contiguously.  This applies to tumors of the chest, 
abdomen, and pelvis.  Head and neck tumors and those of extremities may require 
specific protocols. 
 
11.1.4 WHO Response Criteria  
WHO response criteria will be used for this trial for several reasons: 
1) MPNSTs are typically complex non spherical tumors, and 2-dimensional 
measurements may thus better reflect changes in tumor size than 1-dimensional 
measurements (RECIST). 
2) The phase 2 trial of erlotinib, which will be used as a historical control for 
determination of time to progression, used WHO criteria. In order to allow for the 
closest comparison, this trial will therefore use WHO response criteria. 
 
11.1.4.1 
Evaluation of Index Lesions 
Complete Response (CR): Disappearance of all known disease, determined by 
two consecutive observations not less than 4 weeks apart. 
 
Partial Response (PR):  A > 50% decrease in the total tumor load of the lesions 
that have been measured to determine the effect of therapy not less than four 
weeks apart. The observations must be consecutive. 
 
Bidimensionally measurable: single lesion, > 50% decrease in tumor area 
(multiplication of longest diameter by the greatest perpendicular diameter); 


 
 
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multiple lesions, a 50% decrease in the sum of the products of the 
perpendicular diameters of the multiple lesions. 
 
In addition there can be no appearance of new lesions or progression of any 
lesion. 
 
Stable Disease (SD):  A 50% decrease in total tumor area cannot be established 
nor has a 25% increase in the size of one or more measurable lesions been 
demonstrated. 
 
Progressive Disease (PD):  A > 25% increase in the area of one or more 
measurable lesions or the appearance of new lesions.   
 
 
11.1.4.2 
Evaluation of Non-Index Lesions 
Complete Response (CR): Complete disappearance of all known disease for at 
least four weeks. 
Partial Response (PR): Estimated decrease in tumor area of > 50% for at least four 
weeks. 
Stable Disease (SD): No significant change for at least four weeks.  This 
includes stable disease, estimated decrease of < 50%, and lesions with estimated 
increase of < 25%. 
Progressive Disease (PD): Appearance of any new lesions not previously 
identified or an estimated increase of > 25% in existent lesions. 
 
Although a clear progression of “non-index” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the Principal 
Investigator. 
 
Evaluation of Best Overall Response 
 
Index 
Lesions 
Non-Index 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for 
this Category also 
requires: 
CR 
CR 
No 
CR 
> 4 weeks 
confirmation 
CR 
PR/SD 
No 
PR 
PR 
CR/PR/SD 
No 
PR 
SD 
CR/PR/SD 
No 
SD 
Documented at least 
once > 4 wks from 
baseline 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or 
CR 


 
 
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Any 
PD* 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-
index lesions may be accepted as disease progression. 
 
11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started, best response scan). 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
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.  
 
11.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of objective 
progression or death. 
 
12. DATA REPORTING/REGULATORY CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
 
12.1.1  Method 
 
A final study report describing the outcome of the trial will be created at the end 
of the study.  
 
12.1.2  Data Safety Monitoring and Medical Monitor 
 
SARC is responsible for the Data Safety Monitoring for this trial. SARC Clinical 
Trials Review Committee convenes monthly and will provide safety oversight for 
this trial.  The purpose of the Clinical Trials Review Committee is to review the 
status of the on-going SARC studies, which includes, but is not limited to: 
 
 Review of all safety data (Serious Adverse Events reported)  


 
 
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 Review of protocol deviations/violations 
 Review of study progress/accrual 
 Discussion of statistical aspects of all protocols 
 
The committee is chaired by the SARC Medical Officer, who is responsible for 
leading the meeting and providing medical oversight.  Attendance includes all 
Principal Investigators on active SARC studies, SARC Research Project 
Managers, SARC Chief Executive Officer, and a biostatistician. 
 
Safety oversight for this trial is also supported by the SARC Clinical Research 
Committee which is made up of senior sarcoma investigators and the SARC 
President and Chief Executive Officer.  This committee also convenes monthly.  
The medical officer updates the committee on the ongoing clinical trial status as 
well as any areas of concern particularly related to safety.  This committee 
provides an additional level of medical oversight for this trial. 
 
Dr. Okuno will also be the Medical Monitor for this study.  
 
The Medical Monitor is required to review all unanticipated problems involving 
risk to subjects or others, serious adverse events and all subject deaths associated 
with the protocol and provide an unbiased written report of the event.  At a 
minimum, the Medical Monitor must comment on the outcomes of the event or 
problem, and in the case of a serious adverse event or death, comment on the 
relationship to participation in the study.  The Medical Monitor must also indicate 
whether he/she concurs with the details of the report provided by the principal 
investigator.  Reports for events determined by either the investigator or Medical 
Monitor to be possibly or definitely related to participation and reports of events 
resulting in death must be promptly forwarded to the Genentech and Novartis. 
SARC will be responsible for forwarding reports to the SARC Medical Officer.  
 
In addition to the Medical Monitor role, Scott Okuno, MD will function as the 
Department of Defense required “Independent Research Monitor”.  The 
Independent Research Monitor will be responsible for evaluating any risks or 
concerns of the research in addition to overseeing the safety of the research and 
reporting observations/findings to the IRB of Record or a designated official.  The 
Independent Research Monitor will review all unanticipated problems involving 
risk to volunteers or others associated with the protocol and provide an unbiased 
written report of the event to the IRB of Record.  The Independent Research 
Monitor may discuss the research protocol with the investigators, interview 
human subjects, and consult with others outside of the study about the research.  
The Independent Research Monitor shall have authority to stop the research 
protocol in progress, remove individual human subjects from the study, and take 
whatever steps are necessary to protect the safety and well-being of human 
subjects until the IRB can assess the monitor’s report.  The Independent Research 


 
 
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Monitor is responsible for promptly reporting their observations and findings to 
the IRB. 
 
 
Independent Research Monitor functions may include: 
 
 
Observing recruitment and enrollment procedures and the consent process 
for individuals, groups or units,  
 
Overseeing study interventions and interactions,  
 
Reviewing monitoring plans and UPIRTSO reports;  
 
Overseeing data matching, data collection, and analysis 
 
At a minimum, the Independent Research Monitor: 
 
 
May discuss the research protocol with the investigators, interview human 
subjects, and consult with others outside of the study about the research;  
 
Shall have authority to stop a research protocol in progress, remove 
individual human subjects from a research protocol, and take whatever steps 
are necessary to protect the safety and well-being of human subjects until 
the IRB can assess the monitor’s report; 
 
Shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official and the HRPO. 
 
  
 
 
Participating study sites will be informed of findings on a regular basis and be 
provided with ample information to report to their local IRB in accordance with 
local site policies.  
 
The knowledge of any pending compliance inspection/visit by the FDA, OHRP, 
or other government agency concerning clinical investigation or research, the 
issuance of Inspection Reports, FDA Form 483, warning letters or actions taken 
by any Regulatory Agencies including legal or medical actions and any instances 
of serious or continuing noncompliance with the regulations or requirements will 
be reported immediately to USAMRMC ORP HRPO.  
 
12.1.3  Patient Accrual and Participating Centers 
 
There will be approximately 10 SARC and NF Consortium sites collaborating to 
accrue patients to this study.  We anticipate that accrual will take approximately 2 
years.   
 
This trial will be posted at ClinicalTrials.gov website.  
 
12.2 
Multi-institutional guidelines 
 


 
 
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The trial coordinating center (Operations Center) will be SARC.  Patients will be 
registered electronically via the study website, and adverse events (as defined in 
Section 7.0) will be reported to the operations center.  
 
IRB Approvals: 
SARC will be the Operations Center.  The protocol must be approved at the 
treating institution prior to enrolling patients.  Documentation of individual 
institutional IRB approval, for the current protocol must be provided to the SARC 
Operations Office prior to enrolling patients on the trial. In addition, 
documentation of approval of all protocol amendments and of yearly continuing 
review must be provided to the SARC Operations Office Research Project 
Manager to allow patient entry. The mailing address is: 
 
SARC 
24 Frank Lloyd Wright Drive, PO Box 406 
Ann Arbor, MI  48105 
Phone: 734-930-7600 
Fax: 734-930-7557 
Email: sarc@sarctrials.org 
 
As this trial receives funding by the US Army, approval of the protocol must be 
obtained from the USAMRMC ORP HRPO in addition to the institutional IRB 
prior to implementation.  Documentation of individual institutional IRB approval, 
for the current protocol must be provided to SARC at the Operations Center prior 
to enrolling patients on the trial. In addition, documentation of approval of all 
protocol amendments and of yearly continuing review must be provided to the 
Operations Center to allow patient entry.  SARC will submit these documents to 
the USAMRMC Office of Research Protections (ORP), Human Research 
Protections Office (HRPO).   
 
Major modifications to the research protocol and any modifications that could 
potentially increase risk to subjects must be submitted to the USAMRMC ORP 
HRPO for approval prior to implementation.  The USAMRMC ORP HRPO 
defines a substantive modification as a change in Principal Investigator, change or 
addition of an institution, elimination or alteration of the consent process, change 
to the study population that has regulatory implications (e.g. adding children, 
adding active duty population, etc.), significant change in study design (i.e. would 
prompt additional scientific review) or a change that could potentially increase 
risks to subjects. All other amendments will be submitted with the continuing 
review report to the USAMRMC ORP HRPO for acceptance.  A copy of the 
approved continuing review report and the local IRB approval notification will be 
submitted to the USAMRMC ORP HRPO as soon as these documents become 
available.  A copy of the approved final study report and local IRB approval 
notification will be submitted to the USAMRMC ORP HRPO as soon as these 
documents become available. 


 
 
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Amendments and Consents: 
SARC will be the Operations Center. IRB approval of the current protocol, 
protocol amendments, and yearly continuing review must be provided to the 
SARC Operations Office. In addition, a copy of the currently approved informed 
consent of each participating site will be kept on file at SARC.  SARC will submit 
these documents to the USAMRMC ORP HRPO. 
 
Patient Registration: 
Patient Registration will be centrally managed by the Operations Center 
electronically via the study website (see Section 4.2).  
 
Data Collection and Toxicity Reporting:  
Registration reports will be generated by the Operations Center to monitor patient 
accruals and completeness of registration data. Routine data quality reports will 
be generated to assess missing data and inconsistencies by the study coordinator. 
Any potential problems will be brought to the attention of the Principal 
Investigator for discussion and action. 
 
Access to the password protected study website will be limited to individuals 
involved in the clinical trial: SARC, Study PI, participating site PIs, and research 
nurses and data managers responsible for this trial.  
 
Shipment and receipt of specimens and imaging studies sent for correlative 
studies will be entered on the study website and can thus be tracked.  
 
MRI studies will be sent on CD or optical disk with patient identifiers to the NCI 
POB. CDs and optical disks will be locked in a filing cabinet with access only to 
authorized personnel. Imaging studies will be analyzed on 2 Sun Workstations, 
which are password protected, and limit access to authorized personnel.  
 
A monthly phone conference will be held between the Principal Investigator, the 
Operations Center, associate investigators, and participating sites to address QA 
issues, accrual, observed toxicities, and compliance with submission of required 
studies.  
 
Adverse Events reporting will be performed as outlined in Section 7.0. 
 
12.3 
Data and Participating Institution Monitoring 
 
Approximately 10% of the patients will be monitored on site, every 3 years. 
Selected patient charts as well as the participating institution’s Standard Operating 
Procedures may be monitored at the time of the visit.  Data from participating 
institutions should be available when the protocol is monitored.  The institutional 
principal investigator is responsible for having all records and data for all patients 


 
 
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enrolled at his/her institution available at that institution for monitoring. Data 
entered at the website will be reviewed by the PI and study coordinator for any 
inconsistency.  Queries as appropriate will be submitted to sites to clarify data. 
Submission of biologic specimens and imaging studies will be tracked on the 
study website.  
 
12.4  Human Subjects Protection 
 
12.4.1 Rationale for Subject Selection 
 
Subjects of both genders and from all racial and ethnic groups are eligible for this 
trial if they meet the eligibility criteria outlined in Section 3.1. No groups are 
being excluded from participation in the trial.  Approximately 50% of MPNSTs 
develop in individuals with NF1, and we expect that approximately 50% of 
individuals enrolled will have NF1 associated MPNST, and 50% will have a 
sporadic MPNST. 
 
12.4.2 Participation of Children  
 
The treatment approach to MPNST is similar for children and adults. However, 
enrollment will be limited to patients ≥ 18 years old.. 
 
12.4.3 Evaluation of the Benefits and Risks/Discomforts 
 
The primary risk to patients participating in this research study is from toxicity of 
the combination of everolimus and bevacizumab, the FDA approved agents used 
to treat the refractory MPNST. The primary objective of this phase 2 trial is to 
assess the clinical response rate in patients with refractory MPNST. Patients will 
thus be treated with therapeutic intent and response to the therapy will be closely 
monitored.  Treatment options for these patients are very limited, as all patients 
will have received prior cytotoxic chemotherapy, which is considered first line 
treatment by many oncologists for unresectable high-grade MPNSTs.  The 
potential benefits from this therapy are disease stabilization, tumor shrinkage, and 
a reduction in symptoms caused by the cancer.  Therefore, this greater than 
minimal risk protocol presents the potential for direct benefit to individual 
subjects. 
 
The medical, hospital, and research records associated with this study are 
considered confidential. Members of the treating team and designated research 
study assistants will have access to the records as required to administer treatment 
and comply with the protocol. Neither the name nor other identifying information 
for an individual will be used in the report or publication concerning this study. 
Patient records may be inspected by auditing agencies including the NCI the FDA 
to satisfy regulatory requirements, and Novartis, and Genentech. 
 


 
 
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12.4.4 Risks/Benefits Analysis 
 
The protocol provides for detailed and careful monitoring of all patients to assess 
for toxicity and response to treatment. Patients will be treated with therapeutic 
intent and response to the therapy will be closely monitored. The potential benefit 
from this therapy is disease stabilization, tumor shrinkage, and decrease tumor 
related symptoms. Therefore, this protocol involves greater than minimal risk to 
subjects, but presents the potential for direct benefit to individual subjects. For 
patients who cannot provide informed consent by themselves, but have a durable 
power of attorney (DPA) this legal representative will be able to provide informed 
consent for this study.    
 
12.4.5 Consent and Assent Process and Documentation 
 
The investigational nature and research objectives of this trial, the procedures and 
treatments involved and their attendant risks and discomforts and benefits, and 
potential alternative therapies will be carefully explained to the patient. The PI or 
an associate investigator on the trial will obtain consent from the patient or legal 
representative.  The PI or associate investigator will meet with the patient to 
discuss the protocol treatment and alternative options in detail. It will be stated 
clearly that participation in the research study is voluntary and that participants 
can withdraw from the study without losing benefits they would otherwise be 
entitled to. The patient and family members will be encouraged to ask questions, 
and additional meetings to discuss the treatment options will be arranged as 
necessary.  
 
12.4.6 Handling of Research Samples 
 
This study is sponsored and coordinated by SARC.  Laboratory correlative studies 
are not mandatory and will be conducted as outlined in section 9.  A detailed 
operations manual will be provide to each participating site, which will outline 
sample labeling, collection and processing.  Once analyzed for studies outlined in 
this protocol any remaining samples will be stored at the site performing the 
analyses or at the SARC designated specimen bank until the study is complete, 
and the manuscript describing the study has been accepted for publication. The 
study will remain open and status reported to the IRB until all samples have been 
analyzed, reported, banked or destroyed. Unintentional loss or destruction of any 
samples will be reported to the IRB as part of annual continuing reviews.  Any 
use of these samples for purposes not described in Section 9 will require 
prospective IRB review and approval. Tumor specimens will be sent to a SARC 
identified expert and will be delineated in the Operations Manual.  Should tumor 
sample be left after completion of research studies described in the protocol, 
prospective approval from the appropriate IRB will be obtained prior to 
performing additional studies.  


 
 
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12.4.7 Handling of Patient Data 
 
All patient data will be captured and maintained in a study specific database with 
password protected access. Data is entered using an assigned study subject 
identification number.  
 
The data provided to those reviewing the results, for example the study statistician 
will include the subject identification numbers, but will not include patient 
identifiable data. 
 
The research samples obtained on this study will only be sent using the study 
subject identification number which can only be linked to the patient at a given 
institution by the treating physician. 
 
All documentation that contains personal health information that may include 
patient identifiable information will be maintained at the site to preserve patient 
confidentiality.  
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Primary objectives 
The primary endpoint of the study is the clinical benefit rate (complete response, 
partial response, and stable disease at ≥ 4 months) of patients with progressive 
high-grade, unresectable or metastatic MPNSTs treated on study.  
 
A recently completed trial of the EGFR inhibitor erlotinib for individuals with 
refractory MPNST demonstrated a median time to progression of 48 days and 
progressive disease at the time of the first response evaluation after completion of 
2 treatment cycles in 19/20 evaluable patients36,97. Three other smaller studies had 
showed similar results (see section 2.1). We therefore believe that stable disease 
at ≥ 4 months on treatment with everolimus alone and in combination with 
bevacizumab can be considered as potentially beneficial and worthy of further 
exploration. An evaluable patient will be classified a success for the primary 
endpoint if the patient achieves a PR, CR or stable disease at ≥ 4 months.  
 
The target success rate will be 25%, and a success rate < 5% will be considered 
uninteresting. Using a two-stage Simon Minmax phase II design98 the first stage 
will require 15 patients, with no further accrual if no successes are observed 
within the first 15 patients. If at least one success is observed accrual will 
continue until a total of 25 evaluable patients have been enrolled. If at least four 
successes are observed in the 25 patients everolimus with addition of 
bevacizumab will be considered active in that it would be consistent with a 25% 
success rate. Assuming the number of successes is binomially distributed, this 


 
 
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study has an alpha of 5% and a power of 90% for detecting a true success 
probability of at least 25% versus the null hypothesis success rate of 5% or less. 
Patients will be able to remain on treatment for as long as they do not experience 
progressive disease or unacceptable toxicity. It is expected that 15-25 patients per 
year will be enrolled, thus enrollment is expected to complete within one to two 
years depending on the initial number of responses observed.  
 
All patients meeting the eligibility criteria who have signed a consent form and 
have begun treatment will be evaluable for response. 
 
Patients will be able to remain on treatment for as long as they do not experience 
progressive disease or unacceptable toxicity.  
 
Toxicity data will be presented by severity. The incidence of toxicities will be 
estimated using the binomial proportion and its 95% confidence interval.  The 
incidence of infection related deaths will be estimated using the binomial 
proportion and its 95% confidence interval.   
 
13.2 
Secondary objectives 
 
Summary statistics will be used to describe the study population (such as ranges, 
medians of ages, gender, baseline performance characteristics).  
 
Analysis of secondary endpoints will be predominantly descriptive using 
primarily non-parametric analyses and will be interpreted as being exploratory 
and hypothesis generating. Results will be summarized with scatterplots and 
correlation coefficients.  
 
Pharmacodynamic parameters including p70 S6 kinase 1 activity in PBMCs and 
proangiogenic factors in blood samples will be measured pre-treatment and at 
time of response evaluations during subsequent courses. Changes in these 
parameters will be correlated with radiographic response using the logistic 
regression model.  
 
Comprehensive NF1 mutation analysis and detailed phenotyping including 
quantification of tumor related and non-tumor related NF1 manifestations will be 
performed. Genotyping will be performed in a CLIA approved laboratory. Results 
from genotyping in our cohort of patients with MPNST will be compared to the 
spectrum of >3000 mutations as identified in a large cohort of unrelated patients. 
 
The mutations will be subdivided in 3 main classes: 
1. Nonsense, out-of frame splice mutations, frameshift mutations: these mutations 
are all generally accepted to lead to a premature stop codon. This results in the 
formation of unstable transcripts that will become degraded by the nonsense-
mediated RNA decay. Hence, these types of mutations can be considered as 


 
 
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mutations leading to haplo-insufficiency. 
2. Missense mutations and in-frame splice mutations may fall under a different 
category of mutations that may either present hypomorphic alleles due to some 
residual neurofibromin function or present gain-of-function alleles due to the 
activation or specific inhibition of a particular domain. These mutations will be 
subdivided according to the known and putative (in silico predicted) protein 
domains they are residing in. A distinction will be made between missense 
mutations residing in at least 6 regions: all exons prior to the Cystein-Serine-Rich-
Domain (CSRD), the CSRD, the Tubulin-binding domain, the Gap-Related-
Domain, the Sec-14 domain, and the Syndecan binding region. 
3. Finally, mutations deleting the NF1 gene as well as all genes residing in the 
most common 1.5 Mb deletion versus only a portion of the flanking genes. Using 
a Multiple Ligation Probe Assay (MLPA) and custom designed Agilent oligo 
CGH-array the extent of the deletion in all subjects will be established and 
compared with the severity of the phenotype. 
 
It will be tested whether an association between the type of NF1 mutation and 
NF1 manifestation and complications related to NF1 exists. The common clinical 
abnormalities will be coded as: Lisch nodules (present/ absent), number of CAL 
macules (0, 1–5, 6-100, > 100), axillary freckling (present/absent; 
unilateral/bilateral), number of cutaneous and dermal neurofibromas (0, 2-6, > 6-
100, 101–500, > 500), plexiform neurofibromas (0, 1 or > 2 plexiform 
neurofibromas residing in different parts of the body), optic glioma 
(present/absent; symptomatic/asymptomatic), internal or spinal neurofibromas 
(present/ absent and numerically); skeletal abnormalities including tibial 
dysplasia, pseudarthrosis, sphenoid wing dysplasia, dysplastic vertebrae, osseous 
cysts and scoliosis  (present/absent); other neoplasms including brainstem glioma, 
pheochromocytoma, rhabdomyosarcoma, malignant peripheral nerve sheath 
tumor, JMML, hypothalamic glioma (present/absent); cardiovascular disease 
(present/absent); developmental delay and learning disabilities (present/absent); 
NF-Noonan phenotype (present/absent); Watson syndrome phenotype 
(present/absent). 
 
Logistic regression analysis will be used to calculate significance, relative risks 
(RR) and 95% confidence intervals (CI) for binary outcomes. Linear regression 
analysis will be used for continuous outcomes. Covariate information such as 
gender, type of constitutional NF1 mutation and age at examination (as a 
continuous variable) to name a few will be considered for inclusion in the models. 
The mutation covariate is coded as several binary variables (indicators of 
missense, in-frame and out-of frame splicing, and non-sense mutations). Age at 
examination will be included as a covariate because the penetrance of many NF1 
disease features changes with age. Adjustments for multiple testing will be 
conducted.  
 


 
 
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Volumetric MRI: An automated method of volumetric analysis of plexiform 
neurofibromas in NF1 was recently developed, and is in use in clinical trials. This 
method is reproducible and allows detection of smaller changes in tumor size than 
conventional response criteria (WHO)94. Similar to plexiform neurofibromas, 
MPNSTs have a complex shape (non spherical), and RECIST (1-dimensional)99 
or WHO (2-dimensional)100 criteria may have limited applicability. Volumetric 
MRI tumor analysis will be applied to MPNSTs as a tool for response assessment. 
Response evaluation using volumetric measurements will be compared to 
standard 2-dimensional response measurements (WHO criteria), and to 1-
dimensional measurements (RECIST criteria). Spearman rank correlation will be 
used to describe the association.


 
 
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associated plexiform neurofibromas and malignant peripheral nerve sheath tumors. Am J 
Pathol 159:57-61, 2001 
 
93. 
Dombi E, Solomon J, Gillespie AJ, Fox E, Balis FM, Patronas N, Korf 
BR, Babovic-Vuksanovic D, Packer RJ, Belasco J, Goldman S, Jakacki R, Kieran M, 
Steinberg SM, Widemann BC: NF1 plexiform neurofibroma growth rate by volumetric 
MRI: relationship to age and body weight. Neurology 68:643-7, 2007 


 
 
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94. 
Solomon J, Warren K, Dombi E, Patronas N, Widemann B: Automated 
detection and volume measurement of plexiform neurofibromas in neurofibromatosis 1 
using magnetic resonance imaging. Comput Med Imaging Graph 28:257-65, 2004 
 
95. 
Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, 
Csako G: Systematic review: the effect of preventive lamivudine on hepatitis B 
reactivation during chemotherapy. Ann Intern Med 148:519-28, 2008 
 
96. 
Yeo W, Lam KC, Zee B, Chan PS, Mo FK, Ho WM, Wong WL, Leung 
TW, Chan AT, Ma B, Mok TS, Johnson PJ: Hepatitis B reactivation in patients with 
hepatocellular carcinoma undergoing systemic chemotherapy. Ann Oncol 15:1661-6, 
2004 
 
97. 
Albritton K, Rankin C, Coffin M, Ratner N, Budd G, Schuetze S, Randall 
L, DeClue J, Borden E: Phase II study of erlotinib in metastatic or unresectable malignant 
peripheral nerve sheath tumors (MPNSTs), ASCO. Atlanta, GA, 2006, pp 524s 
 
98. 
Simon R: Optimal two-stage designs for phase II clinical trials. Control 
Clin Trials 10:1-10, 1989 
 
99. 
Therasse P, Arbuck S, Eisenhauer E, Wanders J, Kaplan R, Rubinstein L, 
Verweij J, Van Glabbeke M, Van Oosterom T, Chrisitan M, Gwyther S: New guidelines 
to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205-216, 2000 
 
100. 
Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of 
cancer treatment. Cancer 47:207-14, 1981 
 
 


 
 
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APPENDIX I: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work) 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined in 
bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead. 
 
 


 
 
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APPENDIX II: P450 DRUG INTERACTION TABLE   
(as per http://medicine.iupui.edu/clinpharm/ddis/table.aspx; from Section 6.4, Interactions, Investigator’s Brochure, Afinitor®/Votubia® (everolimus) (07-Nov-2011) 
 


 
 
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voriconazole 


 
 
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APPENDIX III: CLINICALLY RELEVANT DRUG INTERACTIONS: SUBSTRATES, INDUCERS INHIBITORS OF PGP 
AND PGP/CYP3A DUAL INHIBITORS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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OTHER MEDICATIONS TAKEN 
If you take a daily medication (prescribed or otherwise), please use one line per drug and 
indicate the start and stop dates under the “Date(s) Taken” section (i.e., 6/2/09-6/5/09). 
Drug Name 
Dose 
Dates 
Taken 
Reason Taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Participant Initials _____________ Date __________ 
 
FOR OFFICE USE 
Staff Initials:  
Date Dispensed:     
Date Returned:  
# pills/tabs dispensed:  
# pills/tabs returned:  
# pills/tabs that should have been taken:  
Discrepancy Notes: 
 
 
Participant Identifier: ________________________________________ 
Cycle # _______________ Cycle Start Date: _____________________ 
Your MD______________________________  Phone______________  
Your RN_______________________________ Phone______________ 
Study treatment instructions 
Study treatment will be given in 28 day cycles. 
Everolimus 
 Your dose of everolimus  is _____________ 
 You will take everolimus once per day, every day of each 28 day cycle. 
 Take each dose at the same time each day, preferably in the morning. You should 
take the everolimus either in a fasting state (no food one hour before or two hours 
after meals) or with a light fat-free meal.  If you choose one method over the other 
you should use that method every day you take everolimus. 
 If you miss a dose, you may still take it up to 6 hours after the time you would 
normally take it. If more than 6 hours have elapsed, you should skip the dose for that 
day.  The next day, you should take the everolimus at the usual time.  Do not take 2 
doses to make up for the missed dose. 
 If you vomit your dose of everolimus, do not take that dose again. Mark the vomited 
dose in this diary. Take the next day’s dose as scheduled. 
 It is important that your dietary habits remain as consistent as possible throughout the 
study around the time you take everolimus. You should avoid grapefruit, Seville 
oranges, or star fruit and the juices of these fruits, and St. John’s Wort while you are 
taking everolimus, as these items may change how your body handles everolimus. 
 It is important that you maintain good oral hygiene (mouth care) while you are taking 
everolimus to help prevent inflammation of the mouth tissues. 
 You should not receive live vaccines or have close contact with those who have 
received them while you are taking everolimus. 
 Bring any unused everolimus, and this diary to each clinic visit. The study staff will 
make sure you have an adequate supply of everolimus to take home at the end of 
each clinic visit. 
SARC016 Participant Study Drug Diary 
“Site Name” 
APPENDIX IV: PATIENT DIARY 


 
 
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SYMPTOMS/SIDE EFFECTS 
Please record any side effects experienced during this cycle. Include the date the particular symptom started and when it ended. Please evaluate the 
severity of the symptom according to the following scale: 
 
Mild: Awareness of sign or symptom; easily tolerated and did not affect ability to perform normal daily activities. Symptom did not require 
medication or therapeutic intervention. 
Moderate: Significant discomfort which interfered with ability to perform normal daily activities. Symptom was easily resolved with at home 
medication or simple therapeutic intervention. 
Severe: Marked discomfort with an inability to carry out normal daily activities. Symptom required new medication and/or therapeutic intervention 
in order to resolve. 
 
Please Note: The severity should reflect the most severe level experienced during the time period. 
Symptom 
Start Date 
End Date 
Severity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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DOSING LOG 
 
Everolimus: For each dose, take __________.  Please indicate the date, time, amount taken and any comments. 
Date & 
Time 
Amount 
Taken 
Comments 
Ex: 
6/1/09 
4:30 pm 
1 pill 
Vomited dose 
Day 1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
12 
 
 
 
13 
 
 
 
14 
 
 
 


 
 
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DOSING LOG Continued… 
 
Date & 
Time 
Amount 
Taken 
Comments 
Ex: 
6/1/09 
1 pill 
Vomited dose 
15 
 
 
 
16 
 
 
 
17 
 
 
 
18 
 
 
 
19 
 
 
 
20 
 
 
 
21 
 
 
 
22 
 
 
 
23 
 
 
 
24 
 
 
 
25 
 
 
 
26 
 
 
 
27 
 
 
 
28 
 
 
 
 


 
 
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APPENDIX V: HEPATITIS SCREENING/MONITORING/TREATMENT 
Reactivation of Hepatitis B (HBV) has been observed in patients with cancer receiving 
chemotherapy. Sporadic cases of Hepatitis B reactivation have also been seen in this setting 
with everolimus. Use of antivirals during anti-cancer therapy has been shown to reduce the 
risk of Hepatitis B virus reactivation and associated morbidity and mortality. A detailed 
assessment of Hepatitis B/C medical history and risk factors must be done for all patients at 
screening, with testing performed prior to the first dose of everolimus.  
 
Testing for hepatitis B viral load and serologic markers: HBV-DNA, HBsAg, HBs Ab, and 
HBc Ab and HCV RNA PCR are required at screening for all patients in the following risk 
categories:  
o 
All patients who currently live in (or have lived in) Asia, Africa, Central and South 
America, Eastern Europe, Spain, Portugal, and Greece.   
o 
Patients with any of the following risk factors:  
 known or suspected past hepatitis B infection,  
 blood transfusion(s) prior to 1990,  
 current or prior IV drug users,  
 current or prior dialysis,  
 household contact with hepatitis B infected patient(s),  
 current or prior high-risk sexual activity,  
 body piercing or tattoos,  
 mother known to have hepatitis B 
 history suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper 
quadrant pain. 
 
Management of Hepatitis reactivation 
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals 
during anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) 
reactivation and associated HBV morbidity and mortality. 
Monitoring and prophylactic treatment for hepatitis B reactivation 
The tables below provide details of monitoring and prophylactic therapy according to the 
baseline results of viral load and serologic markers testing. 
Action to be taken for positive baseline hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
+ or - 
- 


 
 
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Test 
Result 
Result 
Result 
Result 
Result 
and no prior 
HBV 
vaccination 
or + with prior HBV 
vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendatio
n 
Prophylaxis treatment should be 
started 1-2 weeks prior to first dose 
of  study drug 
Monitor HBV-DNA approximately 
every 4 weeks 
 
No prophylaxis 
Monitor HBV-DNA approximately 
every 4 weeks 
 
No specific action 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug.     
For patients who have already received study drug prior to the approval of the amendment, 
the same process should be followed at the patient's next visit. The first HBV-DNA result 
would be regarded as baseline. 
For hepatitis B reactivation, definition and management guidelines, see Table 3-3 Guidelines 
for management of hepatitis B.   
 
Guidelines for management of hepatitis B 
HBV reactivation  (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
-------------------------------------- 
reactivation 
is 
defined 
as:   
[Increase of 1 log in HBV-
DNA 
relative 
to 
baseline 
HBV-DNA value OR new 
appearance 
of 
measurable 
HBV-DNA] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral  
AND 
Interrupt study drug administration until resolution:  
 ≤ grade 1 ALT (or baseline ALT, if > grade 1) and 
 ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-started at one 
dose lower, if available. If the patient is already receiving the lowest dose of 
study drug according to the protocol, the patient should restart at the same 
dose after resolution. Both antiviral therapies should continue at least 4 
weeks after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue study drug but 
continue both antiviral therapies at least 4 weeks after last dose of study 
drug. 
For patients with baseline 
results:  
Negative 
HBV-DNA 
and 
HBsAg  
AND  
[Positive HBs Ab (with no 
prior history of vaccination 
against HBV), OR positive 
Treat : Start first antiviral medication  
AND 
Interrupt study drug administration until resolution:  
  ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be re-started at one 
dose lower, if available. If the patient is already receiving the lowest dose of 
study drug according to the protocol, the patient should restart at the same 


 
 
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HBc Ab]  
------------------------------------- 
reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
dose after resolution. Antiviral therapy should continue at least 4 weeks 
after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue study drug but 
continue antiviral therapy at least 4 weeks after last dose of study drug. 
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 3.0 Metabolic Laboratory/Other: 
Viral Re-activation), unless considered life threatening by the investigator; in which case they should be 
recorded as grade 4 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral Re-activation). Date of viral reactivation 
is the date on which both DNA and ALT criteria were met (e.g. for a patient who was HBV-DNA positive on 
01-JAN-10 and whose ALT reached ≥ 5 × ULN on 01-APR-10, the date of viral reactivation is 01-APR-10). 
 
Monitoring for hepatitis C 
The following two categories of patients should be monitored every 4 weeks for HCV 
reactivation: 
 Patients with detectable HCV RNA-PCR test at baseline. 
 Patients known to have a history of HCV infection, despite a negative viral load test at 
baseline (including those that were treated and are considered ‘cured’) 
For definition of hepatitis C reactivation and the management guidelines, see the table below 
with guidelines for management of hepatitis C. 
 
Guidelines for management of hepatitis C 
HCV reactivation* 
For patients with baseline results:  
Detectable HCV-RNA,  
 
reactivation is defined as: 
ALT elevation x 5 ULN  
Discontinue study drug  
 
 
For patients with baseline results: 
Knowledge of past hepatitis C 
infection with no detectable HCV-
RNA,   
 
reactivation is defined as: 
New appearance of detectable HCV-
RNA  
Discontinue study drug 
 
* All reactivations of hepatitis C are to be recorded as grade 3 (CTCAE v3.0 Metabolic Laboratory/Other: Viral 
Re-activation), unless considered life threatening by the investigator; in which case they should be recorded as 
grade 4 (CTCAE v 3.0 Metabolic Laboratory/Other: Viral Re-activation).  
 


 
 
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APPENDIX VI: DOCUMENTATION OF FINDINGS OF NF1 
 
Demographic information: 
DOB:  
Sex:  
Mother’s race:  
Father’s race:  
NF1 Inherited: Yes:            No: 
NF1 sporadic: Yes:           No: 
 
 
1 
Exam Date 
_ __ _ / _ _ / _ _ 
  year  month  day 
 
2 
Height/length 
_ _ _ . _ cm 
 
or    _ ft  _ _ . _ in 
 
Unknown 
 
3 
Head circumference 
_ _ . _ cm 
 
_ _ . _ in 
 
Unknown 
4 
 
Number of café au lait  
(In pre-pubertal individuals, include CAL 
between 0.5 and 1.5cm)  
None 
1 
2 
3 
4 
5 
6 or more 
Present, number unknown 
Unknown 
5 
 
Intertriginous Freckling 
Absent 
Present 
Unknown 
 
6 
 
Subcutaneous neurofibromas 
None 
1 
2  
3 - 9 
10-50 
>50 
Unknown 
7 
 
Cutaneous neurofibromas 
(Includes pendulous) 
None 
1 
2  
3 - 9 
10-50 
>50 
Unknown 


 
 
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8 
 
Plexiform neurofibroma  - Location 
(Check as many as apply) 
None 
Orbit 
Face 
Head/neck 
Trunk - dorsal 
Trunk - ventral 
Arm 
Leg 
Unknown 
9 
 
 
 
 
 
10 
 
Paraspinal neurofibromas 
        
 
 
 
 
Xanthogranulomas 
Absent by scan 
Absent clinically 
*Present 
Unknown 
 
 
Absent 
Present 
Unknown 
11 
 
Lisch nodules 
Absent 
Present on slit lamp exam 
Possible 
Unknown 
12 
 
 
 
 
 
Proptosis 
Absent 
Unilateral 
Bilateral 
Present, laterality unknown 
Unknown 
13 
 
Optic glioma 
Absent by scan 
Absent clinically 
Present - asymptomatic 
Present - symptomatic 
Unknown 
14 
 
 
 
 
 
 
 
Seizures - type 
 
 
None 
Febrile only 
Hypsarrhythmia 
Generalized 
Partial 
Multiple types 
Present - type unknown 
*Other 
15 
 
 
 
 
 
 
Hydrocephalus 
Absent clinically 
Absent by scan 
Aqueductal stenosis 
Other non-communicating 
Communicating 
Present - type unknown 
Unknown 


 
 
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16 
 
 
 
Intellectual Development 
 
 
 
Normal 
Mildly Delayed 
Significant delay 
Unknown 
17 
Learning Problems 
None 
Specific learning problems present 
Unknown 
18 
Hypertension 
Absent 
Present 
Unknown 
19 
Congenital heart disease 
 
 
Absent clinically 
Absent by special testing 
Aortic stenosis 
ASD 
Patent ductus arteriosus 
Pulmonic stenosis 
Tetralogy of Fallot 
VSD 
Other type of CHD 
Multiple types of CHD 
Possible CHD 
Unknown 
20 
 
 
 
 
 
 
 
21 
 
Vascular anomalies 
 
 
 
 
 
 
 
Age puberty began 
absent clinically 
*renal artery stenosis 
*arterial stenosis (non-renal) 
*moya moya 
*other 
unknown 
 
 
<10 years 
10-15 years 
>15 years 
Not applicable 
Unknown 
22 
 
Dysmorphic features 
 
 
 
 
No 
Yes 
Possible 
Unknown 
 
23 
 
Congenitally bowed tibia or pseudarthrosis 
Absent clinically 
Absent radiographically 
Present 
Unknown 
24 
 
Dysplastic vertebrae 
Absent clinically 
Absent radiographically 
Present 
Unknown 


 
 
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25 
 
Scoliosis 
Absent clinically 
Absent radiographically 
Present 
Unknown 
26 
 
Dysplastic sphenoid wing 
Absent clinically 
Absent radiographically 
Present, bilateral 
Present, unilateral 
Present, laterality unknown 
Unknown 
 
27 
Neoplasm - type 
(Please check as many as apply) 
 
 
None 
Carcinoma 
Ependymoma 
Glioma 
Leukemia 
Lymphoma  
Malignant peripheral nerve sheath tumour 
Meningioangiomatosis 
Meningioma 
Pheochromocytoma 
Sarcoma 
Schwannoma 
Malignancy present, type unknown 
Other