Conditions: Brain Tumor Glioblastoma Anaplastic Glioma
Keywords: Chemotherapy Brain Tumor Glioblastoma Anaplastic Glioma
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 86
Healthy volunteers: no

Brief summary:
The goal of Phase 1 of this clinical research study is to find the highest tolerable dose and best schedule of the combination of everolimus and sorafenib that can be given to patients with malignant glioma.

The goal of Phase 2 of this study to learn if the combination of everolimus and sorafenib can help to control malignant glioma. The safety of this combination will also be studied in both phases.

Detailed description:
Background

* Although malignant gliomas display genetic heterogeneity, several key proliferation and survival signaling pathways have been identified.
* Recent work has focused on targeting these tumor specific pathways in hopes of improving treatment efficacy and minimizing treatment toxicity. Because molecularly targeted agents have been mostly ineffective when used alone, combination therapy that inhibits multiple pathways is an appealing strategy.
* Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor angiogenesis. Although most GBMs lack rapidly accelerated fibrosarcoma (RAF) mutations, targeting the RAF/methyl ethyl ketone (MEK)/extracellular-signal-regulated kinase (ERK) pathway may be beneficial as this pathway may be activated by other genetic alterations upstream from RAF.
* The mammalian target of rapamycin (mTOR) protein is a downstream component of the Phosphoinositide 3-kinases (PI3K)/Protein kinase B (Akt) pathway. Everolimus (everolimus; Novartis) is a novel oral derivative of rapamycin.
* Combining everolimus and sorafenib allows targeting of both the PI3K pathway and the RAF-MAPK pathway and in addition targets vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), other active targets in malignant glioma.

Objectives

Phase 1

-To determine the maximum tolerated dose and safety of everolimus in combination with

sorafenib for patients with recurrent malignant gliomas.

Phase 2

* 6 months progression free survival rate for glioblastoma patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.
* 3 months progression free survival rate for glioblastoma patients with prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.
* 6 months progression free survival rate for Anaplastic Glioma (AG) patients with no prior bevacizumab exposure treated with everolimus and sorafenib at the maximum tolerated dose as determined in the phase I study.

Eligibility

* Patients with histologically proven recurrent intracranial malignant glioma will be eligible for the phase I/II component of this protocol.
* Patients must be \>= 18 years old with a Karnofsky performance status of greater than or equal to 60
* No more than 2 prior chemotherapies and 1 relapse. Prior bevacizumab therapy is allowed.

Design

* This is a phase 1 /2 study of everolimus and sorafenib in patients with recurrent high-grade gliomas.
* Phase 1: Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib.
* Phase 2: Patients will be treated with the combination of sorafenib and everolimus. Sorafenib will be taken daily for 7 days on, then 7 days off. Everolimus will be taken daily.
* There is not a defined set maximum number of cycles that a patient may have. Patients may continue with protocol therapy until criteria for Off Treatment is met. Patients will then be followed every 3 months for survival status.
* There will be an accrual of approximately 3-6 eligible patients per cohort to the Phase I component of the study. Patients removed at any time for toxicity are evaluable. Phase I patients removed from study treatment within 28 days for reasons other than toxicity may be replaced.
* There will be a total accrual of approximately 82 eligible patients to the Phase II study (34 recurrent GBM with no prior exposure to bevacizumab, 16 recurrent Anaplastic Glioma with no prior exposure to bevacizumab, and 32 glioblastoma with prior exposure to bevacizumab).

Arms:
arm 1: Daily everolimus (days 1- 28) in combination with sorafenib as per the Phase I dosing table. Maximum tolerated dose. Dose Escalation. arm 2: Combination of sorafenib and everolimus. Sorafenib 400mg twice daily will be taken for 7 days on, then 7 days off. Everolimus 5mg will be taken daily. Determined from dose escalation in phase I, maximum tolerated dose -1.

Interventions: intervention 1: everolimus intervention 2: sorafenib
Intervention descriptions: intervention 1: Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib; There is not a defined set maximum number of cycles that a patient may have; Phase I Dose Escalation: 5mg to 10mg daily. intervention 2: Patients will be treated with sorafenib in combination with everolimus (days 1-28); There is not a defined set maximum number of cycles that a patient may have; Phase I Dose Escalation 400mg-600mg twice a day (bid) or 400mg-800mg twice a day, 7 days on and 7 days off.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Ph 1/2 Everolimus & Sorafenib 
 
Version Date: 06/15/18 
Page 1 of 99 
 
BRAIN TUMOR TRIALS COLLABORATIVE (BTTC) 
Abbreviated Title: Ph 1/2 Everolimus & Sorafenib 
CC Protocol #: 16C0011 
Amendment Letter: D 
Version Date: 06-15-2018 
BTTC Protocol #: BTTC09-01 
NCT Number:  NCT01434602 
Title: A Phase I-II trial of Everolimus and Sorafenib in Patients with Recurrent High-Grade 
Gliomas 
 
Coordinating Center: BTTC Coordinating Center, Center for Cancer Research, NCI 
NCI Principal Investigator:  Mark Gilbert, M.D. A,B,C,D,E,F 
Neuro Oncology Branch (NOB), CCR, NCI 
9030 Old Georgetown Road, Building 82, Room 235 
Bethesda, MD 20892 
Phone: 240-760-6023 
Fax: 240-541-4432 
Email: mark.gilbert@nih.gov 
 
Investigational Agents: 
None 
 
Commercial Agents: 
Sorafenib tosylate, hereafter referred to as sorafenib and Everolimus will be supplied from 
commercial sources by their respective manufacturers, Bayer and Novartis 
 
 


Abbreviated Title: Ph 1/2 Everolimus & Sorafenib 
 
Version Date: 06/15/18 
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BTTC Roles: 
 
STUDY CHAIR 
Jeffrey J. Raizer, MD 
710 North Lake Shore Dr. 
Abbott Hall, Room 1123 
Chicago, IL 60611 
Phone: 312-503-4724 
Fax: 312-908-5073 
Email: jraizer@nm.org 
FWA00001549 
 
 
 
LEAD PI 
Mark R. Gilbert, MD 
Neuro-Oncology Branch 
NCI/NINDS 
National Institutes of Health 
Bloch Bldg. 82, Rm. 235 
9030 Old Georgetown Road 
Bethesda, MD 20892 
Email:  mark.gilbert@nih.gov  
 
BTTC COORDINATING 
CENTER 
National Cancer Institute, 
National Institutes of Health 
9030 Old Georgetown Road, 
Room 211 
Bethesda, MD 20892 
Phone: 240-760-6060  
Fax: 301-451-5429 
Email: 
NCI_BTTC@mail.nih.gov 
 
 
A DISCLAIMER STATEMENT FOR BTTC PROTOCOLS 
This is a research protocol of the Brain Tumor Trials Collaborative describing an experimental 
treatment procedure.  It is a privileged document and is not intended to be circulated or used for 
other purposes.  The Brain Tumor Trials Collaborative assumes no responsibility for its use outside 
of the constraints of this research protocol or by investigators other than those approved by the 
Consortium. 


Abbreviated Title: Ph 1/2 Everolimus & Sorafenib 
 
Version Date: 06/15/18 
Page 3 of 99 
 
BTTC PARTICIPATING INVESTIGATORS 
Note: These sites will be collecting and submitting data to the BTTC Coordinating Center at NCI 
(e.g. through data entry in C3D) and will not be re-opening to accrual. 
Site Name 
FWA # 
Participating 
Investigator 
Address 
Email 
Cleveland Clinic 
FWA00005367 
David 
Peereboom, 
MD 
9500 Euclid Ave, R35, 
Cleveland, OH 44195 
peerebd@ccf.
org 
 
Columbia 
University Medical 
Center 
FWA00005846 
Fabio Iwamoto, 
M.D. 
710 West 168th Street, R9-
109, New York, NY 10032 
fi2146@colum
bia.edu 
Henry Ford Health 
System 
FWA00005846 
Tobias 
Walbert, MD 
2799 W Grand Blvd, 
Detroit, MI 48202 
twalber1@hfh
s.org 
Northwestern 
University, 
Feinberg School of 
Medicine 
FWA0001549 
 
Jeffrey Raizer, 
M.D. 
710 North Lake Shore Drive 
Abbott Hall, Room 1123, 
Chicago, IL 60611 
jraizer@nm.or
g 
Texas Oncology – 
Austin Brain 
Tumor Center 
FWA00017020 
 
Morris Groves, 
M.D. 
 
901 W. 38th Street, Suite 
200, Austin, TX 78705 
morris.groves
@usoncology.c
om 
 
UF Health Cancer 
Center at Orlando 
Health 
FWA00000384 
 
Nicholas 
Avgeropoulos, 
M.D. 
1400 South Orange Ave, 
Orlando, FL 32806 
nicholas.avger
opoulos@orla
ndohealth.com 
University of 
Kansas Cancer 
Center 
FWA00016803 
 
Michael Salacz, 
M.D. 
2330 Shawnee Mission 
Parkway, Suite 210, 
Westwood, KS 66205 
msalacz@kum
c.edu 
University of 
North Carolina at 
Chapel Hill 
FWA00004507 
Frances 
Collichio, M.D. 
 
170 Manning Dr. CB#7305, 
Chapel Hill, NC 27599 
fcollich@med.
unc.edu 
 
UT MD Anderson 
Cancer Center 
FWA00000363 
Marta Penas-
Prado, M.D. 
1515 Holcombe Blvd, 
Houston, TX 77030 
mpenaspr@m
danderson.org 
John deGroot, 
M.D. 
1515 Holcombe Blvd, 
Houston, TX 77030 
jdegroot@mda
nderson.org 
Monica Loghin, 
MD 
1515 Holcombe Blvd, 
Houston, TX 77030 
mloghin@mda
nderson.org 
W.K. Alfred 
Yung, MD 
1515 Holcombe Blvd, 
Houston, TX 77030 
wyung@mdan
derson.org 
 
 


Abbreviated Title: Ph 1/2 Everolimus & Sorafenib 
 
Version Date: 06/15/18 
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PRÉCIS 
Background 
• Although malignant gliomas display genetic heterogeneity, several key proliferation and 
survival signaling pathways have been identified. 
• Recent work has focused on targeting these tumor specific pathways in hopes of improving 
treatment efficacy and minimizing treatment toxicity.  Because molecularly targeted agents 
have been mostly ineffective when used alone, combination therapy that inhibits multiple 
pathways is an appealing strategy. 
• Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor 
angiogenesis. Although most GBMs lack RAF mutations, targeting the RAF/MEK/ERK 
pathway may be beneficial as this pathway may be activated by other genetic alterations 
upstream from RAF. 
• The mammalian target of rapamycin (mTOR) protein is a downstream component of the 
PI3K/Akt pathway. Everolimus (everolimus; Novartis) is a novel oral derivative of 
rapamycin 
• Combining everolimus and sorafenib allows targeting of both the PI3K pathway and the 
RAF-MAPK pathway and in addition targets VEGF and PDGF, other active targets in 
malignant glioma.   
Objectives 
Phase 1 
• To determine the maximum tolerated dose and safety of everolimus in combination with 
sorafenib for patients with recurrent malignant gliomas. 
Phase 2 
• 6-month progression free survival rate for glioblastoma patients with no prior bevacizumab 
exposure treated with everolimus and sorafenib at the maximum tolerated dose as 
determined in the phase I study. 
• 3-month progression free survival rate for glioblastoma patients with prior bevacizumab 
exposure treated with everolimus and sorafenib at the maximum tolerated dose as 
determined in the phase I study. 
• 6-month progression free survival rate for AG patients with no prior bevacizumab exposure 
treated with everolimus and sorafenib at the maximum tolerated dose as determined in the 
phase I study. 
Eligibility 
• Patients with histologically proven recurrent intracranial malignant glioma will be eligible 
for the phase I/II component of this protocol.   
• Patients must be ≥ 18 years old with a Karnofsky performance status of ≥ 60. 
• No more than 2 prior chemotherapies and 1 relapse.  Prior bevacizumab therapy is allowed. 
Design 


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• This is a phase 1 /2 study of everolimus and sorafenib in patients with recurrent high-grade 
gliomas. 
• Phase 1: Patients will be treated with daily everolimus (days 1-28) in combination with 
sorafenib.  
• Phase 2: Patients will be treated with the combination of sorafenib and everolimus. 
Sorafenib will be taken daily for 7 days on, then 7 days off.  Everolimus will be taken daily. 
• There is not a defined set maximum number of cycles that a patient may have.  Patients 
may continue with protocol therapy until criteria for “Off Treatment” is met. Patients will 
then be followed every 3 months for survival status. 
• There will be an accrual of approximately 3-6 eligible patients per cohort to the Phase I 
component of the study.  Patients removed at any time for toxicity are evaluable.  Phase I 
patients removed from study treatment within 28 days for reasons other than toxicity may 
be replaced.  
• There will be a total accrual of approximately 82 eligible patients to the Phase II study (34 
recurrent GBM with no prior exposure to bevacizumab, 16 recurrent Anaplastic Glioma 
with no prior exposure to bevacizumab, and 32 glioblastoma with prior exposure to 
bevacizumab). 
 


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TABLE OF CONTENTS 
PRÉCIS ............................................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................6 
1.0 
INTRODUCTION .................................................................................................................8 
 
Objectives .........................................................................................................................8 
 
Background .......................................................................................................................8 
2.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .....................................................13 
 
Eligibility Criteria ...........................................................................................................13 
 
Screening Evaluation ......................................................................................................17 
 
Registration Procedures ..................................................................................................17 
 
Treatment Assignment and Descriptive Factors .............................................................19 
 
Baseline Evaluation ........................................................................................................20 
3.0 
STUDY IMPLEMENTATION ...........................................................................................21 
 
Phase 1 Study Design......................................................................................................21 
 
Phase II Study Design .....................................................................................................23 
 
Dose Modifications in Phase I (post cycle 1) and Phase II.............................................23 
 
Questionnaires.................................................................................................................34 
 
Study Calendar ................................................................................................................35 
 
On Study Evaluation .......................................................................................................37 
 
Criteria for Removal from Protocol Therapy and Off Study Criteria .............................39 
4.0 
CONCOMITANT MEDICATIONS/MEASURES ............................................................40 
5.0 
DATA COLLECTION AND EVALUATION ...................................................................41 
 
Data Collection ...............................................................................................................41 
 
Response Criteria ............................................................................................................43 
 
Toxicity Criteria ..............................................................................................................46 
6.0 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN ...................................................................................................................................46 
 
Definitions.......................................................................................................................46 
 
Assessing Causality ........................................................................................................48 
 
NCI-IRB And Clinical Director Reporting .....................................................................48 
 
Guidelines for Reporting Serious Adverse Events to BTTC ..........................................49 
 
Reporting to the Study Drug Manufacturers ...................................................................50 
 
Guidelines & Procedures for reporting Deviations and Unanticipated Problems ..........52 


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Data and Safety Monitoring Plan ....................................................................................53 
7.0 
STATISTICAL CONSIDERATIONS ................................................................................54 
 
Phase I Component .........................................................................................................54 
 
Phase II Component ........................................................................................................54 
8.0 
COLLABORATIVE AGREEMENTS ................................................................................56 
 
Agreement Type..............................................................................................................56 
9.0 
HUMAN SUBJECTS PROTECTIONS ..............................................................................56 
 
Rationale for Subject Selection .......................................................................................56 
 
Participation of Children .................................................................................................56 
 
Participation of Subjects Unable to Give Consent (NCI) ...............................................56 
 
Participation of Subjects Unable to Give Consent (BTTC) ............................................57 
 
Evaluation of Benefits and Risks/Discomforts ...............................................................57 
 
Risks/Benefits Analysis ..................................................................................................57 
 
Consent and Assent Process and Documentation ...........................................................58 
10.0 PHARMACEUTICAL INFORMATION ...........................................................................59 
 
Sorafenib .........................................................................................................................59 
 
Everolimus ......................................................................................................................69 
11.0 MULTICENTER PROCEDURES ......................................................................................81 
 
General Procedures .........................................................................................................81 
 
Principal Investigators ....................................................................................................81 
 
Procedures for Site Registration .....................................................................................81 
 
Institutional Review ........................................................................................................81 
 
Protocol Revisions and Closure ......................................................................................81 
12.0 REFERENCES ....................................................................................................................83 
13.0 APPENDICES .....................................................................................................................85 
 
Appendix: Karnofsky Performance Status and Neurological Function ..........................85 
 
Appendix:  EIAEDs and Non-EIAEDs ...........................................................................86 
 
Appendix: Drugs known to be metabolized by CYP450 Isoenzymes 2D6 and 3A4 .....87 
 
Appendix: M.D. Anderson Symptom Inventory (MDASI-BT)......................................92 
 
Appendix: Pill Diary and Pill Count Documentation Form............................................94 
 Appendix: CCR Problem Report Form...........................................................................97 
 
Appendix: Unused Study Drug Disposition Form – Bayer ............................................99 
 
 


Abbreviated Title: Ph 1/2 Everolimus & Sorafenib 
 
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1.0 INTRODUCTION 
 
OBJECTIVES 
 
Phase I 
• To determine the maximum tolerated dose and safety of everolimus in combination 
with sorafenib for patients with recurrent malignant gliomas. 
 
Phase II 
1.1.2.1 
Primary endpoints: 
• 6 month progression free survival rate for glioblastoma patients with no prior 
bevacizumab exposure treated with everolimus and sorafenib at the maximum 
tolerated dose as determined in the phase I study. 
• 3 month progression free survival rate for glioblastoma patients with prior 
bevacizumab exposure treated with everolimus and sorafenib at the maximum 
tolerated dose as determined in the phase I study. 
• 6 month progression free survival rate for AG patients with no prior bevacizumab 
exposure treated with everolimus and sorafenib at the maximum tolerated dose as 
determined in the phase I study. 
1.1.2.2 
Secondary endpoints: 
• Time to progression and overall survival for recurrent malignant glioma patients 
(Group A, Group B, and Group C) treated with everolimus and sorafenib measured 
from time of study enrollment. 
• Objective response rate for recurrent malignant gliomas (Group A, Group B, and 
Group C  treated with everolimus and sorafenib  
• Patient related outcome measures 
To evaluate the occurrence of symptoms and correlate to disease progression and 
tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor 
Module (MDASI-BT) self-reporting tool.  This will include: 
o To evaluate longitudinal changes in symptom measures and determine the 
impact of the therapy on these parameters. 
o To measure symptom burden over the course of therapy to evaluate 
differences between patients individual symptom severity, overall mean 
symptom severity, and difference in scores on the interference items 
between responders and non-responders. 
o To describe the variability of symptom severity longitudinally over the 
treatment course and follow-up period.  
 
BACKGROUND 
Glioblastoma (GBM) is the most common primary brain tumor.  With optimal treatment, 
consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant 
chemotherapy, median survival is 14.6 months. (1)  Cure is exceptional and most patients have 


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evidence of tumor progression within one year of diagnosis despite treatment.  At progression, 
treatment options are limited and mostly ineffective; most clinical trials demonstrate six month 
progression free survival rate of only 9-15% and median overall survival is less than 25 weeks 
from time of tumor progression. (2)  Recently, bevacizumab was approved for recurrent GBM 
based on data from Vredenburgh et al. and Kreisl et al.(3, 4)  Data on patients who fail 
bevacizumab indicate a short survival, on the order of 10 weeks, an approximate PFS 3 and 6 
months of 0%. 
Anaplastic Astrocytoma (WHO grade III astrocytoma), although less aggressive than GBM, is a 
malignant tumor with a median survival of less than 3 years from diagnosis and estimated 5-year 
survival of 28% despite best treatment (2, 5) 
Although malignant gliomas display genetic heterogeneity, several key proliferation and survival 
signaling pathways have been identified (6).  Recent work has focused on targeting these tumor 
specific pathways in hopes of improving treatment efficacy and minimizing treatment toxicity.  
Because molecularly targeted agents have been mostly ineffective when used alone, combination 
therapy that inhibits multiple pathways is an appealing strategy. 
 
Kinase Inhibitors: 
Most growth factors initiate intracellular second messenger signaling systems through activation 
of tyrosine and/or serine/threonine kinase receptors.  The kinase regions catalyze transfer of 
phosphate groups from adenosine triphosphate (ATP) to transmembrane receptors or signal 
transducers to initiate signaling pathway activation.    The development of kinase inhibitors in 
cancer treatment has been stimulated by the success of imatinib mesylate in treating chronic 
myeloid leukemia (CML) and gastrointestinal stromal tumors (GIT).  Imatinib mesylate 
specifically inhibits kinase activities associated with bcr-abl, c-kit, and PDGF receptor which are 
improperly regulated in CML and GIT.   
Research has identified specific aberrant pathways that are thought to be important in malignant 
gliomas. (6) Specifically inhibiting these aberrant pathways may improve outcome without 
significant toxicity. 
 
Vascular endothelial growth factor (VEGF) pathway inhibitors: 
Malignant gliomas are highly vascular tumors that depend on angiogenesis for growth and 
proliferation.  VEGF pathway inhibitors were developed to inhibit tumor angiogenesis.  Despite 
promising preclinical results, most VEGF inhibitors failed to yield long term survival benefits as 
single agents.  Success has been achieved by combining inhibitors of VEGF signaling with 
standard cytotoxic chemotherapy (7).  Bevacizumab, an anti-VEGF antibody, has shown 
encouraging results when combined with irinotecan in a phase II trial for GBM.(4) (8) 
 
Multi-targeted kinase inhibitors: 
When used alone, targeted agents have been mostly ineffective in the treatment of malignant 
gliomas.  This is thought to be secondary to the existence of multiple parallel or compensatory 
oncogenic pathways that allow tumor cells to escape and survive.  To combat this problem, newer-
generation small-molecule kinase inhibitors are designed to target multiple aberrant signaling 
pathways in the tumors and tumor-associated vasculature. 
1.2.3.1 
Sorafenib (BAY 43-9006): 


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Sorafenib is an oral multi-kinase inhibitor with effects on tumor proliferation and tumor 
angiogenesis. (9)  It was initially selected based on inhibitory activity against the serine/threonine 
kinases Raf-1 and wild-type B-Raf, which are pivotal components of the Ras/Raf/MEK/ERK 
signaling pathway.  Inhibitory activity was subsequently demonstrated against tyrosine kinases for 
vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor (PDGF) 
receptor as well as Flt-3 and c-Kit. (9) Although most GBMs lack RAF mutations, targeting the 
RAF/MEK/ERK pathway may be beneficial as this pathway may be activated by other genetic 
alterations upstream from Raf. 
The Raf/MEK/ERK pathway is an important mediator of responses to growth factors, and a strong 
inducer of genes involved in tumorigenesis, angiogenesis, apoptosis, and tumorigenesis. (10)   
In preclinical studies, sorafenib demonstrated broad-spectrum anti-tumor activity by inducing 
complete tumor stasis and inhibition of tumor angiogenesis in a variety of tumor types. In the 
murine renal adenocarcinoma (Renca) (11) and VHL -/- xenograft models, sorafenib prevented 
tumor growth, primarily through the inhibition of tumor-cell-induced angiogenesis and also 
induced tumor apoptosis and necrosis.  
The safety and clinical activity of sorafenib, alone (12-15) or in combination (16,17) with 
chemotherapy, has been examined in a series of phase I studies conducted in patients with solid 
tumors. Results of a multi-center, randomized, placebo-controlled, double-blind phase III trial of 
sorafenib in advanced renal cell carcinoma (RCC) were first reported in 2005. (18)  There was a 
progression free survival advantage for the sorafenib group (5.5 months vs 2.8 months). 
Subsequent overall survival was not different between the groups overall, but when patients who 
crossed over to receive sorafenib were excluded, there was a survival benefit.  
1.2.3.2 
Rationale and Experience for Use of Sorafenib in GBM 
Both increased activation of angiogenesis and the MAP Kinase pathway are associated with the 
mesenchymal/angiogenic phenotype and resistance to standard therapy in newly diagnosed 
glioblastoma (GBM). Sorafenib is a multi-functional small molecule inhibitor that targets both the 
Raf/MAP Kinase pathway and VEGF receptors, and is thus a potentially ideal agent for targeting 
GBM with the mesenchymal/angiogenic phenotype.  
A Phase I study of single agent sorafenib in recurrent malignant glioma (B.  Nabors, PI, NABTT 
study) has accrued 43 patients, including 27 glioblastoma patients. Dosages up to 800mg BID were 
tolerated well, with only grade 3 hand-foot syndrome observed in up to 33% of patients at 400mg 
BID and 800mg BID.  Observed toxicities were similar in patients on enzyme-inducing anti-
epileptics and those not on enzyme-inducing anti-epileptics. Pharmacokinetic parameters also 
demonstrated no significant differences between enzyme-inducing and non-enzyme inducing anti-
epileptic medication groups. There were 3 complete responses and 5 partial responses amongst 41 
evaluable patients, suggesting significant single agent activity. 
 
PI3K/AKT/mTOR pathways: 
Apoptosis, commonly called programmed cell death in developmental biology, is a major 
mechanism of cell death in response to many toxic stimuli, including withdrawal of external 
survival signals and DNA damage.  Resistance to apoptosis is one of the hallmarks of cancer.  The 
mammalian target of rapamycin (mTOR) protein is a downstream component of the PI3K/Akt 
pathway.(6)  It regulates proliferation by activating downstream protein kinases required for 
ribosomal biosynthesis and mRNA translation, thus driving cell cycle progression.  Tumors that 


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depend on the activation of the PI3K pathway or that harbor mutations causing constitutive 
activation of the PI3K pathway may be more susceptible to rapamycin and its derivatives that 
inhibit mTOR.  Activation of the PI3K pathway by overexpression of upstream growth factor 
receptors (eg. EGFR and/or deletion of PTEN) is significantly associated with increasing tumor 
grade, decreased levels of apoptosis, and adverse clinical outcome in human gliomas.  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).(19)  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).(20) Activated 
AKT phosphorylates TSC2, which lead to the dissociation of TSC1/TSC2 complex, thus inhibiting 
the ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small G-protein, to 
remain in a GTP bound state and to activate mTORC1. AKT can also activate mTORC1 by 
PRAS40 phosphorylation, thereby relieving the PRAS40-mediated inhibition of mTORC1.(21)  
mTORC2 (mTOR complex 2) is activated through a currently unknown mechanism, possibly by 
receptor tyrosine kinase (RTK) signaling.(21) It has been suggested that mTORC2 phosphorylates 
and activates a different pool of AKT, that is not upstream of mTORC1.  Therefore, targeting 
mTOR is a promising target in the clinical management of glioma patients.  A phase II study of 
temsirolimus, a mTOR inhibitor, in recurrent GBM demonstrated modest efficacy with some 
evidence of activity based on molecular phenotype. (10)  Everolimus (everolimus; Novartis) is a 
novel oral derivative of rapamycin. 
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 (active vs inactive).  
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). 
 
Rationale for combination therapy: 
Preclinical data suggest that blocking more than one target more effectively inhibits tumor growth. 
(22)  Combining everolimus and sorafenib allows targeting of both the PI3K pathway and the 
RAF-MAPK pathway and in addition targets VEGF and PDGF, other active targets in malignant 
glioma.  Trials of mTOR inhibition (not everolimus) with sorafenib are underway but the dose of 
the mTOR inhibitor, in particular CCI-779, being used in one of these trials is sufficiently low that 
it is likely not therapeutic.  We believe that the combination of everolimus and sorafenib will be 
more tolerable, thus allowing therapeutic doses of both.  In addition, continuous oral dosing of 
both may provide a more sustained pathway inhibition. 
 
Rationale for patient outcomes measures: 
1.2.6.1 
Rationale for the patient-reported outcomes:   
This study seeks to establish effective therapies at recurrence and improve on current clinical 
results in patients with glioblastoma.  We hypothesize that using a combination of everolimus and 
sorafenib will result in improved survival.  However, given the intensive nature of this regimen, it 
will be important to determine whether any determined survival benefit is associated with 
improvements in symptoms or does a worsening of symptoms offset the increase in survival.  


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Precedence for measuring “non-therapeutic” endpoints exists in oncology research.  For example, 
Gemcitabine was approved by the FDA partially as a consequence of the decrease in pain reported 
in pancreatic patients who were treated, not on the basis of survival improvement which was 
modest, at best (23).  There have been efforts in neuro-oncology to evaluate secondary endpoints 
using validated instruments as an additional indicator of benefit.   
The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) allows the self-
reporting of symptom severity and interference with daily activities.  The MDASI-BT has 
demonstrated reliability and validity in the adult primary brain tumor patient population (24). This 
tool represents a modification of the widely used and validated MDASI, with particular attention 
to symptoms common in patients with brain tumors.   The availability of validated instruments 
provides an opportunity to prospectively assess the impact of treatment, both positive and negative, 
on patients.  This evaluation of symptom burden in this study will assist in finding the best possible 
treatment with the least toxicity. 
 
Summary of Phase I Toxicities  
Dose Level 1 had 3/6 patients who had a DLT, necessitating a dose reduction to dose level -1.  At 
that level only 1/6 DLTs was seen hence this is the MTD for phase II.   
 (DOSE LEVEL 1) 
 
Patient 1 
Grade 3 
HTN 
DLT 
 
Elevated ALT 
DLT 
Hypercholesterolemia DLT 
Hyperglycemia 
DLT 
Grade 4 
Hypertriglyceridemia 
DLT 
Patient 2 
Grade 3 
Lymphopenia 
 
Patient 3 
Grade 3 
Lymphopenia 
 
Patient 4 
None 
N/A 
n/a 
Patient 5 
Grade 3 
Thrombocytopenia 
 
Chest Pain 
DLT 
Fatigue 
DLT 
Patient 6 
Grade 3 
Fatigue 
DLT 
Lymphopenia 
 
 (DOSE LEVEL -1) 
Patient 1 
Grade 3 
Myositis 
DLT 
Nausea 
DLT 
Fatigue 
DLT 
Hypertension 
DLT 
Lymphopenia 
 
Thrombocytopenia 
 


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Hypercholesterolemia DLT 
Patient 2,3,4,5,6 
None 
N/A 
n/a 
2.0 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
Unless otherwise specified, in the Inclusion Criteria for Phase I or Phase II, all patients must meet 
the General Eligibility Criteria described below. Eligibility waivers are not permitted.  
Subjects must meet all of the inclusion and none of the exclusion criteria to be registered to the 
study. Study treatment may not begin until a subject is registered. See section 2.3 for registration 
procedures. 
 
ELIGIBILITY CRITERIA 
 
General Inclusion Criteria  
2.1.1.1 
Patients with histologically proven recurrent intracranial malignant glioma will be 
eligible for the phase I/II component of this protocol.  Malignant glioma includes 
glioblastoma (GBM), Gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic 
oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant 
astrocytoma NOS (not otherwise specified). Patients will be eligible if the original 
histology was low-grade glioma and a subsequent histological diagnosis of a malignant 
glioma is made. 
2.1.1.2 
All patients must sign an informed consent indicating that they are aware of the 
investigational nature of this study.  Patients must have signed an authorization for the 
release of their protected health information at all sites except the NIH. 
2.1.1.3 
Patients must be > 18 years old. 
2.1.1.4 
Patients must have a Karnofsky performance status of > 60. 
2.1.1.5 
No more than 2 prior chemotherapies and 1 relapse.  Prior bevacizumab therapy is 
allowed. 
• Patients must have recovered from the toxic effects of prior therapy: >3 weeks for 
biologic therapies or non-cytotoxic therapies, >4 weeks for cytotoxic therapies, and 
>6 weeks for nitrosoureas. Any questions related to the definition of non-cytotoxic 
agents should be directed to the Study Chair. 
NOTE:  13 cis-retinoic acid (Accutane) as biologic therapy has a washout period of 14 
days.  
2.1.1.6 
Patients must have adequate bone marrow function (WBC ≥ 3.0 x 109/L, ANC ≥ 1.5 X 
109/L, platelet count of ≥100 x 109/L, and hemoglobin ≥ 10 gm/dL), adequate liver 
function (SGOT and bilirubin < 2 times ULN), and adequate renal function (creatinine 
< 1.7mg/dL or creatinine clearance > 60 cc/min) before starting therapy.  These tests 
must be performed within 14 days prior to registration.  Eligibility level for hemoglobin 
may be reached by transfusion.  
2.1.1.7 
Patients must have shown unequivocal radiographic evidence for tumor progression by 
MRI or CT scan as defined by Section 5.2.1.3.5.  A scan should be performed within 
14 days prior to registration and on a steroid dose that has been stable or decreasing for 


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at least 5 days. If the steroid dose is increased between the date of imaging and 
registration a new baseline MRI/CT is required. The same type of scan, i.e., MRI or 
CT must be used throughout the period of protocol treatment for tumor measurement. 
Measurable disease is NOT required.  
Note:  *MRI is the preferable imaging method; CT scan may be used in cases where 
an MRI cannot be obtained.   
2.1.1.8 
Patients having undergone recent resection of recurrent or progressive tumor will be 
eligible as long as all of the following conditions apply: 
• They have recovered from the effects of surgery and be > 3 weeks from surgery.  
• Residual disease following resection of recurrent malignant glioma is not mandated 
for eligibility into the study. To best assess the extent of residual disease post-
operatively, a CT/ MRI should be done no later than 96 hours in the immediate 
post-operative period or at least 4 weeks post-operatively, within 14 days prior to 
registration.  If the 96-hour scan is more than 14 days before registration, the scan 
needs to be repeated.  If the steroid dose is increased between the date of imaging 
and registration, a new baseline MRI/CT is required on a stable steroid dosage for 
at least 5 days. 
2.1.1.9 
Patients must have failed prior radiation therapy and must have an interval of greater 
than or equal to 12 weeks from the completion of radiation therapy to registration; 
except if patients underwent surgery within 12 weeks and pathology is consistent with 
recurrent tumor. 
2.1.1.10 
Patients with prior therapy that included interstitial brachytherapy or stereotactic 
radiosurgery must have confirmation of true progressive disease rather than radiation 
necrosis based upon either PET or Thallium scanning, MR spectroscopy or 
surgical/pathological documentation of disease. 
2.1.1.11 
Women of childbearing potential must have a negative B-HCG pregnancy test 
documented within 7 days prior to taking the first dose of study medications. 
2.1.1.12 
Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin 
may be allowed to participate.  For patients on warfarin, the INR should be measured 
prior to initiation of sorafenib and monitored at least weekly, or as defined by the local 
standard of care, until INR is stable.  
 
Phase I Inclusion Criteria 
The following modifications to the general eligibility criteria apply to Phase I patients only. 
• 
Patients may have had treatment for any number of prior relapses. Relapse is defined 
as progression following initial therapy (i.e. surgery and radiation+/- chemo if that was 
used as initial therapy). 
 
Phase II Inclusion Criteria 
• 
Phase II patients must meet the following Eligibility Criteria in addition to the General 
Criteria described above. Patients may have had treatment for no more than 1 prior 
relapse (i.e. failed 2 lines of treatment-initial therapy and therapy for first relapse) at 
2nd relapse, treatment per BTTC09-01 is an option; see relapse and treatment count 


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table below).  Relapse is defined as progression following initial therapy (i.e. 
radiation+/- chemo if that was used as initial therapy).  The intent therefore is that 
patients had no more than 2 prior therapies (initial and treatment for 1 relapse). If the 
patient had a surgical resection for relapsed disease and no anti-cancer therapy was 
instituted for up to 12 weeks, and the patient undergoes another surgical resection, this 
is considered as 1 relapse.  For patients who had prior therapy for a low-grade glioma, 
the surgical diagnosis of a high-grade glioma will be considered the first relapse. 
Relapse and Treatment Count 
Initial diagnosis         → 
Surgical resection  
 
Radiation + Chemotherapy #1 
Relapse #1                → 
+/- 
Surgical 
resection 
 
Chemotherapy #2 
Relapse (#2)               → 
Patient to be evaluated for enrollment to BTTC09-01 
 
• 
Patients must not have received prior therapy with sorafenib, everolimus, or related 
drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab), or 
mTOR inhibitors. 
 
General Exclusion Criteria 
2.1.4.1 
Patients has any significant medical illnesses that in the investigator’s opinion cannot 
be adequately controlled with appropriate therapy or would compromise the patient’s 
ability to tolerate this therapy 
2.1.4.2 
Patients with a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for 
that disease for a minimum of 3 years are ineligible. 
2.1.4.3 
Patient has an active infection or serious intercurrent medical illness. 
2.1.4.4 
Patient has any disease that will obscure toxicity or dangerously alter drug metabolism. 
2.1.4.5 
Patients is on an enzyme inducing anti-convulsants.  If patients were previously on 
EIAEDs and these have been discontinued, patients must have been off the agent for at 
least 2 weeks prior to first study drug administration. For patients who need to start an 
AED or the AED needs to be changed, it is strongly recommended that all efforts should 
be made to use a non-EIAED. 
2.1.4.6 
Patients who have any severe and/or uncontrolled medical conditions or other 
conditions that could affect their participation in the study such as:  Symptomatic 
congestive heart failure of New York heart Association Class III or IV unstable angina 
pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months 
of start of study drug or any other clinically significant cardiac disease severely 
impaired lung function as defined as spirometry and DLCO that is 50% of the normal 
predicted value and/or 02 saturation that is 88% or less at rest on room air, uncontrolled 
diabetes as defined by fasting serum glucose >1.5 x ULN, active (acute or chronic) or 


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uncontrolled severe infections, liver disease such as cirrhosis, chronic active hepatitis 
or chronic persistent hepatitis. 
2.1.4.7 
Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. 
2.1.4.8 
Uncontrolled hypertension defined as systolic blood pressure > 140 mmHg or diastolic 
pressure > 90 mmHg, despite optimal medical management. 
2.1.4.9 
Known human immunodeficiency virus (HIV) infection or chronic or acute Hepatitis 
B or C. Note: Patients who have a history of HBV and HCB infection are eligible, 
however, they must receive prophylactic antiviral therapy for 1-2 weeks prior to 
receiving study drug (see Section 3.3.2) 
2.1.4.10 
Thrombolic or embolic events (except DVT or pulmonary embolus) such as a 
Cerebrovascular accident including transient ischemic attacks within the past 6 months.  
2.1.4.11 
Pulmonary hemorrhage/bleeding event ≥ CTCAE Grade 2 within 4 weeks of first dose 
of study drug. 
2.1.4.12 
Any other hemorrhage/bleeding event ≥ CTCAE Grade 3 within 4 weeks of first dose 
of study drug. 
2.1.4.13 
Serious non-healing wound, non-healing ulcer, or bone fracture. 
2.1.4.14 
Evidence or history of bleeding diathesis or coagulopathy 
2.1.4.15 
Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study 
drug.  
2.1.4.16 
Use of St. John’s Wort, orrifampin (rifampicin), or other strong CYP34A inducers.  
Dexamethasone is okay as long as the dose is 16 mg /day or less. Note: Patients who 
are on the above referenced medications may be considered eligible with a washout 
period of 14 days.  Contact the coordinating center to discuss patients with the above 
aforementioned agents before patient registration. 
2.1.4.17 
Known or suspected allergy to sorafenib, everolimus, or any agent given in the course 
of this trial. 
2.1.4.18 
Any condition that impairs patient‘s ability to swallow whole pills. 
2.1.4.19 
Any malabsorption problem. 
2.1.4.20 
Other malignancies within the past 3 years except for adequately treated carcinoma of 
the cervix or basal or squamous cell carcinomas of the skin. 
2.1.4.21 
Female patients who are pregnant or breast feeding, or adults of reproductive potential 
who are not using effective birth control methods. Barrier contraceptives must be used 
throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole 
method of contraception.  (Women of childbearing potential must have a negative urine 
or serum pregnancy test within 7 days prior to administration of everolimus and 
sorafenib). 
2.1.4.22 
Patients who have received prior treatment with an mTOR inhibitor (sirolimus, 
temsirolimus, everolimus). 


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2.1.4.23 
Patients with a known hypersensitivity to everolimus or other rapamycins (sirolimus, 
temsirolimus) or to its excipients. 
2.1.4.24 
History of noncompliance to medical regimens. 
2.1.4.25 
Patients unwilling to or unable to comply with the protocol. 
2.1.4.26 
Patients on total daily dose of dexamethasone greater than 16 mg. 
 
SCREENING EVALUATION 
Prior to registration on the study, all patients will undergo the following screening tests within 14 
days of registration: 
• A complete medical history, concomitant medication review, physical exam with vital 
signs (heart rate, blood pressure, respiration rate, height and weight) and neurological 
examination (to include documentation of the patients Karnofsky Performance Status per 
Appendix 13.1) 
• Neuro-imaging confirming tumor progression shall be performed on all patients.  The scan 
done prior to study entry documenting progression will be reviewed by the patient’s 
treating physician to confirm progression of disease.   
• Pre-study tests shall include ECG chest X-ray (or CT scan with lung windows) within 30 
days of treatment, and laboratory studies including CBC, differential, platelets, serum 
creatinine, phosphate, lipase, amylase, bilirubin, SGOT, PT, PTT, fasting serum glucose 
and lipid panel, urinalysis with microanalysis, HBV-DNA, HbsAg, HBsAb (Qualitative), 
HBcAb, HCV-RNA-PCR and serum pregnancy test for women of childbearing potential.  
All patients should be screened for hepatitis risk factors and any past illnesses of hepatitis 
B and hepatitis C infection.  All patients with positive HBV-DNA or HBsAg should be 
treated prophylactically with an antiviral (i.e. Lamivudine) for 1-2 weeks prior to receiving 
study drug (see Section 3.3.2). The antiviral treatment should continue throughout the 
entire study period and for at least 4 weeks after the last dose of everolimus. Patients with 
viral hepatitis C risk factors should be screened for HCV RNA-PCR.  UPC ratio must be 
obtained if urinalysis has >2+ protein.  Pre-study tests (except pregnancy test) must be 
obtained within 14 days of registration.  Pregnancy test must be obtained within 7 days 
prior to starting the study drugs. 
• Documentation of tumor diagnosis. Following registration, slides from the most recent pre-
registration biopsy or resection must be submitted for review to local institution if surgery 
was not done there. 
• Neuro-imaging confirming tumor.  (See section 2.5) 
 
REGISTRATION PROCEDURES 
Patients who are candidates for the study will first be evaluated for eligibility by the local 
investigator. All patients must be registered both locally and centrally with BTTC. 
BTTC patients will be registered with the BTTC Coordinating Center.  All eligibility requirements 
will be checked prior to registration.  The status of all regulatory documents will be checked prior 
to registration. No patient will be entered on protocol if they do not satisfy all regulatory document 
and eligibility requirements.  


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Informed Consent 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an Institutional 
Review Board (IRB) approved consent form. 
Registrations must be completed after the patient has signed the informed consent and has been 
determined to be eligible by the local investigator.  
At the time of registration, the following information will be requested by the BTTC Coordinating 
Center: 
• A copy of a completed and signed, protocol specific, Eligibility Checklist form  
• One copy of the signed and dated Informed Consent.  
• Copies of all source documents to support protocol specific eligibility.  Please refer to 
the Operations Manual for specific source documents required.  
 
 
Registration at the NCI 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent for patients enrolling at the lead institution.  A registration 
Eligibility Checklist from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) 
must be completed and hand delivered to the BTTC Coordinating Center or sent via encrypted 
email to the BTTC Coordinating Center Research Nurse..  After confirmation of consent, available 
slot, and eligibility, the BTTC CC research nurse will send the registration Eligibility Checklist to 
CRO ncicentralregistration-l@mail.nih.gov via encrypted email. CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 
the research team with a copy to the BTTC Coordinating Center. A recorder is available during 
non-working hours. 
 
Participating Site Registration (Not Applicable as of Amendment C) 
All patients must be registered through the NCI Central Registration Office (CRO).  A protocol 
registration form and cover memo will be supplied by the Coordinating Center, NCI CCR and 
updates will be provided as needed. Subject eligibility and demographic information is required 
for registration. To initially register a subject, after the participant has signed consent, complete 
the top portion of the form and send to NCI BTTC Coordinating Center’s Research Nurse, Melanie 
Herrin, RN, Fax 301-451-5429, email Melanie.Herrin nci_bttc@mail.nih.gov.  Once eligibility is 
confirmed, send the completed eligibility checklist with the attached supporting source documents 
to NCI BTTC Coordinating Center’s Research Nurse, Melanie Herrin, RN. If patient is not 
eligible, please notify NCI BTTC Coordinating Center’s Research Nurse, Melanie Herrin, RN. 
The CRO will notify you either by e-mail or fax that the protocol registration form has been 
received. Questions about eligibility should be directed to the NCI BTTC Coordinating Center’s 
Research Nurse, Melanie Herrin, RN.  
2.3.3.1 
Patient Number for Participating Institutions (Not Applicable as of Amendment C) 
Once eligibility has been confirmed by the Coordinating Center, the patient from the participating 
institution will be registered through the Central Registration Office. A Verification of Registration 
will be received from the Central Registration Office with the assigned patient ID number. The 


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patient ID number is unique to the patient and must be written on all data and correspondence for 
the patient and used to enter data into the C3D database.  The participating site will receive the 
Verification of Registration via fax or email within one working day of registration. 
 
Initiation of Therapy 
Treatment may not be initiated until the participating institution receives a faxed or emailed copy 
of the patient’s Registration Verification Letter from the Central Registration Office.  
All Patients that are eligible to receive therapy must initiate treatment within 96 hours after 
the registration.   
The BTTC Coordinating Center must be notified in writing of any exceptions to this policy.  
 
Eligibility Exceptions 
Eligibility Exceptions will not be granted. 
 
TREATMENT ASSIGNMENT AND DESCRIPTIVE FACTORS 
Patients with recurrent malignant glioma will be enrolled into one of the following groups. Accrual 
goals and endpoints for each group are determined separately as described in the statistical section.   
There will be an accrual of approximately 3-6 eligible patients per dose level to the Phase I 
component of the study.  Patients removed at any time for toxicity are evaluable.  Phase I patients 
removed from study treatment within 28 days for reasons other than toxicity may be replaced. 
 
Cohorts 
Number Name 
Description 
1 
Phase 1 (closed) 
Patients with Glioblastoma or Anaplastic Glioma 
2A 
Phase 2 Group A 
(closed) 
Patients with Glioblastoma with NO prior bevacizumab 
exposure 
2B 
Phase 2 Group B 
Patients with Glioblastoma with PRIOR bevacizumab 
exposure 
2C 
Phase 2 Group C 
(closed) 
Patients with Anaplastic Glioma with NO prior 
exposure to bevacizumab (Grade III Glioma Group) 
 
Arms 
Number 
Name 
De`scription 
1 
Phase 1 (closed) 
Combination of sorafenib (7 days on, 7 days off) and 
everolimus daily over a 28-day cycle at escalating doses 
 


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2 
Phase 2 
Combination of sorafenib (7 days on, 7 days off) and 
everolimus daily over a 28-day cycle: 
Sorafenib 400 mg BID PO (days 1-7 and days 15-21) 
Everolimus 5 mg PO daily (days 1-28) 
 
 
There will be a total accrual of approximately 82 eligible patients to the Phase II study (34 recurrent 
GBM with no prior exposure to bevacizumab, 16 recurrent Anaplastic Glioma with no prior 
exposure to bevacizumab, and 32 glioblastoma with prior exposure to bevacizumab). 
Subjects in Cohort 1 were directly assigned to Arm 1. 
Subjects in Cohorts 2A, 2B and 2C will be directly assigned into Arm 2.  
 
BASELINE EVALUATION 
After eligibility is confirmed, complete the following baseline study tasks: 
• Patients will complete a baseline MD Anderson Symptom Inventory-Brain Tumor 
Module (MDASI-BT) (Appendix 13.4) within 14 days (+ 3 working days) after 
enrollment on the clinical trial. The MDASI-BT will be completed only by the patient, 
unless changes in vision or weakness make this difficult. If this occurs, then the caregiver 
or research assistant may read the questions to the patient or assist with marking the 
severity number or score as described by the patient. A patient caregiver may complete 
the questionnaires as a patient-preference proxy if the patient’s deficits preclude self-
report.  
• The screening scan can be used as the baseline scan if performed within 14 days of 
registration on a stable dose of steroids.  Patients should not be on a steroid dose higher 
than 16 mg/day.  (Refer to 2.1.1.7 and 2.1.1.8) 
• Document baseline adverse events 
• For all women of childbearing potential, negative serum pregnancy test within 7 days of 
starting treatment. 
• If treatment will start > 14 days after screening evaluations were completed, then repeat 
the following labs:  
o CBC, differential, platelets 
o Serum creatinine, phosphate 
o lipase, amylase 
o bilirubin, SGOT 
o PT, PTT 
o Fasting serum glucose and fasting lipid panel 
o Urinalysis with microanalysis; UPC ratio must be obtained if urinalysis has >2+ 
protein.   


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3.0 STUDY IMPLEMENTATION  
This is a phase 1 /2 study of everolimus and sorafenib in patients with recurrent high-grade 
gliomas. Patients must initiate study treatment within 96 hours after registration. 
All patients will be monitored for hematologic or serologic evidence of myelosuppression, hepatic 
injury, renal injury, and electrolyte disturbances and for clinical evidence of other toxicity as is 
described in section 3.5. 
 
PHASE 1 STUDY DESIGN 
 
Drug Administration 
Patients will be treated with daily everolimus (days 1-28) in combination with sorafenib (as per 
the table below).   
The schedule providing highest dose without DLT (as defined above) will be used as the phase II 
dose.  The dose levels are listed in Table 3-11. 
There is not a defined set maximum number of cycles that a patient may have.  Patients may 
continue with protocol therapy until criteria for “Off Treatment” is met.  Off treatment criteria 
could be any of the following events/reasons; disease progression, intolerable side effects 
(toxicities) and/or withdrawal from study. 
 
Dose Escalation 
Patients will be treated at the dose levels in Table 3-11 starting at dose level 1.  Initially everolimus 
and sorafenib will be administered continuously.  If two DLTs are encountered at the first dose 
level (sorafenib 400 mg twice daily and everolimus 5 mg daily) the dose for the next cohort of 
patients will be decreased to sorafenib 400 mg twice daily 7 days on, 7 days off and everolimus 5 
mg daily (dose level -1).  If dose level -1 is tolerated, dose escalations will occur along the “b” 
pathway (-1, 1b, 2b, 3b, 4b). 
If two DLTs are encountered at dose level 2, the dose for the next cohort of patients will be reduced 
to sorafenib 400 twice daily, 7 days on 7 days off and everolimus 7.5 mg daily (dose level 1b).  
Subsequent dose escalations will occur along the “b” pathway (2, 1b, 2b, 3b, 4b). 
The study drugs will be self-administered (by the patients themselves). The investigator will 
instruct the patient to take the study drug exactly as specified in the protocol. Patients will be 
instructed to take the study drugs in the morning, at the same time each day.  
The study drugs must be taken 1 hour before or two hours after food. Consumption of grapefruit 
juice should be avoided while taking the study drugs.  If vomiting occurs, no attempt should be 
made to replace a dose.  
All dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded. 
Table 3-1: Phase I dosing table. 
DOSE 
LEVEL 
SORAFENIB 
EVEROLIMUS 
 -1 
400 mg BID,  
5 mg daily 


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DOSE 
LEVEL 
SORAFENIB 
EVEROLIMUS 
7 days on 7 days off 
1 
400 mg BID 
5 mg daily 
2 
400 mg BID 
7.5 mg daily 
3 
400 mg BID 
10 mg daily 
4 
600 mg BID 
10 mg daily 
 
1b 
400 mg BID, 7 days on 7 days off 7.5 mg daily 
2b 
400 mg BID, 7 days on 7 days off 10 mg daily 
3b 
600 mg BID, 7 days on 7 days off 10 mg daily 
4b 
800 mg BID, 7 days on 7 days off 10 mg daily 
 
Note:  On the sorafenib 7 days on 7 days off schedule, sorafenib will be given on 
days 1-7 and 15-21. 
The MTD will be based on the assessment of DLT during the first 28 days of treatment only (cycle-
1), and will be defined as the dose at which fewer than one-third of patients experience a DLT to 
one of the study drugs.  The MTD is the dose level at which 0/6 or 1/6 patients experience DLT 
with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. Three patients will 
be treated at each dose level.  If one dose limiting toxicity (DLTs) is encountered an additional 3 
patients will be added to that dose level.  If at any point two DLTs are encountered within a given 
dose level, then the MTD has been exceeded and three more patients are treated at the next lower 
dose (if only three patients were previously treated at that prior dose). 
 
 Dose-Limiting Toxicity 
Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. If multiple toxicities are seen, the presence of DLT should be based on the 
most severe toxicity experienced. DLT will be defined as any of the following events occurring 
during treatment with sorafenib and/or everolimus and attributable to one of the study drugs: 
3.1.3.1 
Any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile 
neutropenia of any grade. 
3.1.3.2 
Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or hand/foot 
reaction. 
3.1.3.3 
Failure to recover from toxicities (to grade 1 or less) to be eligible for re-treatment with 
sorafenib and everolimus within 14 of the last dose of sorafenib and everolimus.  


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PHASE II STUDY DESIGN 
 
Drug Administration 
All patients treated on the phase II cohorts will receive a combination of sorafenib (7 days on, 7 
days off) and everolimus daily over a 28-day cycle, as follows: 
Sorafenib 400 mg BID PO (days 1-7 and days 15-21) 
Everolimus 5 mg PO daily (days 1-28) 
There is not a defined set of maximum number of cycles that a patient may have.  Patients may 
continue with protocol therapy until criteria for “Off Treatment” is met.  See Section 3.7.1. 
 
DOSE MODIFICATIONS IN PHASE I (POST CYCLE 1) AND PHASE II 
Patients with stable or responding disease may be retreated at the same dose or at a reduced dose 
level, depending upon the adverse events observed in the current cycle and any adverse events 
(based on the CTCAE v.4) present on the first day of the next cycle. If multiple toxicities are seen, 
the dose administered in a subsequent cycle should be based on the most severe toxicity 
experienced in the current cycle.  
Patients who experience toxicity should have laboratory testing at least weekly until the toxicity 
has resolved. 
Toxicities will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. If multiple toxicities are seen, the toxicity should be based on the most 
severe toxicity experienced. Toxicities will be defined as any of the following events occurring 
during treatment with sorafenib and/or everolimus and attributable to one of the study drugs: 
A. Any grade 3 thrombocytopenia, grade 4 anemia, grade 4 neutropenia, or febrile 
neutropenia of any grade. 
B. Any non-hematologic grade 3 or grade 4 toxicity, excluding alopecia and/or 
hand/foot reaction. 
C. Failure to recover from grade 3 or 4 toxicities (to grade 1 or less) to be eligible 
for re-treatment with sorafenib and everolimus within 14 of the last dose of 
sorafenib and everolimus.  
 
Within Treatment Cycles  
If a patient experiences toxicities during a treatment cycle, the treatment will be immediately 
suspended until a grade 1 or less toxicity.  If the toxicity resolves to less than or equal to grade 1 
within 2 weeks, the patient will be retreated at the dose level described in Table 3-2 below. (Refer 
to Table 3-6 and Table 3-7 for management of everolimus-induced toxicities and Table 3-8, Table 
3-9 and Table 3-10 for management of sorafenib-induced toxicities.) If toxicity persists, the patient 
should be taken off study.  
Two dose reductions are permitted. Doses that are reduced for sorafenib or everolimus related 
toxicity will not be re-escalated, even if there is minimal or no toxicity with the reduced dose. 
Patients whose dose has been reduced for adverse events that are subsequently not felt to be related 
to sorafenib or everolimus may have the dose re-escalated after completion of one cycle with 
toxicities less than or equal to grade 1. If any patient has further toxicities that would require 
additional reductions, or if treatment is held for more than 2 consecutive weeks because of ongoing 


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toxicity, the Study PI will assess if the patient should remain in the study (if the patient has 
benefited from treatment). 
Table 3-2: Dose Modification Table  
DOSE LEVEL 
SORAFENIB 
EVEROLIMUS 
 
1 (starting dose) 
 
400 mg BID 
7 days on 7 days off 
 
5 mg daily 
 
-1 
 
400 mg AM dose 
200 mg PM dose 
7 days on 7 days off 
 
5 mg daily 
 
-2 
 
200 mg AM dose 
200 mg PM dose 
7 days on 7 days off 
 
5 mg daily 
 
3.3.1.1 
Hematologic Toxicity 
Dose Modifications Based on ANC and Platelet Counts obtained weekly for Phase I and every 2 
weeks for Phase II (sorafenib or everolimus):  Please note per CTCAE v 4, ANC 750-999 falls 
within grade 3 adverse event and Platelets 50,000 to <75,000 is grade 2. 
ANC (/mL)       Platelets (/mL) 
% of Dose Planned  
> 1000            and      > 75,000 
 
100%  
750-999(G3)    or 50,000 to < 75,000(G2) 
hold*  
< 750              or        < 50,000 (G3-G4) 
hold**  
* 
Suspect drug should be held.  Upon recovery to ANC > 1,500/mL and  
platelets to > 100,000/mL, the same dose level will be administered. 
**  
Suspect drug should be held.  Upon recovery to ANC > 1,500/mL and   
platelets to > 100,000/mL, one lower dose levels will be administered. 
3.3.1.2 
Non-hematologic Toxicity 
Dose Modifications  
Based on sorafenib or everolimus -Related Non-Hematologic Toxicities: 
CTCAEv.4 Grade 
% of Dose Planned  
0-2+ 
 
100%+ 
3* 
 
hold**  
4 
 
hold*** 
 
+For symptomatic Grade 2 toxicity, the suspect drug dose may be held at the 
discretion of the local investigator until recovery to CTCAE Grade 0-1, then resume 
at one dose lower. 
*Except nausea/vomiting (unless patients are on optimal antiemetic therapy) 
**Hold suspect drug until recovery to CTCAE Grade 0-1 (or to within 1 grade of 
starting values for pre-existing laboratory abnormalities), and then resume at one 
dose level lower.   


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***Hold suspect drug until recovery to CTCAE Grade 0-1 (or to within 1 grade of 
starting values for pre-existing laboratory abnormalities), and then resume at two 
dose levels lower. 
 
Management of Hepatitis 
3.3.2.1 
Management of Hepatitis reactivation 
In cancer patients with hepatitis B, whether carriers or in chronic state, use of antivirals during 
anticancer therapy has been shown to reduce the risk of hepatitis B virus (HBV) reactivation and 
associated HBV morbidity and mortality (Loomba et al. 2008). 
3.3.2.1.1 Monitoring and prophylactic treatment for hepatitis B reactivation 
Table 3-3 provides details of monitoring and prophylactic therapy according to the baseline results 
of viral load and serologic markers testing. 
Table 3-3: Action to be taken for positive baseline hepatitis B results 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
and no 
prior HBV 
vaccination 
+ or - 
- 
or + with prior 
HBV vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment 
should be started 1-2 
weeks prior to first dose 
of study drug 
Monitor HBV-DNA 
approximately every 4 
weeks 
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 hepatitis B reactivation, definition and management guidelines, see Table 3-4 Guidelines for 
management of hepatitis B.   
 


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Table 3-4: Guidelines for management of hepatitis B 
HBV reactivation (with or without clinical signs and symptoms)* 
For patients with baseline 
results:  
Positive HBV-DNA 
OR 
positive HBsAg 
------------------------------- 
reactivation is defined as:   
[Increase of 1 log in HBV-DNA 
relative to baseline HBV-DNA 
value OR new appearance of 
measurable HBV-DNA] 
AND 
ALT elevation x 5 ULN 
Treat: Start a second antiviral  
AND 
Interrupt study drug administration until resolution:  
 ≤ grade 1 ALT (or baseline ALT, if > grade 1) and 
 ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be 
re-started at one dose lower, if available. If the patient is 
already receiving the lowest dose of study drug according 
to the protocol, the patient should restart at the same dose 
after resolution. Both antiviral therapies should continue at 
least 4 weeks after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue 
study drug but continue both antiviral therapies at least 4 
weeks after last dose of study drug. 
For patients with baseline 
results:  
Negative HBV-DNA and 
HBsAg  
AND  
[Positive HBs Ab (with no prior 
history of vaccination against 
HBV), OR positive HBc Ab]  
------------------------------------- 
reactivation is defined as: 
New appearance of measurable 
HBV-DNA 
Treat: Start first antiviral medication  
AND 
Interrupt study drug administration until resolution:  
  ≤ baseline HBV-DNA levels 
If resolution occurs within ≤ 28 days study drug should be 
re-started at one dose lower, if available. If the patient is 
already receiving the lowest dose of study drug according 
to the protocol, the patient should restart at the same dose 
after resolution. Antiviral therapy should continue at least 4 
weeks after last dose of study drug.  
If resolution occurs > 28 days Patients should discontinue 
study drug but continue antiviral therapy at least 4 weeks 
after last dose of study drug. 
* All reactivations of hepatitis B are to be recorded as grade 3 (CTCAE v 4.0 Metabolic 
Laboratory/Other: Viral Re-activation), unless considered life threatening by the investigator; in 
which case, they should be recorded as grade 4 (CTCAE v 4.0 Metabolic Laboratory/Other: Viral 
Re-activation). Date of viral reactivation is the date on which both DNA and ALT criteria were 
met (e.g. for a patient who was HBV-DNA positive on 01-JAN-10 and whose ALT reached ≥ 5 × 
ULN on 01-APR-10, the date of viral reactivation is 01-APR-10). 
3.3.2.2 
Monitoring for hepatitis C 
The following two categories of patients should be monitored every 4 weeks for HCV reactivation: 


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• Patients with detectable HCV RNA-PCR test at baseline. 
• Patients known to have a history of HCV infection, despite a negative viral load 
test at baseline (including those that were treated and are considered ‘cured’) 
For definition of hepatitis C reactivation and the management guidelines, see 
Table 3-5 Guidelines for management of hepatitis C. 
Table 3-5: 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 v4.0 
Metabolic Laboratory/Other: Viral Re-activation), unless considered life 
threatening by the investigator; in which case, they should be recorded as grade 4 
(CTCAE v 4.0 Metabolic Laboratory/Other: Viral Re-activation). 
 
Management of stomatitis/oral mucositis/mouth ulcers  
CTCAE v 4.0 grade 1-2 stomatitis/oral mucositis/mouth ulcers due to everolimus should lead to 
using local supportive care such as use of mouthwash (avoid those containing alcohol). The use of 
topical high potency steroids such as triamcinolone oral paste 0.1% (Kenalog in Orabase®) is 
allowed. Please refer to section 3.3.1.2 for dose modifications.  Suggested guidelines 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 (e.g., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 


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3.  Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
4.  Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong inhibition of 
everolimus and sorafenib metabolism, therefore 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-CTCAE, version 4.0. 
 
 
Management of hyperlipidemia 
Everolimus causes hyperlipidemia.  Treatment of hyperlipidemia should take into account the pre-
treatment status and dietary habits. Blood tests to monitor hyperlipidemia must be taken in the 
fasting state. Grade 2 or higher hypercholesterolemia (>300 mg/dL or 7.75 mmol/L) or grade 2 or 
higher hypertriglyceridemia (>2.5 x upper normal limit) should be treated with a statin or 
appropriate lipid-lowering medication, in addition to diet. Patients should be monitored clinically 
and through serum biochemistry for the development of rhabdomyolysis and other adverse events 
as required in the product label/data sheets for HMG-CoA reductase inhibitors. Please refer to 
section 3.3.1.2 for dose modifications of everolimus. 
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. 
 
Management of hyperglycemia 
Grade 3 hyperglycemia has been observed in patients receiving everolimus therapy. In many cases 
the affected patients had an abnormal should have their glucose levels monitored during 
everolimus therapy. Please refer to section 3.3.1.2 for dose modifications. 
 
Management of non-infectious pneumonitis 
Table 3-6: Management of Everolimus-induced Pneumonitis 
Worst grade 
pneumonitis 
Required investigations 
Management of 
pneumonitis 
everolimus dose 
adjustment 
Grade 1  
 
CT scan with lung 
windows 
No specific 
therapy is 
required 
 
Administer 100% 
of everolimus 
dose 
Grade 2 
 
CT scan with lung 
windows.  Consider 
pulmonary function 
Symptomatic 
only.  Prescribe 
corticosteroids if 
Reduce 
everolimus dose 


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Worst grade 
pneumonitis 
Required investigations 
Management of 
pneumonitis 
everolimus dose 
adjustment 
testing including: 
spirometry, DLCO, and 
room air O2 saturation at 
rest. Repeat each 
subsequent Cycle until 
return to within normal 
limits. Consider a 
bronchoscopy. 
cough is 
troublesome. 
until recovery to ≤ 
grade 1.  
Everolimus may 
also be interrupted 
if symptoms are 
troublesome. 
Patients will be 
withdrawn from 
the study if they 
fail to recover to ≤ 
grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung 
windows and pulmonary 
function testing includes: 
spirometry, DLCO, and 
room air O2 saturation at 
rest; Repeat each 
subsequent Cycle until 
return to normal limits.  
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 a reduced 
dose (by one 
level) if evidence 
of clinical benefit. 
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 strongly 
recommended. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated. 
Discontinue 
treatment. 
 


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Management of suspected everolimus toxicity 
Table 3-7: Criteria for dose-modification in case of suspected everolimus toxicity and re-
initiation of everolimus treatment  
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
(except pneumonitis – refer to Table 3-6) 
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 same dose level. 
Grade 3 
(except hyperlipidemia*) 
(except pneumonitis – refer to Table 3-6) 
Interrupt everolimus until recovery 
to grade ≤1. Then reintroduce 
everolimus at same dose level. For 
pneumonitis consider the use of a 
short course of corticosteroids. 
Grade 4 
Discontinue everolimus. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥ 
50x109/L)  
Interrupt everolimus until recovery 
to grade ≤1 (>75 x109/L). Then 
reintroduce everolimus at initial 
dose. 
If thrombocytopenia again returns 
to grade 2, interrupt everolimus 
until recovery to grade ≤1. Then 
reintroduce everolimus at same dose 
level.  
Grade 3 Thrombocytopenia (platelets <50, ≥ 25 x109/L) Interrupt everolimus until recovery 
to grade ≤1 (platelets ≥ 75 x109/L).  
Then resume everolimus at same 
dose level.  If grade 3 
thrombocytopenia recurs, 
discontinue everolimus. 
Grade 4 Thrombocytopenia (platelets < 25 
x109/L) 
Discontinue everolimus. 


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Toxicity 
Actions 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt everolimus until recovery 
to grade ≤1 (neutrophils ≥ 1.5 x 
109/L). Then resume everolimus at 
the initial dose.  If ANC again 
returns to Grade 3, hold everolimus 
until the ANC ≥ 1.5 x 109/L.  Then 
resume everolimus dosing at same 
dose level.  Discontinue patient 
from study therapy for a third 
episode of grade 3 neutropenia. 
Grade 4 Neutropenia (neutrophils < 0.5 x109/L) 
Interrupt everolimus until recovery 
to grade ≤ 1 (neutrophils ≥ 1.5 x 
109/L). Then resume everolimus at 
the lower dose level. If grade 3 or 
grade 4 neutropenia occurs despite 
this dose reduction, discontinue 
everolimus. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt everolimus until resolution 
of fever and neutropenia to grade ≤ 
1. Hold further everolimus until the 
ANC ≥ 1,500/mm3 and fever has 
resolved. Then resume everolimus 
at same dose level. If febrile 
neutropenia recurs, discontinue 
everolimus. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue everolimus. 
Any hematological or non-hematological toxicity 
requiring interruption for ≥ 3 weeks 
Discontinue everolimus 
*Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) 
should be managed using medical therapies (see Sec. 3.3.4). 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value suspected to be related to everolimus must be followed at least weekly 
until the adverse event or abnormal laboratory resolves or returns to grade 1. If a patient requires 
a dose delay of > 21 days from the intended day of the next scheduled dose, then the patient must 
be discontinued from the study. 
 
Management of sorafenib induced skin toxicity  
It is common for patients treated with sorafenib to experience skin toxicity (rash/desquamation, 
hand/foot reaction, etc.).  Guidelines for management are specified in the table below. 


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Table 3-8: Guidelines for management of sorafenib induced skin toxicity 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 
1: 
 
Numbness, 
dysesthesia, 
paresthesia, 
tingling, painless swelling, 
and erythema or discomfort of 
the hands or feet which does 
not 
disrupt 
the 
patient’s 
normal activities. 
Any occurrence 
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief. 
Grade 2: Painful erythema and 
swelling of the hands or feet 
and/or discomfort affecting 
the patient’s normal activities. 
First occurrence 
 
 
 
No 
improvement 
within 7 days or 2nd 
occurrence 
 
 
Third occurrence 
 
 
 
Fourth occurrence 
Continue treatment with sorafenib and 
consider topical therapy for symptomatic 
relief.  If no improvement within 7 days, 
see below. 
 
Interrupt 
sorafenib 
treatment 
until 
toxicity resolves to Grade 0-1.  When 
resuming treatment, decrease sorafenib 
dose by one dose level. 
 
Interrupt until resolved to grade 0-1.  
When resuming treatment, decrease dose 
by two dose levels (from the starting 
dose).  
 
Discontinue sorafenib treatment. 
Grade 3: Moist desquamation, 
ulceration, blistering or severe 
pain of the hands or feet, or 
severe discomfort that causes 
the patient to be unable to 
work or perform activities. 
 
First occurrence 
 
 
 
Second occurrence 
 
 
 
Third occurrence 
Interrupt 
sorafenib 
treatment 
until 
toxicity resolves to Grade 0-1.  When 
resuming treatment, decrease sorafenib 
by one dose level. 
 
Interrupt until resolved to grade 0-1.  
When resuming treatment, decrease dose 
by two dose levels (from the starting 
dose). 
 
Discontinue sorafenib treatment. 
 
 


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Table 3-9: Dose Modifications for Sorafenib-Associated Toxicity1 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non-
hematologic 
Continue 
at the 
same 
dose 
level. 
Continue at 
the 
same 
dose level. 
Withhold dose until 
toxicity is < 1.  When 
resuming 
treatment 
reduce dose by one 
dose level.  
Discontinue treatment. 
Hematologic 
Continue 
at 
the 
same 
dose 
level. 
Continue at 
the 
same 
dose level. 
Withhold dose until 
toxicity is grade <2. 
When 
resuming 
treatment reduce dose 
by one dose level. 
Withhold 
dose 
until 
toxicity is grade <2. When 
resuming treatment reduce 
dose by two dose levels. 
1 See separate suggestions for dose modification due to hand-foot skin reactions.     
*Patients who develop grade 3 fever/chills, grade 3 elevation of hepatic transaminases with ALT 
and AST <10X ULN, grade 3 hyperlipidemia or hyperamylasemia without clinical or other 
evidence of pancreatitis, grade 3 leukopenia, or grade 3/grade 4 lymphopenia may continue study 
treatment without interruption at the discretion of the investigator.   
 
 
Hypertension: Dose Modifications of Sorafenib for Hypertension 
Hypertension is a known and potentially serious adverse event associated with sorafenib treatment. 
Patients will have their blood pressure monitored and recorded weekly during the Cycle 1 and then 
every cycle of the entire treatment period, either at the doctor’s office or by using any calibrated 
electronic device (such as those found at a local drug store or pharmacy). Patients will have a 
Blood Pressure Diary on which to record the measurements, which will be kept with research chart. 
If the patient’s blood pressure is elevated at any time (>140/100), even outside clinic visits, they 
should contact their treating physician. 


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Table 3-10: Dose modifications for Sorafenib-associated hypertension 
Grade 
(CTCAE v 4.0) 
Antihypertensive 
       Therapy 
Blood Pressure  
Monitoring 
Sorafenib Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
(asymptomatic) 
Initiate monotherapy 
(suggest 
dihydropyridine 
calcium-channel 
blocker) 
Increase 
frequency 
and 
monitor 
(by 
health 
professional) 
every 2 days until 
stabilized 
No change 
Grade 
2 
(symptomatic/ 
persistent) 
OR 
Diastolic BP > 
110 mm Hg 
OR 
Grade 3 
Add agent(s):  
Ca++ channel blocker 
(if not already used), 
K+ channel opener 
(angiotensin 
blockers), 
beta-
blocker, 
thiazide 
diuretic 
Increase 
frequency 
and 
monitor 
(by 
health 
professional) 
every 2 days until 
stabilized; 
continue 
qod 
monitoring 
to 
stabilization 
after 
dosing restarted. 
Hold* 
Sorafenib 
until 
symptoms 
resolve 
and 
diastolic BP < 100 
mm/Hg. 
 
Resume treatment 
at 1 dose level 
lower** 
Grade 4 
 
 
Off 
protocol 
therapy 
* Patients requiring a delay of > 28 days should go off protocol therapy unless, in the 
treating physician’s opinion, the patient may benefit from continued treatment. 
** Patients requiring >2 dose reductions should go off protocol therapy. 
CTCAE v 4.0 definitions 
Grade 1: asymptomatic, transient (<24 hrs) increase by > 20 mmHg (diastolic) or > 
150/100 if previously WNL; intervention not indicated 
Grade 2: recurrent or persistent (>24 hrs) or symptomatic increase by >20 mmHg 
(diastolic) or to >150/100 if previously WNL; monotherapy may be indicated. 
Grade 3: requiring more than one drug or more intensive therapy than previously 
Grade 4: life threatening (e.g., hypertensive crisis) 
 
For treatment or dose modification related questions, please contact the Study Chair or the BTTC 
Coordinating Center’s Research Nurse. 
 
QUESTIONNAIRES 
The MDASI-BT will be utilized for this portion of the study. Full instruments are provided in the 
Appendix 13.4.  In addition, information regarding demographics and treatment history will be 
collected as part of the larger study and used in this analysis.    


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The MDASI-BT consists of 23 symptoms rated on an 11-point scale (0 to 10) to indicate the 
presence and severity of the symptom, with 0 being “not present” and 10 being “as bad as you can 
imagine.” Each symptom is rated at its worst in the last 24 hours. Symptoms included on the 
instrument include those commonly associated with cancer therapies, those associated with 
increased intracranial pressure, and those related to focal deficits.  The questionnaire also includes 
ratings of how much symptoms interfered with different aspects of a patient’s life in the last 24 
hours. These interference items include: general activity, mood, work (includes both work outside 
the home and housework), relations with other people, walking, and enjoyment of life. The 
interference items are also measured on 0 - 10 scales. The average time to complete these 
instruments is 5 minutes. The MDASI-BT has been translated into 18 languages (24, 25). 
 
STUDY CALENDAR 
STUDIES TO BE OBTAINED 
PRE 
TREATMENT 
DURING 
TREATMENT 
OFF 
TREATMENT 
Consent & HIPAA Authorization 
X 
 
 
History 
 
X1 
 
 
Physical exam (including vital signs) 
and Neurologic Examination  
X1 
X5 
 
Karnofsky Performance Status 
X1 
X5 
 
Blood Pressure 
X1 
X14,  X5 
 
CBC, with differential, platelets  
X1 
X4 , X15 
 
PT, PTT 
 
X1 
 
 
Serum creatinine, phosphate, lipase, 
amylase, bilirubin, SGOT, fasting 
serum glucose, fasting lipid panel 
X1 
X5 , X15 
 
HBV-DNA, HbsAg, HBsAb, HBcAb, 
HCV-RNA-PCR 
X1 
 
 
MRI or CT (brain) 
(X5 (times 2) or X5 (times 4) whichever 
is applicable per section 3.6.1.2 
X1 
X5 (times 2) or 
X5 (times 4) then 
X6, X16 
 
MDASI Symptom Assessment 
X5 (times 2) or X5 (times 4) whichever 
is applicable per sections 3.6.1.2 and 
3.6.1.5 
X10 
X5 (times 2) or 
X5 (times 4) then 
X6 
 
ECG 
X3 
 
 
Chest X-ray or chest CT 
X3 
 
 


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STUDIES TO BE OBTAINED 
PRE 
TREATMENT 
DURING 
TREATMENT 
OFF 
TREATMENT 
Urinalysis with microanalysis 
X1 
 
 
Serum pregnancy test (β-HCG) 
X2 
 
 
UPC ratio 
 
X12 
X12 
 
Urine Dipstick/urinalysis 
X1 
X5, X15 
 
HBV-DNA, HCV-RNA-PCR 
 
X9 
 
Prophylactic antiviral agent 
(i.e. Lamivudine) 
X11 
X11 
X11 
Documentation of tumor diagnosis 
X 
 
 
Information 
on 
drug 
doses, 
concomitant medications and doses, 
(baseline 
and 
treatment 
related) 
toxicity monitoring 
X 
X5 
 
Measurable 
lesions 
with 
measurements-tumor response 
(X5 or X6, whichever is applicable per 
section 3.6.1.2) 
X 
X5, X6 
 
Follow up for survival by phone or 
clinic visit on patients who discontinue 
treatment due to progression 
 
 
X7 
Follow up for survival by phone or 
clinic visit, for those who come off 
treatment 
other 
than 
progression 
should be followed until progression or 
institution of new anti- tumor therapy 
 
 
X7 
Adverse Events Notation 
X 
X13 
 
X1  To be performed within 14 days of registration 
X2 To be performed within 14 days prior to starting study treatment  
X3 To be performed within 30 days prior to starting study treatment  
X4  To be performed every 2 weeks during treatment 
X5  To be performed every 4 weeks during treatment (prior to each cycle);  
X6  To be performed every 2 months during treatment (every other month)  
X7  To be performed every 3 months 
X8  To be performed weekly for Phase I Cycle 1 
X9 To be performed on Cycle 1 Day 1 and Day 1 of all subsequent cycles. Applicable to patients 
that are on antiviral prophylaxis treatment or positive HBV antibodies, and patients with positive 


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HCV RNA- PCR results at screening and/or a history of past infection (even if treated or 
considered cured). 
X10 To be performed within 14 days (+3 working days) after enrollment on the clinical trial. 
X11 All patients with positive HBV-DNA or HBsAg should be treated prophylactically with 
antiviral agent to be given 1 -2 weeks prior to study drugs, and should continue throughout the 
entire study period, to 
last until at least 4 weeks after the last dose of everolimus. 
X12 If urinalysis has > 2+ protein present, then UPC will be obtained  
X13 To be performed at the end of each cycle 
X14 To be performed weekly during Cycle 1 
X15 Lab work (blood draws/urine) has a window of +/- 3 days of the cycle  
X16 MRI/CT imaging has a window of within 7 days of new cycle 
 
ON STUDY EVALUATION  
 
General Requirements 
3.6.1.1 
CBC with differential and platelets will be performed every two weeks during 
treatment. Creatinine, bilirubin, SGOT, phosphate, lipase, amylase, fasting glucose, 
serum lipid panel and urinalysis/urine dipstick will be performed every four weeks (+/-
3 days) prior to each cycle.  If > 2+ protein is present on urine dipstick/urinalysis, then 
UPC should be obtained. 
3.6.1.2 
Brain MRI/CT 
3.6.1.2.1 A brain MRI/CT will be done monthly x 2 then every other month, within 7 days of 
new cycle.   
OR 
3.6.1.2.2 For Phase II patients enrolled to the bevacizumab failure cohort, MRI/CT will be 
done every 4 weeks x 4, then every 8 weeks thereafter, within 7 days of new cycle.  
Note:  *MRI is the preferable imaging method, CT scan may be used in cases where an MRI cannot 
be obtained.   
3.6.1.3 
All relevant information regarding drug doses, concomitant medications, and doses, 
measurable lesions with measurements, tumor response, laboratory examinations, and 
treatment-related toxicities shall be documented in the patient’s medical record and 
flow sheets. 
3.6.1.4 
A complete physical exam (with vital signs) and neurologic exam (to include 
documentation of the patients Karnofsky Performance Status) will be performed 
monthly. The MDASI-BT will be completed at baseline and at the time of each 
evaluation that includes an imaging study. 
3.6.1.5 
The patient will complete the MDASI-BT (Appendix 13.4) at the time of clinical 
evaluation with MRI as long as the clinical therapy is being administered, unless 
clinical deterioration makes self-report not possible before that time.  The time when 
patients are unable to complete the self-report questionnaires will be used as part of the 
study analysis.  The MDASI-BT will be completed only by the patient, unless changes 
in vision or weakness make this difficult. If this occurs, then the caregiver or research 


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assistant may read the questions to the patient or assist with marking the severity 
number or score as described by the patient. A patient caregiver may complete the 
questionnaires as a patient-preference proxy if the patient’s deficits preclude self-
report. 
3.6.1.6 
Patients on antiviral prophylaxis treatment or positive HBV antibodies should be tested 
for HBV-DNA on Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) 
to monitor for re-activation. If re-activation is confirmed, everolimus must be 
interrupted or discontinued according to the guidance in Table 6-3. 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 on 
Cycle 1 Day 1 and Day 1 of all subsequent cycles (every 28 days) to monitor for 
reactivation. Everolimus must be discontinued if HCV reactivation is confirmed 
according to the guidance in Table 3-5. 
3.6.1.7 
All patients will be followed for overall survival, when possible. 
a) Patients who discontinue treatment due to progression will be followed for survival 
every 3 months by phone call or clinic visit. 
b) Patients who come off therapy for reasons other than progression should be followed 
until progression or institution of new anti-tumor therapy.  They should then be 
followed for survival. 
 
Phase I Requirements 
3.6.2.1 
Phase I patients will be evaluated for adverse events at least weekly during their first 
cycle of therapy (by either phone contact or personal visit). These adverse events will 
be reported to the Lead PI and the BTTC Coordinating Center weekly.  
3.6.2.2 
Adverse events for subsequent cycles will be reported to BTTC Coordinating Center at 
the end of each cycle. In addition all serious adverse events will be reported to the 
BTTC Coordinating Center and the Lead PI, as directed in section 6.4  
 
Phase II Requirements 
3.6.3.1 
Phase II patients will be evaluated for adverse events at the end of each cycle. In 
addition, all serious adverse events will be reported to the BTTC Coordinating Center 
and the Lead PI as directed in section 6.4  
 
Follow-up 
When a subject is removed from treatment as per section 3.7.1, they should continue to be followed 
until removed from protocol.  
Follow up for survival should be done every 3 months by phone or clinic visit on patients who 
discontinue treatment due to progression.  Those who come off treatment other than progression 
should be followed every 3 months by phone call or clinic visit until progression or institution of 
new anti- tumor therapy. Survival status will only be collected by phone or clinic visit. This data 
must be recorded on the appropriate follow up case report form. 


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CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
 
Criteria for Removal from Protocol Therapy: 
3.7.1.1 
Progression of disease (as defined in Section 5.2.1). 
Patients must be followed by the same type of brain scan, as was used for baseline tumor 
measurements, and will be removed from study if progression is documented after any cycle of 
treatment.  Patients with stable disease, partial or complete response will continue on therapy as 
defined in Section 3.0. 
3.7.1.2 
Unacceptable toxicity (as defined by the investigator). 
3.7.1.3 
The patient may withdraw from the study at any time for any reason. 
3.7.1.4 
Medical or psychiatric illness which in the investigator's judgment renders the patient 
incapable of further therapy. 
3.7.1.5 
Treatment delay due to toxicity greater than 21 days measured from the start of the 
preceding cycle. 
 
Off Study Criteria 
3.7.2.1 
Participant requests to be withdrawn from study 
3.7.2.2 
Institution of new anti-tumor therapy 
3.7.2.3 
Investigator discretion 
3.7.2.4 
Death 
All reasons for discontinuation of treatment must be documented in the flow sheets. 
 
Off Protocol Therapy and Off Study Procedure  
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off study.  
• NCI site: Complete the Participant Status Updates Form available from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page.  Hand deliver the 
completed form to the BTTC Coordinating Center Research Nurse or send via encrypted 
email. 
• Participating sites: The Participant Status Update Form will be supplied by the BTTC 
Coordinating Center’s Research Nurse. Sites will send the completed form by secure fax 
to 240-541-4432 or by secure email (NIH Secure Email and File Transfer Service 
[SEFT]).  
• BTTC Coordinating Center: The BTTC Research Nurse will review the Participant Status 
Updates Form and forward to the Central Registration Office (CRO). 
 


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4.0 CONCOMITANT MEDICATIONS/MEASURES 
 
G-CSF Administration: Routine prophylactic use of G-CSF is not permitted. However, 
therapeutic use in patients with serious neutropenic complications, such as sepsis, may 
be considered at the investigator’s discretion. 
 
Corticosteroids should be used in the smallest dose to control symptoms of cerebral 
edema and mass effect, and discontinued if possible.  Patients must not be on a 
dexamethasone dose of greater than 16 mg/ day. 
 
Anti-seizure medications should be used as indicated. If for unavoidable clinical reasons 
(severe allergies, toxicities etc.) a patients AED is switched to the alternate AED group 
the following guidelines must be followed: 
EVERY EFFORT SHOULD BE MADE TO MAINTAIN THE PATIENT ON NON-EIAED 
Patients, who were previously on a non-EIAED and need to change anticonvulsants, should be 
started on another non-EIAED if at all possible. No delays in treatment would be required. 
Patients who were previously on a non- EIAED and were inadvertently and temporarily changed 
to an EIAED, should immediately be started on another non-EIAED. The patient may continue the 
current treatment dose while a non- EIAED is re-started. 
Patients who were previously on a non-EIAED and need to permanently change anticonvulsant, 
but who cannot change to another non-EIAED may continue the current treatment dose for the 
next 2 weeks while an EIAED is started. FOLLOWING  
THIS 2 WEEK PERIOD, THE SUBSEQUENT TREATMENT DOSE MUST BE DISCUSSED 
WITH THE STUDY CHAIR. In some cases this dose may be higher than the previously used 
dose. 
 
Febrile neutropenia may be managed according to the local institution's Infectious 
Disease guidelines.  Measures may include appropriate laboratory testing, including 
blood and urine cultures and the institution of broad-spectrum antibiotics.  If a source for 
the fever is not identified or the fever resolves when the neutrophil count recovers, 
antibiotics may be discontinued and the patient observed. 
 
Antiemetics: The use of antiemetics will be left to the investigators’ discretion. 
 
Other Concomitant Medications: Therapies considered necessary for the well-being of 
the patient may be given at the discretion of the investigator. Other concomitant 
medications should be avoided except for analgesics, chronic treatments for concomitant 
medical conditions, or agents required for life-threatening medical problems.  All 
concomitant medications must be recorded. 
 
Other Anticancer or Experimental Therapies: No other anticancer therapy (including 
chemotherapy, radiation, hormonal treatment or immunotherapy) of any kind is 
permitted during the study period. No other drug under investigation may be used 
concomitantly with the study drug. 
 
Surgery: If neurosurgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for surgery, 
the surgical operative note and pathology report. If possible, defer surgery for 4 weeks 
from last dose of therapy.  Patients who undergo resection for presumed tumor 


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progression but are shown to only have treatment associated changes can resume 
treatment once they have recovered from the surgical procedure.  Everolimus treatment 
can only resume > 1 week after surgery. 
5.0 DATA COLLECTION AND EVALUATION 
 
DATA COLLECTION 
Certain BTTC participating institutions have collected baseline data of relevance to this clinical 
trial including certain identifiable private information, such as patient treatment dates.  For 
purposes of this clinical trial, these BTTC participating institutions will transfer these data to NCI 
through direct data entry in the NCI-designated study database (C3D) and via secure transfer 
through the NIH’s Secure Email and File Transfer Service (SEFT) system, in accordance with 
their applicable laws, regulations, and policies. The BTTC Research Nurse will provide 
instructions to these BTTC participating institutions for use of C3D and SEFT. 
The PI at the site will be responsible for overseeing entry of data into an in-house password 
protected electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  
Data on this study will be entered into C3D and Scribe/Labmatrix.  Designated research staff from 
the registering institution will enter the data via remote electronic data entry. The protocol specific 
electronic forms are to be used by the participating site.  All investigators will utilize these forms 
for Baseline, Treatment, Adverse Events, Tumor Evaluation, Off Treatment, Survival, and Off-
study data. 
All data obtained during the conduct of the protocol will be kept in secure network drives or in 
approved alternative sites that comply with NIH security standards. Primary and final analyzed 
data will have identifiers so that research data can be attributed to an individual human subject 
participant.  
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse events 
that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of at least possibly related to the agent/intervention should be recorded and 
reported as per Sections 6.3 and 6.5. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
 
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the patient’s outcome. 
 


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End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
Source Documentation Timeframes 
The following information will be entered into C3D and Scribe/Labmatrix within the indicated 
timeframes. In addition, the source documents should be provided to the BTTC Coordinating 
Center’s Research Nurse, fax 301-451-5429, or email within the indicated timeframe. 
Data Set / Source Documents 
Schedule for Submission 
Regulatory Documents 
(as described in the BTTC Operations Manual) 
Prior to Patient Registration 
Eligibility Checklist  
Prior to Patient Registration  
Copy of signed & dated Informed Consent w/ 
HIPAA Authorization  
Prior to Patient Registration  
Pathology Report (from the most recent pre-
registration diagnostic biopsy or surgery) 
Prior to registration 
Baseline Data 
(To include prior disease/treatment history, and 
baseline clinical evaluation information) 
Within 14 days after the registration date 
Baseline MDASI – BT Questionnaire 
Within 14 days after the registration date 
Baseline Source Documents 
Within 14 days after the registration date 
 
Database Entry Timeframes 
The following data should be entered into C3D/Labmatrix within the specified timeframes.  Source 
documentation will be kept at the participating site. 
Treatment (Cycle) Data 
(To include treatment, response, AE, and 
clinical evaluation information) 
Within 40 days after the first day of each 
treatment cycle. 
Off Treatment Data 
Within 10 days after the last date of any modality 
of protocol treatment 
Follow-up (Survival) Data 
Within 52 days after the last treatment date and 
then every 90 days until Off Study (unless 
otherwise specified by the protocol) 
Non-Treatment Data 
(May include Quality of Life questionnaires 
(MDASI-BT), Specimen Tracking 
information, Pathology Specimen 
Submission, etc.) 
Within 10 days after each scheduled assessment, 
event, or activity 
Off Study Data 
Within 10 days after the date the patient is 
removed from the study. 


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Confidentiality  
All documents, investigative reports, or information relating to the patient are strictly confidential. 
Any patient specific reports (i.e. Pathology Reports, MRI Reports, Operative Reports, etc.) 
submitted to the BTTC Coordinating Center must have the patient’s full name & social security 
number “blacked out” and the assigned patient ID number and protocol number written in. Patient 
initials may be included or retained for cross verification of identification. 
 
Safety Data  
All patients receiving study agents will be evaluated for safety.  The safety parameters include all 
laboratory tests and hematological abnormalities, CNS observations, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by patients.  All 
toxicities encountered during the study will be evaluated according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and recorded prior to each course 
of therapy.  Life-threatening toxicities that are unexpected and assessed to be possibly related to 
the study agent/s should be reported immediately as per Section 6.5.   
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other means, 
will be collected and recorded on the Adverse Event Case Report Form and followed as 
appropriate. An adverse event is any undesirable sign, symptom or medical condition occurring 
after starting study drug (or therapy) even if the event is not considered to be related to study drug. 
Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment (any procedures specified in the protocol). 
Adverse events occurring before starting study treatment but after signing the informed consent 
form are recorded on the Baseline Evaluations Case Report Form. Abnormal laboratory values or 
test results constitute adverse events only if they induce clinical signs or symptoms or require 
therapy, and are also recorded on the Adverse Events Case Report Form. 
 
Data Sharing with Pharmaceutical Collaborators, Bayer and Novartis 
NCI may share data from this study with pharmaceutical collaborators, Bayer and Novartis, 
pursuant to the NCI M-CRADAs with each company. Specifically, the collaborators may access 
and review analytical results and primary quantitative and empirical data including identifiable 
private information in accordance with the terms of the M-CRADAs. 
 
RESPONSE CRITERIA 
The primary efficacy endpoint for BTTC studies will be progression free survival (PFS) at six 
months from patient registration for bevacizumab naïve patients and at 3 months for patients with 
prior bevacizumab treatment.  However, objective response status should be measured and 
recorded.  
All measurements will be performed on the axial MRI T1 post contrast images when possible, 
although coronal images may be used if axial is not optimal for measurements (or CT post contrast 
if MRI is contraindicated).  The same plane should be used for all measurements.  Tumor size is 
defined as the largest (contrast enhancing) cross sectional area (largest cross-sectional diameter x 
largest diameter perpendicular to it).   
• Evaluable for toxicity: All patients will be evaluated for toxicity from the time of their first 
treatment with Sorafenib or Everolimus. 


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• Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
 
Definitions of Response 
5.2.1.1 
Measurable Disease: Bi-dimensionally measurable CE lesions with clearly defined 
margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial 
slices which are at least 5 mm apart with 0 mm skip.  Measurement of tumor around a 
cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm. 
5.2.1.2 
Non-measurable Disease (contrast enhancing): Uni-dimensionally measurable lesions, 
masses with margins not clearly defined, lesions with maximal diameter < 1 cm. 
5.2.1.3 
Objective Status, To Be Recorded at Each Evaluation: If there are too many measurable 
lesions to measure at each evaluation, choose the largest two to be followed before a 
patient is entered on study.  The remaining lesions will be considered evaluable for the 
purpose of objective status determination.  Unless progression is observed, objective 
status can only be determined when ALL measurable and evaluable sites and lesions 
are assessed. 
5.2.1.3.1 
Complete Response (CR)   
Complete disappearance of all CE measurable and evaluable disease.  No new lesions.  No 
evidence of non-evaluable disease.  All measurable, evaluable and non-evaluable lesions and sites 
must be assessed using the same techniques as baseline.  Patients must be on no steroids.  There 
must be stable or improved non-enhancing (T2/FLAIR) lesions.  Stable or improved clinically.  
Note:  Patients with non-measurable disease cannot have a partial response.  The best possible 
response is stable disease. 
5.2.1.3.2 
Partial Response (PR)   
Greater than or equal to 50% decrease under baseline in the sum of products of perpendicular 
diameters of the two largest CE measurable lesions, sustained for at least 4 weeks.  In the absence 
of a confirming scan 4 weeks later, this scan will be considered only stable disease.  If more than 
two clearly defined lesions exist, the remaining lesions will be considered as evaluable.  No 
progression of evaluable or non-measurable disease.  No new lesions.  All measurable and 
evaluable lesions and sites must be assessed using the same techniques as baseline. The steroid 
dose at the time of the scan evaluation should be no greater than the maximum dose used in the 
first 8 weeks from initiation of therapy.  Stable or improved non-enhancing (T2/FLAIR) lesions 
on same or lower dose of corticosteroids compared to baseline.  Stable or improved clinically.  
Note:  Patients with non-measurable disease cannot have a partial response.  The best response 
possible is stable disease. 
5.2.1.3.3 
Partial Response, Non-Measurable (PRNM) 
 Not applicable. 
5.2.1.3.4 
Stable/No Response  


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Does not qualify for CR, PR, or progression.  The designation of stable disease requires a minimum 
of 4-week duration.  All measurable and non-measurable sites must be assessed using the same 
techniques as baseline.  Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
steroids as compared to the baseline scan.  In the event that the steroid dose has been increased, 
the last scan considered to show stable disease will be the scan obtained when the corticosteroid 
dose was equivalent to the baseline dose.   
5.2.1.3.5 Progression  
a.   >25% increase in the sum of products of perpendicular diameters of enhancing 
lesions (over baseline if no decrease) on stable or increasing dose of corticosteroids.  
and/or 
b.  Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing 
doses of corticosteroids compared to baseline scan or best response following 
initiation or therapy, not due to co-morbid events (radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment 
effects). 
c.  Any new lesion 
d.  Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g., seizures, medication side effects, complications of therapy, cerebrovascular 
events, infection, etc.).  The definition of clinical deterioration is left to the 
discretion of the treating physician, but it is recommended that a decrease in 20% 
of KPS or from any baseline to 50% or less be considered, unless attributable to 
comorbid events. 
e.  Failure to return for evaluation due to death or deteriorating condition. 
5.2.1.3.6 Unknown  
Progression has not been documented and one or more measurable or evaluable sites have not been 
assessed. 
 
Best Response  
This will be calculated from the sequence of objective statuses. 
For patients with all disease sites assessed every evaluation period, the best response will be 
defined as the best objective status as measured according to Section 5.2.1.  If the response does 
not persist at the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response.  If the response is sustained, e. g. still 
present on the subsequent MRI, it will be recorded as a sustained response, lasting until the time 
of tumor progression.  Best response is unknown if the patient does not qualify for a best response 
or increasing disease and if all objective status determinations before progression are unknown. 
 
Neurological Exam  
Although not used for determining response, it is useful to evaluate improvement in the neurologic 
exam, (as compared to the baseline assessment), that should coincide with objective measurement 
of tumor size.  
+2 
Definitely better 


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+1 
Possibly better 
  0 
Unchanged 
 -1 
Possibly worse 
 -2 
Definitely worse 
 
Performance Status:  
Patients will be graded according to Karnofsky Performance Status (see Appendix 13.1). 
 
Time to Treatment Failure:  
From date of registration to the date of first observation of progressive disease (as defined in 
Section 5.2.1), non-reversible neurologic progression or permanently increased steroid 
requirement (applies to stable disease only), death due to any cause, or early discontinuation of 
treatment. If a patient is registered on the pre-operative portion of the study, the start date for 
calculation of time to event will be the date of first post-operative study drug administration. 
 
Time to Death  
From date of registration to date of death due to any cause. 
 
Evaluability   
Patients are required to receive at least 2 weeks of treatment of both agents, and the protocol 
defined evaluations are performed per protocol to be considered evaluable.  Inevaluable patients 
will be replaced.    
 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
6.0 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
 
DEFINITIONS 
 
Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with 
the subject’s participation in research, whether or not considered related to the subject’s 
participation in the research. 
 
Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 


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Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. "Unexpected” 
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
 
Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
 
Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 
 
Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
 
Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, 
IRB requirements, or regulatory requirements for the protection of human research subjects. 


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Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
 
ASSESSING CAUSALITY 
Investigators are required to assess whether there is a reasonable possibility that the study agent/s 
caused or contributed to an adverse event.  The following general guidance may be used. 
Yes: 
If the temporal relationship of the clinical event to the study agent/s administration 
makes a causal relationship possible, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the observed event. 
No: 
If the temporal relationship of the clinical event to the study agent/s administration 
makes a causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
 
NCI-IRB AND CLINICAL DIRECTOR REPORTING 
 
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Lead PI will report on the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
 
NCI-IRB Requirements for PI Reporting at Continuing Review 
The Lead PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  


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• All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
 Request for waiver from IRB reporting: Anticipated Protocol Deviations  
Brief interruption and delay in the 28-day cycle may occasionally be required due to travel delays, 
airport closure, inclement weather, family responsibilities, security alerts and government 
holidays, etc. This can also extend to complications of disease not attributable to disease 
progression or protocol therapy. These delays will not be considered protocol deviations. We 
expect 1-2 anticipated delays per patient.  However, any interruption more than 14 calendar days 
will not be permitted. 
If the rate of these events exceeds the rate of more than 2 anticipated delays per patient, the events 
will be classified and reported as though they are unanticipated problems.  
 
Multi-Institutional Guidelines 
6.3.4.1 
IRB Approvals  
The Lead PI will provide the NCI IRB with a copy of the participating institution’s approved yearly 
continuing review.  Registration will be halted at any participating institution in which a current 
continuing approval is not on file at the NCI IRB. 
6.3.4.2 
Amendments and Consents 
The Lead PI will provide the NCI IRB with copies of all amendments, consents and approvals 
from each participating institution. 
 
GUIDELINES FOR REPORTING SERIOUS ADVERSE EVENTS TO BTTC 
 
What to Report? 
When to Report? 
1. All Deaths, except that due to progressive 
disease, occurring from the time the 
consent is signed through 30 days after the 
last day of active treatment 
Within 1 working day (24 hours) from the time 
the research team becomes aware of event 
2. Other 
Serious 
Unexpected 
Suspected 
Adverse Reactions (that did not result in 
death) occurring from the time the consent 
is signed through 30 days after the last day 
of active treatment 
Within 5 working days from the time the 
research team becomes aware of event 
3. All protocol deviations, non-compliance 
and unanticipated problems 
Within 5 working days from the time the 
research team becomes aware of event 


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What to Report? 
When to Report? 
4. Pregnancy, although not itself a serious 
adverse event, should also be reported on a 
serious adverse event form and be followed 
up to determine outcome, including 
spontaneous or voluntary termination, 
details of birth, and the presence or absence 
of 
any 
birth 
defects 
or congenital 
abnormalities. 
Within 5 working days from the time the 
research team becomes aware of event 
 
The CCR problem report form will be used to submit adverse events to BTTC.  See Appendix 
13.6. 
Participating centers must also submit the report to their IRB in accordance with their institutional 
policies.  
The BTTC Coordinating Center will maintain documentation of all Serious Adverse Events from 
each institution. The BTTC Coordinating Center will notify all investigators of any serious and 
unexpected adverse experiences that are possibly related to the study agent/s.  The investigators 
are to file a copy with their protocol file and send a copy to their IRB according to their local IRB’s 
policies and procedures.  
 
 
REPORTING TO THE STUDY DRUG MANUFACTURERS 
The BTTC Coordinating Center will forward all SAE reports to the NCI IRB via the Lead PI, FDA 
(when applicable), and Novartis and Bayer Pharmaceuticals. 
The Lead Principal Investigator will report any SAEs, study drug exposure during pregnancy, and 
reports of misuse or abuse of study drug, including initial and follow up reports, to Novartis on a 
MedWatch form (including coversheet and Novartis Study Code found in M-CRADA) within 1 
business day of becoming aware of such information. 
The Lead Principal Investigator will forward to Novartis any findings that might alter the current 
benefit-risk profile of the study drug or that would be sufficient to consider changes in the study 
drug administration or in the overall conduct of the study within five calendar days of becoming 
aware of such information. 
 
Bayer HealthCare Pharmaceuticals Inc. 
FAX: (973) 709-2185  
Telephone: 1-888-842-2937 
Email: DrugSafety.GPV.US@bayer.com 
Novartis Pharmaceuticals Corporation 


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Novartis Pharmaceutical U.S. DS&E Department 
FAX:  877-778-9739 
If above Fax # is non-functional, send to: 
clinicalsafetyop.phuseh@novartis.com 
 
 
SAEs will be forwarded to Bayer/Onyx via the BTTC Coordinating Center in accordance 
with the following: 
All serious adverse events should be reported to Bayer/Onyx within 24 hours.  In the event of an 
SAE, the investigator should refer to the Pharmacovigilance section of the contract for reporting 
procedures.  In brief: 
The Lead PI may report serious adverse drug reactions (SADRs) using either:  
An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
OR 
A MedWatch form available at http://www.fda.gov/medwatch/  
All reports shall be sent electronically to:  
Electronic Mailbox:  DrugSafety.GPV.US@bayer.com  
Facsimile:   
 
(973) 709-2185  
 
Address: 
 
Global Pharmacovigilance - USA  
Mail only 
 
Bayer HealthCare Pharmaceuticals Inc.          
P.O. Box 1000  
Montville, NJ 07045-1000  
 
Address:   
 
340 Changebridge Road  
FDX or UPS only   Pine Brook, NJ  07058  
 
Reports for all Bayer products can also be phoned in via our Clinical 
Communications Dept:  
 
Phone:  
 
1-888-842-2937 
 
Occasionally BTTC may contact the reporter for additional information, clarification, or current 
status of the subject for whom an adverse event was reported.  
 
Novartis Safety Information 
The Lead PI shall report any other relevant/ important safety information to Novartis in the final 
study report and at such other periods as Novartis may request.   
The Sponsor Principal Investigator shall ensure that at a minimum the form contains: 
(a) 
Information on the person who contacted Sponsor (i.e., the initial reporter); 


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(b) 
Information about the patient or clinical trial subject; 
(c) 
Details of the suspected Study Drug   
(d) 
Details on the safety events experienced by the patient  
The Lead PI shall cooperate with all reasonable requests by Novartis to ensure that individual 
safety reports are sufficiently investigated, including requests to seek additional information 
relating to an individual safety reports or other relevant safety information. 
The Lead PI shall perform SAE reconciliation between the Sponsor’s Study database and an output 
of the Novartis Safety Database at the following time points: 
• One year after First Patient First Visit and yearly thereafter  
• At Last Patient Last Visit 
The Lead PI will confirm that, for the period being reconciled, all information in the Sponsor’s 
Study database that needed to be transferred to Novartis as per Novartis Annex, are contained in 
the output from the Novartis Safety Database. Where discrepancies are identified the Lead PI shall 
send/resend the information to Novartis DS&E as per the contact information in and using the 
supplied Novartis cover sheet. 
 
Novartis U.S. Drug Safety and Epidemiology (DS&E) contact information for 
forwarding individual safety reports  
 
• All reports of SAEs, drug exposure during pregnancy, study drug abuse or misuse Any 
Adverse Drug Reactions to Novartis products should be sent to U.S. DS&E at fax#: 
877-778-9739 
 
• The Novartis Coversheets must be attached to all SAE submissions 
 
• SAE Submissions must reference the Novartis Study Code. 
 
• Should the designated SAE Fax# be non-functional please send SAEs to the 
designated SAE mailbox: clinicalsafetyop.phuseh@novartis.com) 
 
The Lead PI shall provide the Novartis Medical contact listed in Novartis Annex  with a written 
confirmation that the reconciliation was performed, the outcome of the reconciliation and 
documentation that, where discrepancies were identified, Novartis DS&E was informed (e.g. 
delivery confirmations). 
 
 
GUIDELINES & PROCEDURES FOR REPORTING DEVIATIONS AND UNANTICIPATED 
PROBLEMS 
 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or “protocol 
deviation.”  The definition is often left to the Lead Institution IRB.  Accordingly, since NCI, Center 


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for Cancer Research is the Coordinating Center and the Lead PI must adhere to those policies set 
by the NCI IRB, the definitions for unanticipated problem and protocol deviation as described by 
the NCI IRB will be applied for reporting purposes for all institutions participating in the NCI 
Center for Cancer Research Multi-center Project. Definitions are listed in section 6.1. 
Protocol Deviations or Unanticipated problems occurring at a participating institution will be 
submitted to that institution’s own IRB in accordance with local policies and procedures.   
However, the participating institution must submit a report to the BTTC Coordinating Center even 
in instances where the local IRB does not require a report.  
Deviations or Unanticipated Problems must be submitted to the BTTC Coordinating Center within 
5 business calendar days after becoming aware of the event (if not reportable to the local IRB. 
When Deviations or Unanticipated Problems are reported to BTTC, but, the local IRB does not 
require a report, the report that is submitted to the BTTC Coordinating Center must be 
accompanied by a formal memo explaining the local policy and the rationale for not reporting the 
event to the local IRB. 
Deviation or Unanticipated Problem Reports and any accompanying documentation (to include 
the local IRB acknowledgement of the event when applicable) are to be submitted to the BTTC 
Coordinating Center’s Research Nurse, via fax 301-451-4432, or email using the problem report 
form in Appendix 13.6 
NCI Center for Cancer Research Coordinating Center:  Upon receipt of the deviation/unanticipated 
problem report from the participating institution, the BTTC Coordinating Center will submit the 
report to the Lead Principal Investigator for review. Subsequently, the participating institution’s 
IRB deviation/unanticipated problem report will be submitted to the NCI IRB for review. 
 
DATA AND SAFETY MONITORING PLAN 
 
Principal Investigator/Research Team  
The clinical research team will have a teleconference every other week when patients are being 
actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or protocol 
deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
 
BTTC Coordinating Center Monitoring Plan 
As the CCR is the coordinating center for this multi-site study, the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on: 


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• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
 
Safety Monitoring Committee (SMC) 
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial review 
will occur as soon as possible after the annual NCI-IRB continuing review date.   Subsequently, 
each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or 
more frequently as may be required by the SMC.   For initial and subsequent reviews, protocols 
will not be reviewed if there is no accrual within the review period. Written outcome letters will 
be generated in response to the monitoring activities and submitted to the Principal investigator 
and Clinical Director or Deputy Clinical Director, CCR, NCI. 
7.0 STATISTICAL CONSIDERATIONS  
 
PHASE I COMPONENT 
A Phase I design will be used where up to 6 patients will be treated at each dose combination.  For 
each dose combination, three patients will be treated.  If none show a DLT as defined in section 
3.1.3, then the dose will be escalated for the next cohort of patients.  If 2 or 3 have a DLT, then 
the previous dose (as defined in the cohort sequence above) is the maximum tolerated dose (MTD).  
If 1 of 3 patients has a DLT, then an additional 3 patients will be added to this dose.  If 1 of 6 has 
a DLT, then the dose will be escalated.  If 2 or more of 6 have a DLT, then the previous dose will 
be the MTD given that 6 patients have been treated in that dose.     This 3+3 design has a 91% 
chance (70%, 17%) of dose escalating when the true toxicity rate for that dose is 10% (30%, 50%).  
It is expected that up to 6 dose combination will be observed, so that the expected sample size will 
range from 6 (if unacceptable toxicities are seen at the lowest doses) to 36 (if 6 patients per cohort 
are required for all 6 cohorts). 
 
PHASE II COMPONENT   
Time to progression and overall survival will be evaluated using the Kaplan-Meier product-limit 
survival curve methodology.  Six-month Progression Free Survival (PFS) will be estimated using 
Kaplan-Meier estimates and associated two-sided 95% confidence intervals.   
 Group A:  Recurrent glioblastoma with no prior exposure to bevacizumab cohort:  
A maximum of 34 patients will be observed in a two-stage Simon optimum design.  In 
the first stage, 9 patients will be accrued.  If two or more patients are progression-free 
at 6 months (PFS6), an additional 25 patients will be accrued.  We halt registering 
patients after 9 patients until we have at least 2 patients are progression free at six 
months.  If 9 or more out of 34 have PFS6, then the study will be declared 


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promising.  This study has a 5% chance of declaring promise if the PFS6 rate is at most 
15%.  It has an 80% chance of declaring promise if the PFS rate is at least 35%.  
 Group B:  Recurrent glioblastoma with prior exposure to bevacizumab cohort:  In 
the group that failed bevacizumab, a maximum of 32 patients will be observed in a two-
stage Simon optimum design.  In the first stage, 14 patients will be accrued.  If one or 
more patients is progression-free at 3 months (PFS3), an additional 18 patients will be 
accrued.  We will halt registration after 14 patients until at least 1 patient is progression 
free at 3-months.  If 2 or more out of 32 have PFS3, then the study will be declared 
promising.  This study has a 5% chance of declaring promise if the PFS3 rate is at most 
1%.  It has an 80% chance of declaring promise if the PFS rate is at least 12%.  
 Group C:  A third cohort consisting of 16 patients with anaplastic glioma (as defined 
in section 2.1.1.1) will enroll independently but will not be included in the primary 
endpoint assessment. 
The Phase II Multicenter component of the trial will be monitored by the Study Chair, Jeffrey 
Raizer, MD, and the study statistician, Yuan Ying PhD, as described below. 
At phase II, we will monitor the toxicity based on the combined data from the above three cohorts 
with a total sample size of 82. All grade 3 or greater toxicities attributable to the study treatment 
in the first 28-day cycle will be counted. Accrual will be temporarily suspended for analysis after 
each of the following interim accrual goals. We will monitor the toxicity when the accrual is 5, 10, 
20, 35, 50 and 65 based on using the following stopping rule: if the posterior probability of toxicity 
greater than 0.3 is greater than 0.95 (i.e., Pr(toxicity>0.3|data) >0.95), we terminate the study for 
toxicity. Assuming the beta prior Beta(0.6, 1.4) for the toxicity, we have the following operating 
characteristics.  
Operating characteristics of the proposed stopping rule  
True toxicity probability 
0.2 
0.3 
0.4 
0.5 
Stopping Probability 
1.4% 
14.1% 64.6% 97.2% 
Average number of patients treated 
82 
74.9 
49.9 
24.9 
 
We obtain the following stopping boundary: the study will be terminated if we observe >= 4/5, 
6/10, 10/20, 16/35, 21/50, 26/65 (# of patients experienced DLTs/# of patients treated).  Note that 
our safety monitoring starts with a small cohort size of 5, and then gradually increases to 15. 
Therefore, if the treatment agents are overly toxic, the trial will stop before exposing many patients 
to toxicities. 
Patient-reported outcomes:  The sample size for this trial was based on the primary end point of 
the study. 
Received MDASI-BT forms will be checked versus the timing schedule and considered as valid if 
they fall within ten days of the scheduled assessment.  Compliance rates will be calculated as the 
number of received valid forms over the number of expected forms. Differences between groups 
in compliance will be tested by use of Fisher’s exact test at every time point. 
We will use descriptive statistics to describe how patients rate symptom severity and interference 
with function at each time point.  Error bar graphs for each of the symptoms will be constructed at 


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each time point.  The proportion of patients rating their symptoms to be 7 or greater (on a 0-10 
scale) will also be reported.  We will construct individual patient profiles for each of the selected 
symptoms to describe the individual patients’ patterns of change over time. We will calculate the 
mean core symptom severity, mean severity of the MDASI-BT and mean symptom interference at 
the time of clinical evaluation. Estimates of differences in the mean symptom severity and mean 
symptom interference between responders and non-responders will be estimated in the intent to 
treat population.  All patients with at least one valid questionnaire will be included in the analyses.  
Questionnaires completed at study registration will be considered baseline.  All questionnaire data 
received after randomization will be used in the primary analyses. 
Differences of at least 2 points will be classified as the minimum clinically meaningful change in 
the symptom severity and symptom interference measures. For example, an increase of 2 points or 
more would mean a moderate improvement, whereas a decrease of 2 points or more would be 
interpreted as moderate worsening. For individual symptoms, a rise in a symptom score means 
deterioration, whereas a reduced score means improvement of the specific symptom. 
8.0 COLLABORATIVE AGREEMENTS  
 
AGREEMENT TYPE 
There is a BTTC consortium agreement in place between all of the participating institutions listed 
on the title page of this study. There is a CDA in place (CDA #13471-17).  In addition, there is an 
executed CRADA agreement with Novartis (#03235) and an executed CRADA with Bayer 
(#03195) who support this study.  
9.0 HUMAN SUBJECTS PROTECTIONS 
 
RATIONALE FOR SUBJECT SELECTION 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  Males and females will be recruited with no preference to 
gender.  No exclusion to this study will be based on race.  Minorities will actively be recruited to 
participate.  High grade gliomas occur in patients of all races and although there is a slight 
predominance in men, this is a disease that is also common in women.  The molecular targets of 
the everolimus and sorafenib within the tumor are not known to be different among patients based 
on gender or race; hence this study will be open to all adults. 
 
PARTICIPATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have glioblastoma, and because of unknown toxicities of the study agents in the 
pediatric patient.  Furthermore, the targets of the everolimus and sorafenib are not as prevalent in 
pediatric malignant gliomas and therefore, the efficacy of this regimen will be initially determined 
in the adult population before consideration of its use in pediatrics. 
 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT (NCI) 
For adults who are or may be unable to consent: All research protocols should state whether 
adults who are unable to provide initial informed consent are excluded or are eligible to enroll, 
and the conditions, if any, under which adults who lose the ability to provide on-going consent 
subsequent to giving initial consent, may continue to participate.  


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Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 9.6.3), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in MAS Policy 87-4 f and 
NIH HRPP SOP 14E or appointing a surrogate decision maker for adult subjects who are (a) 
decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, 
will be followed. 
 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT (BTTC) 
Each institution will follow their own procedure for re-consenting subjects unable to re-consent 
and will notify the Coordinating Center at time of continuing review of these occurrences.  At 
time of  Amendment C, Version 10-04-2017, subjects enrolled at non-NCI sites are off 
treatment. 
 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The primary risk to patients participating in this research study is from the toxicity of sorafenib, 
everolimus, or both drugs.  Both are investigational agents in the treatment of gliomas, although 
bevacizumab is an FDA-approved drug for the treatment of colorectal carcinoma.  The protocol 
provides for detailed and careful monitoring of all patients to assess for toxicity.  Toxicity data 
from the current dose level will be collected and reviewed to ensure that there were no severe 
toxicities that would preclude further patient enrollment.  Patients will be treated with therapeutic 
intent and response to the therapy will be closely monitored.  
 
RISKS/BENEFITS ANALYSIS 
 
Benefits 
The potential benefit to a patient on this study is a reduction in the bulk of their tumor and 
improvement in cancer lesions, which may or may not have favorable impact on symptoms and/or 
survival.   
 
Risks 
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document.  Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents. 
 
Risks/Benefits Analysis 
The potential benefits from this therapy are disease stabilization or shrinkage and a reduction in 
symptoms caused by the brain tumor such as neurological deficits and headache.  Given the efforts 


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to minimize risk with the administration of this combination, this protocol involves greater than 
minimal risk, but presents the potential for direct benefit to individual subjects. 
 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
All patients who are being considered for this trial will undergo informed consent prior to being 
enrolled on the trial. The PI or associate investigator will perform the consenting process. Patients 
and family members when applicable will be asked to read the consent and will be encouraged to 
ask questions. 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. Patients will be enrolled after the consent document has been signed. Separate consents will be 
obtained for any surgical procedures performed.  The informed consent process will be 
documented in the patient’s medical record and on the informed consent document. This process 
will be performed by the local Principal Investigator or designee. 
If new safety information results in significant changes in the risk/ benefit assessment, the consent 
form will be reviewed and updated as necessary. All subjects (including those already being 
treated) will be informed of the new information, be given a copy of the revised form, and be asked 
give their consent to continue in the study. 
 
Reconsent via phone (at NCI) 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will sign 
and date the consent. 
The original informed consent document will be sent back to the consenting investigator who will 
sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented on a progress note by the consenting 
investigator. 
 
Informed Consent of non-English speaking subjects (at NCI) 
If there is an unexpected enrollment of a research participant for whom there is no translated extant 
IRB approved consent document, the principal investigator and/or those authorized to obtain 
informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-
2, OHSRP SOP 12, and 45 CFR 46.117 (b) (2).  The summary that will be used is the English 
version of the extant IRB approved consent document.  Signed copies of both the English version 
of the consent and the translated short form will be given to the subject or their legally authorized 
representative and the signed original will be filed in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of the 
relevant consent documents well before the consent conversation with the subject (24 to 48 hours 
if possible).  


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We request prospective IRB approval of the use of the short form process for non-English speaking 
subjects and will notify the IRB at the time of continuing review of the frequency of the use of the 
Short Form. 
 
10.0 PHARMACEUTICAL INFORMATION 
There will be no IND obtained for the use of Sorafenib or Everolimus for this study.  
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; the drugs are 
already approved and marketed and the investigation is not intended to support a significant change 
in advertising; and the investigation does not involve a route of administration or dosage level in 
use in a patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product. 
 
 SORAFENIB 
 
Drug Name:  
Sorafenib tosylate 
 
Chemical Name:  
4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-
carboxamide-4methylbenzenesulfonate 
 
Molecular Formula:   
C21H16ClF3N4O3 X C7H8O3S 
 
Molecular Weight:   
637.0 
 
Appearance:   
White to yellowish or brownish solid.  
 
How supplied:  
Sorafenib tablets are supplied as round, biconvex, red film-coated tablets, debossed with the 
“Bayer cross” on one side and “200” on the other side, each containing sorafenib tosylate 
equivalent to 200 mg of sorafenib.  Bottles of 120 tablets NDC 50419-488-58. 
 
Formulation:   
Red, round, biconvex, film coated tablet.  Each tablet contains 274 mg sorafenib tosylate 
equivalent to 200 mg sorafenib and the inactive ingredients cellulose microcrystalline, 
croscarmellose sodium, hypromelose, magnesium stearate, and sodium lauryl sulfate.  The coating 
material consists of hypromellose, macrogol (synthetic polyethylene glycol), titanium dioxide, and 
ferric oxide-red. 


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Storage and Stability:   
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Store in a dry place.  
 
Mechanism of Action:  
Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown 
to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, 
FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are 
thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited 
tumor growth and angiogenesis of human hepatocellular carcinoma and renal cell carcinoma, and 
several other human tumor xenografts in immunocompromised mice. 
 Pharmacology:   
After administration of sorafenib-containing tablets, the drug’s mean elimination half-life is 
between 25 and 48 h.  Sorafenib reaches peak plasma levels f3 h after oral administration. With a 
high-fat meal, sorafenib bioavailability was reduced 29% compared with fasting bioavailability. 
In vitro binding of sorafenib to human plasma proteins is 99.5%.  Sorafenib is metabolized 
primarily in the liver; oxidative metabolism is mediated by CYP3A4, and glucuronidation is 
mediated by UGT1A9.  Sorafenib accounts for 70% to 85% of the circulating analytes in plasma 
at steady state. Following oral administration of a 100 mg sorafenib dose in a solution formulation, 
77% of the dose was excreted in feces, and 19% was excreted in urine as glucuronidated 
metabolites. Unchanged sorafenib, which accounted for 51% of the dose, was found in feces but 
not in urine. 
Analyses of demographic data suggest that no dose adjustments are necessary based on patient age 
or gender. No pharmacokinetic data exist for pediatric patients. In patients with mild (Child-Pugh 
A, n = 14 patients) or moderate (Child-Pugh B, n = 8) hepatic impairment, drug exposure values 
were within the range observed in patients with no hepatic impairment. Sorafenib’s 
pharmacokinetics has not been studied in patients with severe (Child-Pugh C) hepatic impairment.  
In four phase 1 clinical trials, sorafenib was evaluated in patients with normal renal function, mild 
renal impairment (creatinine clearance >50-80 mL/min, n = 24), and moderate renal impairment 
(creatinine clearance = 30-50 mL/min, n = 4).  No relationship was observed between renal 
function and steady-state sorafenib area under the curve at doses of 400 mg twice daily. The drug’s 
pharmacokinetics has not been studied in patients with severe renal impairment (creatinine 
clearance <30 mL/min) or in patients undergoing dialysis. 
Steady-state dosing of ketoconazole (400 mg), a potent inhibitor of cytochrome P450 3A4 
(CYP3A4) did not alter the mean area under the curve of an oral dose of sorafenib.  
Administration of sorafenib tablets did not alter the exposure of concomitantly given midazolam 
(CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), or omeprazole (CYP2C19 
substrate). The possible effect of sorafenib on the CYP2C9 substrate warfarin was assessed 
indirectly by measuring the PT-INR. Mean changes from baseline in PT-INR were not higher in 
patients administered sorafenib tablets compared with patients given a placebo. Although not 
studied clinically, inducers of CYP3A4 activity are expected to increase metabolism of sorafenib 
and thus decrease sorafenib concentrations. 
Sorafenib tablets have been given with the antineoplastic agent’s gemcitabine, oxaliplatin, 
doxorubicin, and irinotecan.  Concomitant treatment with sorafenib resulted in a 21% increase in 
the area under the curve of doxorubicin. When given with irinotecan, whose active metabolite 


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SN-38 is further metabolized by the UGT1A1 pathway, sorafenib produced a 67% to 120% 
increase in the area under the curve of SN-38 and a 26% to 42% increase in the area under the 
curve of irinotecan. Because sorafenib inhibits CYP2B6 and CYP2C8 in vitro, systemic 
exposure to substrates of CYP2B6 and CYP2C8 might be expected to increase when co-
administered with sorafenib. Similarly, although not studied clinically, sorafenib inhibits 
glucuronidation by the UGT1A1 and UGT1A9 pathways, and systemic exposure to substrates of 
UGT1A1 and UGT1A9 may increase when co-administered with sorafenib. CYP1A2 and 
CYP3A4 activities were not altered after treatment of cultured human hepatocytes with 
sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4 in vivo. 
 Pre-clinical Toxicology: 
Repeat-dose animal toxicology was generally predictive of the toxicities observed in humans as 
indicated by the clinical adverse events. In the repeat-dose toxicology studies, findings included 
cirrhotic changes, glomerulopathy and renal tubular dilation, gastrointestinal hemorrhage, adrenal 
necrosis and hemorrhage, hypothyroidism, pancreatitis, and changes in serum a-amylase. 
Osteodystrophy of the jaw was noted in rats.  Young animals showed incomplete epiphyseal 
closure, thickening of growth plates, and dentin alteration. Potential cardiotoxicity was evidenced 
by 
positive 
findings 
in 
the 
in 
vitro 
hERG 
and 
action 
potential 
assays 
and 
inflammation/congestion/hemorrhage in the heart and increased creatine kinase in the chronic dog 
toxicity study. Changes in coagulation values were inconclusive. Sorafenib can cross the blood-
brain barrier. Based on a safety pharmacology study, sorafenib may cause sensory neuropathy. 
Sorafenib is teratogenic. Embryo-fetal toxicities, observed in rats and rabbits, occurred at 
subtherapeutic exposures and included increased post-implantation loss, fetal malformations, and 
necrotic placentas. Although fertility and early developmental studies were not conducted, adverse 
findings in the reproductive organs in the repeat dose toxicity studies suggest that sorafenib has 
the potential to impair reproductive function and fertility in males and females. Pharmacokinetic 
studies in rats with radiolabeled sorafenib indicated that sorafenib is excreted into the milk. 
 Human Toxicity: 
Likely (occurring in more than 20% of patients)* 
Fatigue, rash/desquamation, hand/foot reaction, alopecia, diarrhea, nausea, anorexia, abdominal 
pain. 
Laboratory abnormalities include hypophosphatemia, elevated lipase, elevated amylase, and 
lymphopenia. 
*Information obtained from sorafenib package insert 
Common (occurring in 3 – 20% of Patients) 
Hypertension, weight loss, pruritis, dry skin, vomiting, constipation, hemorrhage (all sites, 
including gastrointestinal tract and respiratory tract), sensory neuropathy, joint pain, headache, 
dyspnea, mucositis, stomatitis (including dry mouth and glossodynia), myalgia, depression, renal 
failure, erectile dysfunction, hoarseness. 
Laboratory abnormalities include neutropenia, thrombocytopenia, and transaminase elevation. 


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Rare but Serious (occurring in fewer than 3% of patients) 
Hypertensive crisis, myocardial ischemia and/or infarction, congestive heart failure, 
keratoacanthomas/squamous cell cancer of skin, pancreatitis, gastrointestinal perforation, cerebral 
hemorrhage, hypersensitivity reactions (including skin reactions and urticaria, and reversible 
posterior encephalopathy. 
The overall safety profile of sorafenib is based on 1286 cancer patients, who received sorafenib as 
single agent. This table will be used to determine the “expectedness” of ADRs used for reporting 
of adverse events to Regulatory Agencies from clinical studies. It is not a complete list of adverse 
events reported in clinical trials. 
Adverse Drug Reactions in patients in multiple clinical trials (MedDRA coded) 
System Organ 
Class 
Very Common 
> 10% 
Common 
> 1% to < 10% 
Uncommon 
> 0.1% to < 1% 
Infections and 
infestations 
 
 
Folliculitis infection 
Blood and 
lymphatic 
system 
disorders 
Lymphopenia 
Leucopenia 
Neutropenia 
Anemia 
Thrombocytopenia 
 
Immune 
system 
disorders 
 
 
Hypersensitivity 
reactions (including 
skin reactions and 
urticaria) 
Endocrine 
disorders 
 
 
Hypothyroidism 
Metabolism 
and nutrition 
disorders 
Hypophosphatemia 
Anorexia 
Hyponatremia 
Dehydration 
Psychiatric 
disorders 
 
Depression 
 
Nervous 
system 
disorders 
 
Peripheral sensory 
neuropathy 
Reversible posterior 
leukoencephalopath
y* 
Ear and 
labyrinth 
disorders 
 
Tinnitus 
 
Cardiac 
disorders 
 
 
Myocardial ischemia 
and infarction* 
Congestive heart 
failure* 


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Vascular 
disorders 
Hemorrhage 
(including 
gastrointestinal* and 
respiratory tract* and 
cerebral 
hemorrhage*) 
Hypertension 
 
Hypertensive crisis* 
 
 
 
 
Respiratory, 
thoracic and 
mediastinal 
disorders 
 
Hoarseness 
Rhinorrhea 
Gastrointestina
l disorders 
Diarrhea 
Nausea 
Vomiting 
Constipation 
Stomatis (including dry 
mouth and 
glossodynea) 
Dyspepsia 
Dysphagia 
Gastro esophageal 
reflux disease 
Pancreatitis 
Gastritis 
Gastrointestinal 
perforation* 
Hepato-biliary 
disorders 
 
 
Increase in bilirubin 
and jaundice 
Skin and 
subcutaneous 
tissue disorders 
Rash 
Alopecia 
Hand-foot reaction** 
Pruritis 
Erythema 
Dry skin 
Dermatitis exfoliative 
Acne 
Skin desquamation 
Eczema 
Erythema 
multiforme minor 
Musculoskelet
al, connective 
tissue and bone 
disorders 
 
Arthralgia 
Myalgia 
 
 
Reproductive 
system and 
breast 
disorders 
 
Erectile 
dysfunction 
Gynaecomastia 
General 
disorders and 
administration 
site conditions 
Fatigue 
Pain (inc. mouth, 
abdominal, bone 
pain, headache and 
tumor pain) 
Asthenia 
Fever 
Influenza-like illness 
 
Investigations 
Increased amylase 
Increased lipase 
Weight decreased 
Transient increase in 
transaminases 
Transient increase in 
blood alkaline 
phosphatase, INR 
abnormal, 
prothrombin level 
abnormal 
 
 
*   Events may have a life-threatening or fatal outcome.  Such events are uncommon. 


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**   Palmar plantar erythrodysaethesia syndrome in MedDRA 
In combination with cytotoxic agents, myelosuppression leading to febrile neutropenia has 
also been observed. Such events may have a life-threatening or fatal outcome. 
10.1.12.1 Laboratory Abnormalities 
The following laboratory abnormalities were observed in the phase III advanced RCC 
(TARGETS) trial:  
Elevated lipase and amylase:  Elevated lipase and amylase levels were very commonly reported. 
CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the sorafenib group compared 
to 7% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 
1% of patients in the sorafenib group compared to 3% of patients in the placebo group. Clinical 
pancreatitis was reported in 2 of 451 sorafenib treated patients (CTCAE Grade 4) and 1 of 451 
patients (CTCAE Grade 2) in the placebo group. 
Hypophosphatemia:  Hypophosphataemia was a common laboratory finding, observed in 45% of 
sorafenib treated patients compared to 12% of placebo patients. CTCAE Grade 3 
hypophosphataemia (1–2 mg/dl) occurred in 13% on sorafenib treated patients and 3% of patients 
in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/dl) 
reported in either sorafenib or placebo patients. The etiology of hypophosphataemia associated 
with sorafenib is not known. 
Lymphopenia:  CTCAE Grade 3 or 4 were reported for lymphopenia in 13% of sorafenib treated 
patients and 7% of placebo patients, for neutropenia in 5% of sorafenib treated patients and 2% of 
placebo patients, for anemia in 2% of sorafenib treated patients and 4% of placebo patients and for 
thrombocytopenia in 1% of sorafenib treated patients and 0% of placebo. 
Anemia:  Observed in 44% of sorafenib-treated patients and 49% of placebo patients.  CTCAE 
Grade 3 or 4 anemia was reported in 2% of sorafenib-treated patients and 4% of placebo patients. 
Thrombocytopenia:  Observed in 12% of sorafenib-treated patients and 5% of placebo patients.  
CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of sorafenib-treated patients and 0% 
of placebo patients. 
Special Warnings and Precautions for Use 
Sorafenib (Nexavar®) is approved for treatment of patients with advanced renal cancer and 
unresectable hepatocellular cancer.  Because this is a novel agent, current knowledge of the adverse 
events associated with this compound is limited. As with any new chemical entity, there is always 
potential for unexpected adverse events. 
Pregnancy: Women should avoid becoming pregnant while on therapy. 
Women of childbearing potential must be apprised of the potential hazard to the fetus, which 
includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity). 
Sorafenib should not be used during pregnancy. Prescribers may only consider it to be used, if the 
potential benefits justify the potential risks to the fetus.  
Based on the proposed mechanism of multikinase inhibition and multiple adverse effects seen in 
animals at exposure levels significantly below the clinical dose, sorafenib should be assumed to 
cause fetal harm when administered to a pregnant woman. 


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Breastfeeding should be discontinued during sorafenib therapy. 
Dermatological Toxicities: Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and 
rash represent the most common adverse drug reactions with sorafenib. Rash and hand-foot skin 
reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of 
treatment with sorafenib. Management of dermatologic toxicities may include topical therapies for 
symptomatic relief, temporary treatment interruption and/or dose modification of sorafenib, or in 
severe or persistent cases, permanent discontinuation of sorafenib. Patients who take sorafenib 
should be suggested to avoid long exposure to hot water such as washing dishes, long showers, or 
tub bath, and to avoid the activities to cause excessive pressure and friction on the soles of the feet 
or palms of hands such as jogging, aerobics, power walking, jumping, and/or using garden and 
household tools.  Hand-foot syndrome may be treated with topical emollients (such as 
Aquaphor), topical/systemic steroids, and/or antihistamine agents. Vitamin B6 (pyridoxine; 500-
1250 mg orally each day) may also be used.  
Hypertension: An increased incidence of hypertension was observed in sorafenib-treated patients. 
Hypertension was usually mild to moderate, occurred early in the course of treatment, and was 
amenable to management with standard antihypertensive therapy. Blood pressure should be 
monitored regularly and treated, if required, in accordance with standard medical practice. In cases 
of severe or persistent hypertension, or hypertensive crisis despite adequate antihypertensive 
therapy, permanent discontinuation of sorafenib should be considered. 
Hemorrhage: An increase in the risk of bleeding may occur following sorafenib administration. 
The incidence of severe bleeding events is uncommon. If any bleeding event necessitates medical 
intervention, it is recommended that permanent discontinuation of sorafenib should be considered. 
Wound healing complications: No formal studies of the effect of sorafenib on wound healing 
have been conducted. In patients undergoing major surgical procedures, temporary interruption of 
sorafenib therapy is recommended for precautionary reasons. There is limited clinical experience 
regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, 
the decision to resume sorafenib therapy following a major surgical intervention should be based 
on clinical judgment of adequate wound healing. 
Cardiac Ischemia and/or Infarction: In the Phase 3 Advanced RCC study (TARGETS), the 
incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib 
group (2.9%) compared with the placebo group (0.4%). Patients with unstable coronary artery 
disease or recent myocardial infarction were excluded from this study. Temporary or permanent 
discontinuation of sorafenib should be considered in patients who develop cardiac ischemia and/or 
infarction.  
Gastrointestinal perforation: Gastrointestinal perforation is an uncommon event and has been 
reported in less than 1% of patients taking sorafenib. In some cases this was not associated with 
apparent intra-abdominal tumor. Sorafenib therapy should be discontinued in patients with GI 
perforation.    
Effects on ability to drive and use machines: No studies on the effects of sorafenib on the ability 
to drive or use machines have been performed. There is no evidence that sorafenib affects the 
ability to drive or operate machinery. 
Patients with Hepatic Impairment:   In vitro and in vivo data indicate that sorafenib is primarily 
metabolized by the liver.  Systemic exposure and safety data were comparable in patients with 


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Child-Pugh A and B hepatic impairment.  Sorafenib has not been studied in patients with Child-
Pugh C hepatic impairment.  No dose adjustment is necessary when administering sorafenib to 
patients with Child-Pugh A and B hepatic impairment.  
Patients with Renal Impairment:  Sorafenib has not been studied in patients with severe renal 
impairment (CrCl <30 mL/min) or in patients undergoing dialysis. 
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been 
performed with sorafenib.  Sorafenib was clastogenic when tested in an in vitro mammalian cell 
assay (Chinese Hamster Ovary) in the presence of metabolic activation.  Sorafenib was not 
mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus 
assay.  One intermediate in the manufacturing process, which is also present in the final drug 
substance (<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test) 
when tested independently.  No specific studies with sorafenib have been conducted in animals to 
evaluate the effect on fertility.  However, results from the repeat-dose toxicity studies suggest there 
is a potential for sorafenib to impair reproductive performance and fertility.  Multiple adverse 
effects were observed in male and female reproductive organs, with the rat being more susceptible 
than mice or dogs.  Typical changes in rats consisted of testicular atrophy or degeneration, 
degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea 
and arrested follicular development.  Sorafenib-related effects on the reproductive organs of rats 
were manifested at daily oral doses ≥30 mg/m2 (approximately 0.5 times the AUC in cancer 
patients at the recommended human dose).  Dogs showed tubular degeneration in the testes at 600 
mg/m2/day (approximately 0.3 times the AUC at the recommended human dose) and oligospermia 
at 1200 mg/m2/day of sorafenib. Adequate contraception should be used during therapy and for at 
least 2 weeks after completing therapy.  
Pediatric Use:  The safety and effectiveness of sorafenib in pediatric patients have not been 
studied.  Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of 
the femoral growth plate at daily sorafenib doses ≥600 mg/m2 (approximately 0.3 times the AUC 
at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate 
at 200 mg/m2/day (approximately 0.1 times the AUC at the recommended human dose), and 
alterations of the dentin composition at 600 mg/m2/day.  Similar effects were not observed in adult 
dogs when dosed for 4 weeks or less. 
Geriatric Use:  In total, 32% of RCC patients treated with sorafenib were age 65 years or older, 
and 4% were 75 and older. No differences in safety or efficacy were observed between older and 
younger patients, and other reported clinical experience has not identified differences in responses 
between the elderly and younger patients, but greater sensitivity of some older individuals cannot 
be ruled out. 
10.1.12.2 Interaction with Other Medications  
Drug-Drug Interactions: Caution is recommended when administering sorafenib together with 
compounds that are metabolized/ eliminated predominantly by the UGT1A1 pathway (e.g. 
irinotecan).. 
• 
CYP3A4 inducers: There is no clinical information on the effect of CYP3A4 inducers on 
the pharmacokinetics of sorafenib. Inducers of CYP3A4 activity (e.g. rifampicin, 
Hypericum perforatum also known as St. John’s wort, phenytoin, carbamazepine, 


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phenobarbital, and dexamethasone) may increase metabolism of sorafenib and thus 
decrease sorafenib plasma concentrations. 
• 
CYP3A4 inhibitors: Ketoconazole, a potent inhibitor of CYP3A4, administered once 
daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg 
dose of sorafenib. Therefore, clinical pharmacokinetic interactions of sorafenib with 
CYP3A4 inhibitors are unlikely. 
• 
CYP2C9 substrates: The possible effect of sorafenib on the metabolism of the CYP2C9 
substrate warfarin was assessed indirectly by measuring PTINR. The mean changes from 
baseline in PT-INR were not higher in sorafenib patients compared to placebo patients, 
suggesting that sorafenib did not inhibit warfarin metabolism in vivo. However, patients 
taking warfarin should have their INR checked regularly. 
• 
CYP isoform-selective substrates: Concomitant administration of midazolam, 
dextromethorphan and omeprazole, which are substrates of cytochromes CYP3A4, 
CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration did 
not significantly alter the exposure of these agents. This indicates that sorafenib is neither 
an inhibitor nor a clinically meaningful inducer of these cytochrome P450 isoenzymes. 
• 
Combination with other anti-neoplastic agents: In clinical studies, sorafenib has been 
administered together with a variety of other antineoplastic agents at their commonly used 
dosing regimens, including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. 
Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. 
Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of 
doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further 
metabolized by the UGT1A1 pathway, there was a 67-120% increase in the AUC of SN-
38 and a 26-42% increase in the AUC of irinotecan. The clinical significance of these 
findings is unknown. However, caution is recommended when administering sorafenib 
with doxorubicin and with compounds that are metabolized/eliminated predominantly by 
the UGT1A1 pathway (e.g. irinotecan).  
• 
Warfarin: Infrequent bleeding events or elevations in the International Normalized Ratio 
(INR) have been reported in some patients taking warfarin while on sorafenib therapy. 
Patients taking warfarin concomitantly should be monitored regularly for changes in 
prothrombin time, INR and for clinical bleeding episodes. 
10.1.12.3 Pregnancy and Lactation 
Pregnancy: Women should avoid becoming pregnant while on therapy. Women of childbearing 
potential must be apprised of the potential hazard to the fetus, which includes severe malformation 
(teratogenicity), failure to thrive and fetal death (embryotoxicity). Sorafenib should not be used 
during pregnancy. Prescribers may only consider it to be used, if the potential benefits justify the 
potential risks to the fetus. 
• 
There are no adequate and well-controlled studies in pregnant women using sorafenib. 
Studies in animals have shown reproductive toxicity including malformations. In rats, 
sorafenib and its metabolites were demonstrated to cross the placenta and sorafenib is 
anticipated to inhibit angiogenesis in the fetus. 


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• 
Women should avoid becoming pregnant while on therapy. Women of childbearing 
potential must be apprised of the potential hazard to the fetus, which includes severe 
malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity). 
• 
Sorafenib should not be used during pregnancy. Prescribers may only consider it to be 
used, if the potential benefits justify the potential risks to the fetus. 
• 
In animals, sorafenib has been shown to be teratogenic and embryotoxic. Adequate 
contraception should be used during therapy and for at least 2 weeks after completion of 
therapy. 
Breastfeeding should be discontinued during sorafenib therapy. 
• 
It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or 
its metabolites were excreted in milk. Because many drugs are excreted in human milk and 
because the effects of sorafenib on infants have not been studied, woman should 
discontinue breastfeeding during sorafenib treatment. 
Effects on fertility: Results from animal studies indicate that sorafenib can impair male and 
female fertility. 
 Clinical Pharmacokinetic Properties: 
After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when 
compared to an oral solution. The mean elimination half-life of sorafenib is approximately 25-48 
hours. Multiple dosing of sorafenib for 7 days resulted in a 2.5-to 7-fold accumulation compared 
to single dose administration.   
Steady-state plasma sorafenib concentrations are achieved within 7 days, with a peak-to-trough 
ratio of mean concentrations of less than 2. 
10.1.13.1 Absorption and Distribution 
Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. 
When given with a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that 
in the fasted state. With a high-fat meal (50% fat; 900 calories), sorafenib bioavailability was 
reduced by 29% compared to administration in the fasted state. It is recommended that sorafenib 
be administered without food.  Mean Cmax and AUC increased less than proportionally beyond          
doses of 400 mg administered orally twice daily.  In vitro binding of sorafenib to human plasma 
proteins is 99.5%. 
10.1.13.2 Metabolism and Elimination 
Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by 
CYP3A4, as well as glucuronidation mediated by UGT1A9.  Sorafenib accounts for approximately 
70-85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have 
been identified, of which five have been detected in plasma. The main circulating metabolite of 
sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib. This 
metabolite comprises approximately 9-16% of circulating analytes at steady-state.  Following oral 
administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was 
recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted 
in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was 
found in feces but not in urine. 


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10.1.13.3 Special Populations 
Age: Analyses of demographic data suggest that no dose adjustments are necessary for age. 
Gender: Analyses of demographic data suggest that no dose adjustments are necessary for gender. 
Race: A study of the pharmacokinetics of sorafenib indicated that the mean AUC of sorafenib in 
Asians (N=78) was 30% lower than in Caucasians (N=40). 
Pediatric: There are no pharmacokinetic data in pediatric patients. 
Hepatic Impairment: Sorafenib is cleared primarily by the liver.  Comparison of data across 
studies suggests that in HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) 
hepatic impairment, 400 mg doses of sorafenib appear to be associated with AUC values that were 
23 to 65% lower than those of other subjects without hepatic impairment. The AUC of sorafenib 
is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic 
impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe 
(Child-Pugh C) hepatic impairment. 
Renal Impairment: In a study of drug disposition after a single oral dose of radiolabeled sorafenib 
to healthy subjects, 19% of the administered dose of sorafenib was excreted in urine.  In a clinical 
pharmacology study, the pharmacokinetics of sorafenib were evaluated following administration 
of a single 400 mg dose to subjects with normal renal function, and in subjects with mild (CrCl > 
50-80 ml/min), moderate (CrCl 30-50 ml/min), or severe (CrCl <30 ml/min) renal impairment, not 
undergoing dialysis. There was no relationship observed between sorafenib exposure and renal 
function. No dosage adjustment is necessary based on mild, moderate or severe renal impairment 
not undergoing dialysis.  Monitoring of fluid balance and electrolytes in patients at risk of renal 
dysfunction is advised. 
 
 Administration:  
 400 mg (2 tablets) orally twice daily without food (at least 1 hour before or 2 hours after a meal). 
 Supplier:   
Bayer Pharmaceuticals 
 Unused or defective agent:   
Refer to the detailed instructions described in Section 10.2.18   Unused or defective drug will be 
destroyed.  Bayer Pharmaceuticals should be notified of this action. 
 EVEROLIMUS 
 
Drug Name:   
 
Everolimus 
 
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. 


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Molecular Formula:    
C53H83NO14 
 
Molecular Weight:   
 958.2 
 
Appearance:     
 2.5 mg tablet White to slightly yellow, elongated tablets with a beveled edge and no 
score, engraved with “LCL” on one side and “NVR” on the other. 
 5 mg tablet - White to slightly yellow, elongated tablets with a beveled edge and no 
score, engraved with “5” on one side and “NVR” on the other. 
 7.5 mg tablet White to slightly yellow, elongated tablets with a beveled edge and 
engraved with “7P5” on one side and “NVR” on the other. 
 10 mg tablet - White to slightly yellow, elongated tablets with a beveled edge and no 
score, engraved with “UHE” on one side and “NVR” on the other. 
 
How supplied: 
Each carton contains 4 blister cards of 7 tablets per card, total 28 tablets per carton. 
Store everolimus tablets at 25° C (77°F); excursions permitted between 15°–30°C (59°–86°F). 
[See USP Controlled Room Temperature.] Store in the original container, protect from light and 
moisture. Keep this and all drugs out of the reach of children.  Procedures for proper handling and 
disposal of anticancer drugs should be considered.  Everolimus tablets should not be crushed. 
Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such 
contact occurs, wash thoroughly. Personnel should avoid exposure to crushed tablets. 
 
Formulation:  
Everolimus is supplied as tablets for oral administration containing everolimus together with 
butylated hydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone 
and lactose anhydrous as inactive ingredients. 
 
Storage and Stability:   
Current stability data permits a shelf-life of 36 months at storage conditions below 30°C and 
maintenance in the original packs. 
 
Mechanism of Action:  
Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, 
downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human 
cancers. Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex 
formation and inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 
ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP), 
downstream effectors of mTOR, involved in protein synthesis. In addition, everolimus inhibited 
the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular 
endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce 
cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies. 


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 Pharmacology: 
10.2.10.1 Drug Interactions 
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug 
efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor 
of CYP2D6.  
 
10.2.10.1.1 Agents that may Increase Everolimus Blood Concentrations 
CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to everolimus treatment 
alone there were significant increases in everolimus exposure when everolimus was co-
administered with: 
• 
ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased 
by 3.9- and 15.0-fold, respectively. 
• 
erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC 
increased by 2.0- and 4.4-fold, respectively. 
• 
verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased 
by 2.3-and 3.5-fold, respectively. 
Concomitant strong or moderate inhibitors of CYP3A4 and PgP inhibitors should not be used. 
10.2.10.1.2 Agents that may Decrease Everolimus Blood Concentrations  
CYP3A4 Inducers: In healthy subjects, co-administration of everolimus with rifampin, a strong 
inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, 
compared to everolimus treatment alone. Consider a dose increase of everolimus when co-
administered with strong inducers of CYP3A4 or PgP if alternative treatment cannot be 
administered. 
Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects 
indicate that there are no clinically significant pharmacokinetic interactions between everolimus 
and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-
CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of 
simvastatin (a CYP3A4 substrate) on the clearance of everolimus. 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without prior consultation with the investigator. At each 
visit, the investigator will ask the patient about any new medications he/she is or has taken after 
the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be recorded. 
• 
Growth factors (e.g. G-CSF, GM-CSF, erythropoietin, platelets growth factors etc.) are not 
to be administered prophylactically but may be prescribed by the investigator for rescue 
from severe hematologic events, if this is thought to be appropriate. 
• 
Concurrent administration of everolimus and strong CYP3A4 inhibitors (such as 
ketoconazole, itraconazole, ritonavir) and inducers (such as rifampin, rifabutin) should be 


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avoided. Provided there is no alternative treatment available, patients should be closely 
monitored for potential toxicities. 
• 
Concurrent administration of everolimus and moderate CYP3A4 inhibitors (such as 
erythromycin, fluconazole, calcium channel blockers, benzodiazepines) and moderate 
CYP3A4 inducers (e.g. carbamazepine, phenobarbital) should also be avoided if possible, 
or used subject to caution (e.g. increased frequency of safety monitoring, temporary 
interruption of everolimus). 
• 
Competitive inhibition could occur when everolimus is combined with drugs which are 
also CYP3A4 substrates. Therefore caution should be exercised in such cases. 
• 
Co-administration with substrates, inducers, or inhibitors of P-glycoprotein should be 
avoided, if possible, or used subject to caution (e.g. increased frequency of safety 
monitoring, temporary interruption of everolimus).  
• 
Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity and 
should therefore be avoided.  
• 
In addition, patients should avoid Seville oranges and star fruit, as well as the juice of these 
fruits, which are potent CYP3A4-inhibitors.  
• 
No chronic treatment with immunosuppressive agents. Topical or inhaled corticosteroids 
are allowed. 
• 
Everolimus may affect the response to vaccinations making the response to the vaccination 
less effective. Live vaccines should be avoided while a patient is treated with everolimus. 
Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction with 
everolimus is expected. However, drug-drug interaction studies between macrolide antibiotics and 
warfarin have produced mixed outcomes and the disparity in these findings has led to the 
conclusion that multiple factors may alter the clearance of warfarin. The co-administration of 
everolimus and oral anticoagulants is possible but should be subject to verification of coagulation 
(INR) once steady state is reached (after one week’s treatment). 
Examples are provided in Table 3-3. A comprehensive list of cytochrome P450 isoenzymes and 
CYP3A4 inhibitors, inducers, and substrates can be found at http://medicine.iupui.edu/flockhart.  
This website is continually revised and should be checked frequently for updates. 
 Pre-clinical Toxicology: 
In safety pharmacology studies, Everolimus was devoid of relevant effects on vital functions 
including the cardiovascular, respiratory and nervous systems. Everolimus had no influence on QT 
interval prolongation. Furthermore, everolimus showed no antigenic potential. Although 
everolimus passes the blood-brain barrier, there was no indication of relevant changes in the 
behavior of rodents, even after single oral doses up to 2000mg/kg or after repeated administration 
at up to 40 mg/kg/day. Based on these findings, the potential of everolimus to affect vital functions 
in patients is considered to be low.  Everolimus is considered to have no genotoxicity or 
carcinogenicity potential. All significant adverse events observed in preclinical toxicology studies 
with everolimus in mice, rats, monkeys and minipigs were consistent with its anticipated 
pharmacologic action as an antiproliferative and immunosuppressant and at least in part reversible 
after a 2- or 4-week recovery period with the exception of the changes in male reproductive organs, 


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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. 
 Human Toxicity: 
Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. 
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 and other rapamycin 
derivatives. 
WARNINGS AND PRECAUTIONS 
10.2.12.1 Non-infectious Pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. In the 
randomized study, non-infectious pneumonitis was reported in 14% of patients treated with 
everolimus. The incidence of CTCAE grade 3 and 4 non-infectious pneumonitis was 4% and 0%, 
respectively. Fatal outcomes have been observed. 
Consider a diagnosis of non-infectious pneumonitis 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 causes have been excluded by means of appropriate investigations. 
Advise patients 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, consider interrupting 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, discontinue everolimus 
therapy 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. 
10.2.12.2 Infections 
Everolimus has immunosuppressive properties and may predispose patients to infections, 
especially infections with opportunistic pathogens. Localized and systemic infections, including 
pneumonia, other bacterial infections and invasive fungal infections, such as aspergillosis or 
candidiasis, have occurred in patients taking everolimus. Some of these infections have been 
severe (e.g., leading to respiratory failure) or fatal. Physicians and patients should be aware of the 
increased risk of infection with everolimus, be vigilant for signs and symptoms of infection and 
institute appropriate treatment promptly. Complete treatment of pre-existing invasive fungal 
infections prior to starting treatment with everolimus. If a diagnosis of invasive systemic fungal 
infection is made, discontinue everolimus and treat with appropriate antifungal therapy. 
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. 


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10.2.12.3 Oral Ulceration 
Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with everolimus. In 
the randomized study, approximately 44% of everolimus treated patients developed mouth ulcers, 
stomatitis, or oral mucositis, which were mostly CTCAE grade 1 and 2. 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. 
10.2.12.4 Renal Function 
Elevations of serum creatinine, usually mild, have been reported in clinical trials. Monitoring of 
renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is 
recommended prior to the start of everolimus therapy and periodically thereafter. 
10.2.12.5 Blood Glucose and Lipids 
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials. 
Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of 
everolimus therapy and periodically thereafter. When possible, optimal glucose and lipid control 
should be achieved before starting a patient on everolimus. 
10.2.12.6 Hematological Parameters 
Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical 
trials. Monitoring of complete blood count is recommended prior to the start of everolimus therapy 
and periodically thereafter. 
10.2.12.7 CYP3A4 Interactions 
Due to significant increases in exposure of everolimus, co-administration with strong or moderate 
inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, 
saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, 
voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil or diltazem) or P-
glycoprotein (PgP) should be avoided. 
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug 
efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor 
of CYP2D6. 
10.2.12.7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors 
and PgP Inhibitors:  
In healthy subjects, compared to everolimus treatment alone there were significant increases in 
everolimus exposure when everolimus was coadministered with: 
• 
ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased 
by 3.9- and 15.0-fold, respectively. 
• 
erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC 
increased by 2.0- and 4.4-fold, respectively. 
• 
verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased 
by 2.3-and 3.5-fold, respectively. 


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Concomitant strong or moderate inhibitors of CYP3A4 and PgP inhibitors should not be 
used. 
10.2.12.7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers:  
In healthy subjects, co-administration of everolimus with rifampin, a strong inducer of CYP3A4, 
decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus 
treatment alone. Consider a dose increase of everolimus when co-administered with strong 
inducers of CYP3A4 or PgP if alternative treatment cannot be administered. 
10.2.12.7.3 Agents whose Plasma Concentrations may be Altered by Everolimus 
Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic 
interactions between everolimus and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 
substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses 
also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of everolimus. 
10.2.12.8 Adverse Reactions 
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates 
observed cannot be directly compared to rates in other trials and may not reflect the rates observed 
in clinical practice. 
The data described below reflect exposure to everolimus (n=274) and placebo (n=137) in a 
randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior 
treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 
88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 
141 days (range 19-451) for patients receiving everolimus and 60 days (range 21-295) for those 
receiving placebo. 
The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, 
fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were 
infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. 
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 but none on the placebo arm. The rates of treatment-emergent adverse 
events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the 
everolimus and placebo treatment groups, respectively. The most common adverse reactions 
(irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. 
Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose 
reduction. The most common medical interventions required during everolimus treatment were for 
infections, anemia, and stomatitis. 
Likely (occurring in more than 20% of patients) 
Adverse events most frequently observed with everolimus are rash, stomatitis/oral mucositis, 
fatigue, anorexia, nausea, diarrhea, peripheral edema, asthenia, cough, dyspnea, ocular toxicity 
and infections.  Infections include nasopharyngitis (6%), pneumonia (6%), urinary tract infection 
(5%), bronchitis (4%), sinusitis (3%), aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).   


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Laboratory abnormalities include anemia, neutropenia, thrombocytopenia, lymphopenia, 
hypercholesterolemia, and/or hypertriglyceridemia, hyperglycemia, hypophosphatemia, aspartate 
and alanine transaminase elevation. The majority of these AEs have been of mild to moderate 
severity (CTCAE grade 1-2). 
Common (occurring in 3 – 20% of Patients) 
Adverse events occurring in 3-20% of patients include vomiting, pyrexia, mucosal inflammation, 
epistaxis, pneumonitis (includes pneumonitis, interstitial lung disease, lung infiltration,, 
pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis), pruritus, dry skin, headache, 
dysgeusia, pain in extremity, abdominal pain, dry mouth, hemorrhoids, dysphagia, chest pain, 
chills, pleural effusion, pharyngolaryngeal pain, rhinorrhea, hand-foot syndrome, nail disorder, 
erythema, onychoclasis, skin lesion, acneiform dermatitis, insomnia, dizziness, paresthesia, eyelid 
edema, hypertension, renal failure, tachycardia, jaw pain, and  hemorrhage. 
Laboratory abnormalities include increased bilirubin (<1% grade 3 or 4). 
Rare but Serious (occurring in fewer than 3% of patients) 
Acute respiratory failure and acute renal failure. 
10.2.12.9 Pregnancy and Breast Feeding 
There are no adequate and well-controlled studies of everolimus in pregnant women. However, 
based on mechanism of action, everolimus may cause fetal harm when administered to a pregnant 
woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were 
lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during 
pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised 
of the potential hazard to the fetus. Women of childbearing potential should be advised to use 
highly effective methods of contraception while receiving everolimus and for up to 8 weeks after 
ending treatment. 
In animal reproductive studies, oral administration of everolimus to female rats before mating and 
through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-
implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., 
sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal 
toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in 
patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an 
increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human 
dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal 
toxicities. 
In a pre- and post-natal development study in rats, animals were dosed from implantation through 
lactation. At approximately 10% of the recommended human dose based on body surface area, 
there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. 
However, there was reduced body weight (up to 9% reduction from the control) and slight 
reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the 
developmental parameters (morphological development, motor activity, learning, or fertility 
assessment) in the offspring. 


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Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 
0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats 
that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 
10.2.12.10 Nursing Mothers 
It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites 
passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. 
Therefore, women who are taking everolimus should not breastfeed during treatment and for 2 
weeks after the last dose. 
 Clinical Pharmacokinetic Properties: 
Absorption 
In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours 
after administration of oral doses ranging from 5 mg to 70 mg.  Following single doses, Cmax is 
dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax 
is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg 
dose range. Steady-state was achieved within two weeks following once-daily dosing.  Food effect: 
Based on data in healthy subjects taking 10 mg everolimus tablets, a high-fat meal reduced Cmax 
and AUC by 54% and 22%, respectively.   
Distribution 
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 
5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 
20% at blood concentrations observed in cancer patients given everolimus 10 mg/day. Plasma 
protein binding is approximately 74% both in healthy subjects and in patients with moderate 
hepatic impairment.  
Metabolism 
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the 
main circulating component in human blood. Six main metabolites of everolimus have been 
detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-
opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also 
identified in animal species used in toxicity studies, and showed approximately 100-times less 
activity than everolimus itself.  In vitro, everolimus competitively inhibited the metabolism of 
CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan. The mean steady 
state Cmax following an oral dose of 10 mg daily is more than 12-fold below the Ki-values of the 
in vitro inhibition. Therefore, an effect of everolimus on the metabolism of CYP3A4 and CYP2D6 
substrates is unlikely. 
Excretion 
No specific excretion studies have been undertaken in cancer patients. Following the 
administration of a 3 mg single dose of radiolabelled everolimus in patients who were receiving 
cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the 
urine. The parent substance was not detected in urine or feces. The mean elimination half-life of 
everolimus is approximately 30 hours. 


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Patients with Renal Impairment 
Approximately 5% of total radioactivity was excreted in the urine following a 3 mg dose of [14C]-
labeled everolimus. In a population pharmacokinetic analysis which included 170 patients with 
advanced cancer, no significant influence of creatinine clearance (25 – 178 mL/min) was detected 
on oral clearance (CL/F) of everolimus. 
Patients with Hepatic Impairment 
The average AUC of everolimus in eight subjects with moderate hepatic impairment (Child-Pugh 
class B) was twice that found in eight subjects with normal hepatic function. AUC was positively 
correlated with serum bilirubin concentration and with prolongation of prothrombin time and 
negatively correlated with serum albumin concentration. A dose reduction for patients with Child-
Pugh class B hepatic impairment is recommended. Everolimus should not be used in patients with 
severe (Child-Pugh class C) hepatic impairment as the impact of severe hepatic impairment on 
everolimus exposure has not been assessed. 
Effects of Age and Gender 
In a population pharmacokinetic evaluation in cancer patients, no relationship was apparent 
between oral clearance and patient age or gender. 
Ethnicity 
Based on a cross-study comparison, Japanese patients (n = 6) had on average exposures that were 
higher than non-Japanese patients receiving the same dose.  Based on analysis of population 
pharmacokinetics, oral clearance (CL/F) is on average 20% higher in Black patients than in 
Caucasians.  The significance of these differences on the safety and efficacy of everolimus in 
Japanese or Black patients has not been established. 
 Administration: 
Everolimus should be taken whole by mouth with a full glass of water as instructed by the 
investigator. Everolimus should be taken by the patient in a fasting state or with no more than a 
light fat-free meal. Patients should take their tablets at the same time of the day and at the same 
time in relation to meals. Patients should avoid eating grapefruit and/or grapefruit juice for the 
entire duration of the study.  All patients should be instructed to contact the investigator if he/she 
is unable to take the study drug as prescribed for any reason.  
 Supplier:  Novartis 
 Unused or defective agent:  Refer to the detailed instructions described in Section 
10.2.18.2 below. 
 Agent Storage and Accountability  
The investigator is responsible for the proper and secure physical storage and record keeping of 
investigational agents received for BTTC protocols. Specifically, the investigator must:   
• Maintain a careful record of the receipt, use and final disposition of all investigational 
agents received, using the NCI Agent Accountability Record Form (DARF), 
http://ctep.cancer.gov/forms/index.html.   
• Store the agent in a secure location, accessible to only authorized personnel, preferably in 
the pharmacy. 


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• Maintain appropriate storage of the investigational agent to ensure the stability and 
integrity of the agent. 
• Return any unused investigational agents at the completion of the study or upon notification 
that an agent is being withdrawn. 
The intent of the agent accountability procedures described in this section is to assist the 
investigator in making certain that agents received from BTTC are used only for patients entered 
onto an approved protocol. The record keeping described in this section is required under FDA 
regulation.  
 
10.2.17.1 BTTC Procedures for Agent Accountability and Storage  
• Each investigational agent should be stored separately by protocol. If an agent is used for 
more than one protocol, there should be separate physical storage for each protocol. 
Remember that agents are provided and accounted for on a protocol-by-protocol basis. 
• Each agent should be accounted for separately by protocol. If an agent is used for more 
than one protocol, there should be a separate Drug Accountability Record Form (DARF) 
for each protocol, http://ctep.cancer.gov/forms/index.html. There should be a separate 
DARF for each agent in a multi-agent protocol. 
• Separate accountability forms should be maintained for each different strength or dosage 
form of a particular agent (e.g., an agent with a 1-mg vial and a 5-mg vial would require a 
different DARF for the 1-mg vial than for the 5-mg vial). 
• The DARF has been designed for use at each location where agents are stored, e.g., main 
pharmacy, satellite pharmacy, physician's office, or other dispensing areas. 
• The DARF is also designed to accommodate both dispensing records and other agent 
transaction documentation (e.g., receipt of agent, returns, broken vials, etc.). A copy of the 
DARF may be found at http://ctep.cancer.gov/forms/index.html. 
• Unauthorized inter-institutional transfer of BTTC investigational agents from one 
participating institution to another is not permitted.  For some protocols the lead 
institution may enter into contractual agreements to forward agents to participating 
institutions (see BTTC Operations Manual). 
Verification of Compliance 
Investigators are reminded that compliance with procedures to ensure proper agent usage will be 
reviewed during site visits conducted under the monitoring program. Specifically, site visitors will 
check that the agent accountability system is being maintained, and will spot-check the agent 
accountability records by comparing them with the patients' medical records to verify that the 
agents were administered to a patient entered in the recorded protocol 
 Returning or destroying unused and/or defective Agent:  
Investigators/Designees should make every effort to minimize the amount of agent ordered and 
returned unused, (e.g. limit inventories to an 8 week supply or less). Investigators/Designees must 
return unused supplied agent as directed in the protocol when:  


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• The agent is no longer required because the study is completed.  
• Agent is outdated. Investigators/designees should only return outdated agents with a firm 
expiration date or if they have received written notification that an agent has expired and 
should be returned.  
• The agent is damaged or unfit for use. Investigators/designees should contact the supplier 
prior to returning investigational agents because of stability concerns, (e.g. loss of 
refrigeration or exposure to elevated temperatures). Do NOT return broken vials. Broken 
vials should be destroyed at the clinical site.  Follow the appropriate agent accountability 
guidelines.  
General Guidelines  
• Regulations require that all agents received be returned to the supplier for accountability 
and disposition.  
• Return only unused vials/bottles. Do NOT return opened or partially used vials/bottles 
unless specifically requested otherwise in the protocol.  
• Return only supplied agents. Do NOT ship agents received from other sources to the 
supplier.  
10.2.18.1 Sorafenib Return Procedure 
All unused and returned sorafenib may be destroyed on site.  The site must follow their local drug 
destruction policy and procedure.  A copy of the drug destruction record must be submitted to 
Bayer Pharmaceuticals using the Bayer form provided (attached as a separate form).  
Contact:  Amanda Rozner   
Bayer Healthcare, US Medical Affairs 
Investigator Sponsored Studies & Medical Education 
100 Bayer Boulevard, P.O. Box 915 
Bldg 200, 4th Floor  
Whippany, NJ 07981-0915 
Phone:  1-862-404-5842 
Email:  amanda.rozner@bayer.com 
 
10.2.18.2 Everolimus Return Procedure  
All unused and returned everolimus may be destroyed on site.  The site must follow their local 
drug destruction policy and procedure.  A copy of the drug destruction record must be submitted 
to Novartis.  
Contact:  Krystal Saintil 
Novartis Pharmaceuticals Corporation 
USEH 
One Health Plaza 
Building 345 
East Hanover, NJ 07936-1080 
USA 


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Phone:  +1 862778 7169 
Email:  krystal.saintil@novartis.com   
                                                                                                                                                         
10.2.18.3 Handling of study medication: Pharmacists should use appropriate precautions in 
handling and disposal of hazardous agents. 
 
10.2.18.4 Notice of Defect or Non-Conformity: 
The Sponsor (NCI) shall ensure that any notice of defect or non-conformity is sent to Novartis 
within ten (10) days from receipt of Study Drug. The failure to provide such notice shall be deemed 
an acceptance of Study Drug by the Sponsor or its Subcontractors. Latent defects which are 
detected later shall be immediately reported to Novartis for further processing within Novartis. 
11.0  MULTICENTER PROCEDURES 
 GENERAL PROCEDURES 
The BTTC Operations Manual and Data Submission Forms, on file at all BTTC institutions, 
document the data management and quality assurance programs for this collaboration.  BTTC 
institutions will follow the guidelines as addressed below and throughout this protocol. 
 PRINCIPAL INVESTIGATORS 
The principal investigator(s) will be responsible for the conduct of the study and monitoring its 
progress.  The responsibility for all reports and forms required by BTTC will be that of the 
principal investigator(s). 
 PROCEDURES FOR SITE REGISTRATION 
Before an institution may begin participating in a BTTC protocol, they must complete the 
following steps: 
• Submit all required regulatory documents to the BTTC Coordinating Center as outlined 
in the BTTC Operations Manual 
• Participate in a site initiation visit, webcast, or conference call 
• Receive training regarding study specific CRF’s and/or databases 
After these requirements have been fulfilled, the participating institution will receive by fax, e-
mail, or hard copy memo a Site Activation Notification.  Once the Site Activation Notification has 
been received, the participating institution may begin to register patients to the protocol. 
  INSTITUTIONAL REVIEW  
Each cooperating center will submit the protocol to its own IRB.  Documentation of the IRB 
approval will be forwarded to the BTTC Coordinating Center before a patient from that institution 
can be registered on protocol.  No changes in the protocol will be allowed unless approved by the 
principal investigator and BTTC. 
 PROTOCOL REVISIONS AND CLOSURE 
Non life-threatening revisions: BTTC investigators will receive written notification of protocol 
revisions regarding non life-threatening events. 


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Life-threatening revisions: BTTC investigators will receive telephone notification of life-
threatening revisions with follow-up by fax and/or e-mail.  Life-threatening protocol revisions will 
be implemented immediately. 
Protocol closures and temporary holds: BTTC investigators will receive email notification of 
protocol closures and holds.  Closures and holds will be effective immediately.  Centers will be 
updated on an ongoing basis about protocol accrual data so that they will be aware of imminent 
protocol closures. 


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12.0 REFERENCES 
 
1. 
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. 
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England 
journal of medicine. 2005;352(10):987-96. 
2. 
Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, et al. 
Progression-free survival: an important end point in evaluating therapy for recurrent high-grade 
gliomas. Neuro-oncology. 2008;10(2):162-70. 
3. 
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-
agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent 
glioblastoma. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2009;27(5):740-5. 
4. 
Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, Marcello J, Reardon DA, Quinn JA, et 
al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2007;25(30):4722-9. 
5. 
CBTRUS. CBTUS. Statistical Report: Primary Brain Tumors in the United States, 1998-
2002. In: Published by the Central Brain Tumor Registry of the United States. 2005. 
6. 
Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN. 
Molecularly targeted therapy for malignant glioma. Cancer. 2007;110(1):13-24. 
7. 
Duda DG, Jain RK, Willett CG. Antiangiogenics: the potential role of integrating this 
novel treatment modality with chemoradiation for solid cancers. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology. 2007;25(26):4033-42. 
8. 
Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, Dowell JM, Reardon DA, Quinn JA, et 
al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 2007;13(4):1253-
9. 
9. 
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 
exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and 
receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer research. 
2004;64(19):7099-109. 
10. 
Hilger RA, Scheulen ME, Strumberg D. The Ras-Raf-MEK-ERK pathway in the 
treatment of cancer. Onkologie. 2002;25(6):511-8. 
11. 
Chang YS, Henderson A, Xue D, Chen C, McNabola A, Wilkie D, et al. BAY 43-9006 
(Sorafenib) inhibits ectopic (s.c.) and orthotopic growth of a murine model of renal 
adenocarcinoma (Renca) predominantly through inhibition of tumor angiogenesis. Cancer 
research. 2005;65(9 Supplement):1372. 
12. 
Awada A, Hendlisz A, Gil T, Bartholomeus S, Mano M, de Valeriola D, et al. Phase I 
safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients 
with advanced, refractory solid tumours. British journal of cancer. 2005;92(10):1855-61. 
13. 
Clark JW, Eder JP, Ryan D, Lathia C, Lenz HJ. Safety and pharmacokinetics of the dual 
action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in 
patients with advanced, refractory solid tumors. Clinical cancer research : an official journal of 
the American Association for Cancer Research. 2005;11(15):5472-80. 
14. 
Moore M, Hirte HW, Siu L, Oza A, Hotte SJ, Petrenciuc O, et al. Phase I study to 
determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 
43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid 


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tumors. Annals of oncology : official journal of the European Society for Medical Oncology. 
2005;16(10):1688-94. 
15. 
Strumberg D, Richly H, Hilger RA, Schleucher N, Korfee S, Tewes M, et al. Phase I 
clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth 
factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology. 
2005;23(5):965-72. 
16. 
Richly H, Henning BF, Kupsch P, Passarge K, Grubert M, Hilger RA, et al. Results of a 
Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with 
refractory solid tumors. Annals of oncology : official journal of the European Society for 
Medical Oncology. 2006;17(5):866-73. 
17. 
Siu LL, Awada A, Takimoto CH, Piccart M, Schwartz B, Giannaris T, et al. Phase I trial 
of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced 
pancreatic cancer. Clinical cancer research : an official journal of the American Association for 
Cancer Research. 2006;12(1):144-51. 
18. 
Escudier B, Szczylik C, Eisen T, Stadler WM, Schwartz B, Shan M, et al. Randomized 
phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43–9006) in patients with 
advanced renal cell carcinoma (RCC). Journal of Clinical Oncology. 
2005;23(16_suppl):LBA4510-LBA. 
19. 
Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 
2006;124(3):471-84. 
20. 
Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nature 
reviews Cancer. 2004;4(5):335-48. 
21. 
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 
2007;129(7):1261-74. 
22. 
Fan QW, Specht KM, Zhang C, Goldenberg DD, Shokat KM, Weiss WA. Combinatorial 
efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic 
approach. Cancer research. 2003;63(24):8930-8. 
23. 
Carmichael J, Fink U, Russell RC, Spittle MF, Harris AL, Spiessi G, et al. Phase II study 
of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer. 1996;73(1):101-5. 
24. 
Armstrong TS, Mendoza TR, Gring I, Coco C, Cohen MZ, Ericksen L, et al. Validation 
of the M. D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT). J Neurooncol. 
2006;In press. 
25. 
Armstrong C, Mollman, J., Corn, B.W., Alavi, J., Grossman, M. Effects of radiation 
therapy on adult brain behavior:  evidence for a rebound phenomenon in a Phase I trial. 
Neurology. 1993;43(1961-1965). 
 
 
 
  
 


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13.0 APPENDICES  
 APPENDIX: KARNOFSKY PERFORMANCE STATUS AND NEUROLOGICAL FUNCTION 
Patient's performance status and Neurologic Functions will be graded according to the following 
scales: 
Karnofsky Performance Status 
KPS 100 
Normal; no complaints; no evidence of disease 
KPS   90 
Able to carry on normal activity; minor signs or symptoms of disease 
KPS   80 
Normal activity with effort; some sign or symptoms of disease 
KPS   70 
Cares for self; unable to carry on normal activity or do active work 
KPS   60 
Requires occasional assistance, but is able to care for most personal needs 
KPS   50 
Requires considerable assistance and frequent medical care 
KPS   40 
Disabled; requires special care and assistance 
KPS   30 
Severely disabled; hospitalization is indicated, although death no imminent 
KPS   20 
 Very sick; hospitalization necessary; active support treatment is necessary 
KPS   10 
Moribund; fatal processes progressing rapidly 
KPS     0 
Dead 
Neurologic Function 
 
+2 
Definitely Better 
 
+1 
Possibly Better 
 
 0 
Unchanged 
 
-1 
Possibly Worse 
 
-2 
Definitely Worse 
 
 B 
Baseline 
 
 
 
 


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 APPENDIX:  EIAEDS AND NON-EIAEDS 
 
EIAED 
Carbamazipine  
(Tegretol, Tegretol XR, Carbatrol) 
Oxcarbazepine 
(Trileptal) 
Phenytoin 
 
(Dilantin, Phenytek) 
Fosphenytoin  
(Cerebyx) 
Phenobarbital 
Primidone 
 
(Mysoline) 
 
Non-EIAEDs: 
Valproic acid  
(Depakote, Depakene) 
Gabapentin  
 
(Neurontin) 
Lamotrigine 
 
(Lamictil) 
Topriamate 
 
(Topamax) 
Tiagabine  
 
(Gabatril) 
Zonisamide 
 
(Zonegran) 
Levatriacetam  
(Keppra) 
Clonazepam   
(Klonopin) 
Clonozam 
 
(Frisium) 
 
 
 


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 APPENDIX: DRUGS KNOWN TO BE METABOLIZED BY CYP450 ISOENZYMES 2D6 AND 3A4 
CYP3A3/4 
Substrates 
Acetaminophen 
Aifentanil 
Alosetron 
Alprazolam 
Amiodarone 
Amitriptyline (minor) 
Amlodipine 
Anastrozole 
Androsterone 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busutfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Digitoxin 
Diltiazem 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erythromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Chlorpromazine 
Cimetidine 
Cisapride 
Citałopram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine (demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, N-
demethylation)  
Diazepam (minor; hydroxylation, N-
demethylation) 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 


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Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Flutamide 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
lfosfamide 
lmipramine 
lndinavir 
lsradipine 
ltraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
Toremifene 
Trazodone 
Tretinoin 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
Quercetin 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 
 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Phenytoin 
Primidone 
Progesterone 


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Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
 
  Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, 
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, 
OH; LexiComp Inc. 2000: 1364-1371) 
 
Table 13-1:  Examples of clinically relevant drug interaction: substrates, inducers and 
inhibitors of isoenzyme CYP3A.  
Substrates 
(competitive 
inhibition) 
 


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Antibiotics1: 
 
clarithromycin* 
 
erythromycin  
 
telithromycin* 
Anti-arrhythmics: 
 
quinidine 
Benzodiazepines: 
 
alprazolam 
 
diazepam 
 
midazolam 
 
triazolam 
Immune Modulators: 
 
cyclosporine 
 
tacrolimus (FK506) 
HIV Protease Inhibitors: 
 
indinavir* 
 
ritonavir* 
 
saquinavir* 
Prokinetic: 
 
cisapride 
Antihistamines: 
 
astemizole 
 
chlorpheniramine90 
Calcium Channel Blockers: 
 
amlodipine 
 
diltiazem 
 
felodipine 
 
nifedipine 
 
nisoldipine 
 
nitrendipine 
 
verapamil 
HMG CoA Reductase Inhibitors2:  
 
atorvastatin 
 
cerivastatin 
 
lovastatin 
 
simvastatin 
Miscellaneous: 
 
aprepitant 
 
buspirone 
 
haloperidol 
 
methadone 
 
pimozide  
 
quinine 
 
sildenafil 
 
tamoxifen 
 
trazodone 
 
vincristine 
Inducers 
Carbamazepine 
Phenobarbital 
Phenytoin* 
Rifabutin* 
Rifampin* 
St John’s wort 
Troglitazone 
Inhibitors 
Amiodarone 
Cimetidine 
Clarithromycin 
Delaviridine 
Diltiazem 
Erythromycin 
Fluvoxamine* 
Grapefruit juice 
Sevilla orange 
Indinavir 
Itraconazole* 
Ketoconazole* 
Voriconazole* 
Posaconazole* 
Mibefradil 
Nefazodone* 
Nelfinavir* 
Troleandomycin 
Verapamil 
 
 


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Based on: Ingelman-Sundberg M, Human drug metabolising cytochrome P450 
enzymes: properties and polymorphisms, Naunyn Schmiedebergs Arch Pharmacol. 
2004 Jan;369(1):89-104.  and [http://www.medicine.iupui.edu/flockhart/clinlist.htm 
as of July 13, 2006] 
* asterisk denotes strong inhibition/ induction  
Please note: 
- strong inhibitor implies that it can cause ≥5-fold increase in AUC or ≥80% 
decrease in clearance of sensitive CYP substrates 
- moderate inhibitor implies that it can cause 2 to 5-fold increase in AUC values 
or 50-80% decrease in clearance  of sensitive CYP substrates. 
(Distinction is not always categorical as interaction can vary according to 
conditions). 
1. Macrolide antibiotics:  Azithromycin is not a CYP3A substrate. It may therefore be 
employed where antibiotherapy with a macrolide is desirable in a patient being 
treated with everolimus 
2. Statins: Atorvastatin and pravastatin may be associated with everolimus, since a PK 
interaction study has shown that there is no relevant PK interaction.  
 


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 APPENDIX: M.D. ANDERSON SYMPTOM INVENTORY (MDASI-BT) 
 


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 APPENDIX: PILL DIARY AND PILL COUNT DOCUMENTATION FORM  
 
The Pill Diary  
 


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The Pill Count Documentation Form A and B  
 


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 APPENDIX: CCR PROBLEM REPORT FORM 
 
NCI Protocol #:  
Protocol Title:  
 
 
Report version: (select one) 
____Initial Report  
____Revised Report 
____Follow-up  
Site Principal Investigator: 
 
  
Date of problem:     
Location of problem: (e.g.,  patient’s home, 
doctor’s office ) 
 
 
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, 
etc…) 
 
Brief Description of Subject (if 
applicable)  
(Do 
NOT 
include 
personal 
identifiers)  
Sex:  ___ Male  ___ Female Age:   
 ___ Not applicable (more than subject is involved) 
 
Diagnosis under study:   
Name the problem: (select all that apply)   
[  ] Adverse drug reaction   
[  ] Abnormal lab value   
[  ] Death   
[  ] Cardiac Arrest/ code  
[  ] Anaphylaxis  
[  ] Sepsis/Infection   
[  ] Blood product reaction 
[  ] Unanticipated surgery/procedure   
[  ] Change in status (e.g. increased level of care required)    
[  ] Allergy (non-medication)  
[  ] Fall  
[  ] Injury/Accident (not fall)  
[  ] Specimen collection issue   
[  ] Informed consent issue   
[  ] Ineligible for enrollment   
[  ] Breach of PII  
[  ] Tests/procedures not performed on schedule  
[  ]  Other, brief  1-2 word description: _________________________ 
 
 
 


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Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history): 
 
 
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  
Please explain: 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  
Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of harm 
than was previously known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 
[  ] Non-compliance 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NCI IRB, this problem is also being reported to: (select all that apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
 
DATE:   
 
 


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 APPENDIX: UNUSED STUDY DRUG DISPOSITION FORM – BAYER 
 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
16-C-0011 
PRINCIPAL INVESTIGATOR: 
Mark Gilbert, M.D. 
STUDY TITLE:  
BTTC09-01: A Phase I-II Trial of Everolimus and Sorafenib in Patients with 
Recurrent High-Grade Gliomas 
 
Continuing Review Approved by the IRB on 07/28/20 
Amendment Approved by the IRB on 08/20/18 (D) 
 
Date posted to web: 08/14/20  
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
This is an investigational study.  Everolimus is FDA approved and commercially available for 
the treatment of kidney cancer and certain types of brain tumors. It is designed to block a special 
protein in tumor cells and block the formation of new blood vessels, which is important in tumor 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 2 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
growth.  Sorafenib is FDA approved and commercially available for the treatment of kidney 
cancer. Sorafenib is designed to stop cell growth and to block the formation of new blood vessels 
(the tubes that carry blood around the body), which are involved in the growth and development 
of tumors. The combination of everolimus and sorafenib to treat brain tumors is investigational. 
At this time, this combination is only being used in research. 
The goal of Phase 1 of this clinical research study is to find the highest tolerable dose and best 
schedule of the combination of everolimus and sorafenib that can be given to patients with 
malignant glioma. 
The goal of Phase 2 of this study to learn if the combination of everolimus and sorafenib can 
help to control malignant glioma.  The safety of this combination will also be studied in both 
phases. 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have malignant glioma (such as 
glioblastoma multiforme, gliosarcoma, anaplastic astrocytoma, anaplastic oligodendroglioma, 
anaplastic mixed oligoastrocytoma, or malignant astrocytoma) that has returned after treatment. 
How many people will take part in this study?  
Up to 118 participants will take part in this multicenter study.  Up to 30 will be enrolled at NCI. 
Description of Research Study 
Before you begin the study 
Before starting the study, the Study Doctor will ask you about your health and your medical 
history. The doctor will examine you and measure your height, weight, blood pressure and heart 
rate. You will be asked about any medicines you have been taking. You will also have screening 
tests to help the doctor decide if you are eligible to take part in this study. If some of these tests 
have been performed within the past 14 days, they may not need to be repeated. These tests 
include routine blood and urine tests. You will also have tests done for hepatitis B and/or C if: 
• You have a risk of having hepatitis B and/or C or; 
• You live in or have lived in specific areas such as Asia, Africa, Central and South 
America, Eastern Europe and Spain, Portugal or Greece or; 
• If your study doctor thinks it is appropriate.  
If you test positive for hepatitis B, you may not be allowed into the study.  If you test negative 
for hepatitis B, the study doctor may continue to monitor your blood for the hepatitis B virus and 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 3 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
to see if your liver is damaged or inflamed. Your study doctor will inform you if there is a need 
for treatment. This may mean you are given an anti-viral drug and you will stop taking the study 
drug. 
If you test positive for hepatitis C, you will not be allowed into the study. If you test positive for 
hepatitis C while you are taking study drug, you will need to stop the study drug because the 
treatment for hepatitis C has serious side effects. 
Other screening tests include CT scan or MRI of your brain, a CT scan or x-ray of your chest, an 
EKG and you will also complete a questionnaire about your quality of life. If you are a woman 
of childbearing potential (able to get pregnant), you will be tested to see if you are pregnant. 
During the study 
If you are found to be eligible to take part in this study, you will be assigned to a study phase 
based on when you join this study. 
If you are enrolled in Phase 1, you will be assigned to 1 of 6 dose levels of the combination of 
everolimus and sorafenib based on when you join this study.  You will remain on the same dose 
level for the entire study.  Up to 3 participants will be enrolled at each dose level.  The first 3 
participants in each group will receive the lowest dose level. Each set of 3 new participants will 
receive a higher dose than the one before it, if no intolerable side effects were seen.  This will 
continue until the highest tolerable dose of study drugs given in combination is found. 
If you are enrolled in Phase 2, you will receive the combination of everolimus and sorafenib at 
the highest dose and on the same schedule that was tolerated in Phase 1. 
Study Drug Administration 
Each cycle is 28 days. 
You will take everolimus by mouth 1 time a day every day while you are on study. You should 
take everolimus whole without chewing them.  You should take everolimus without food (1 hour 
before or 2 hours after eating), with at least 1 cup (8 oz.) of water in the morning, at the same 
time each day.   
You will take sorafenib by mouth 2 times each day on Days 1-7 and Days 15-21 of every cycle. 
You should take sorafenib without food (1 hour before or 2 hours after eating), with at least 1 
cup (8 oz.) of water. 
You may take the study drugs at the same time. Your study doctor will tell you about any 
changes needed in the way you take the medicine. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 4 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
It is very important for you to take the study drug just as the study doctor tells you. Do not skip 
any doses unless your study doctor tells you to skip doses.  If you throw up after taking the study 
drug, you should NOT take another tablet that day. Let your study doctor know that you got sick. 
If you do forget to take the study drug one day, do not take any extra doses the next day.  Call 
your study doctor and ask for advice. 
During the study, you must talk to the study doctor before you take any drug other than the study 
drug. This includes homeopathic, alternative, or herbal medicines, and vitamins. Please avoid 
eating grapefruit, star fruit, and Seville oranges or drinking their juices while in the study.  The 
juices in these fruits can change the way your body treats or breaks down everolimus (Afinitor®). 
You will be given a study drug diary where you will write down the study drugs that you take at 
home. You should also bring the diary, study drug, and any empty bottles, with you to each study 
visit.  
Study Visits 
Every 2 weeks: 
• Blood (about 1-2 teaspoons) will be drawn for routine tests. 
Every 4 weeks: 
• You will have a physical exam and neurologic exam. 
• Routine blood and urine tests 
• You will be asked about any drugs you may be taking and if you have had any side 
effects. (For the first cycle, this is every week if you are in Phase 1.) 
• Your blood pressure will be recorded (For the first cycle, this is every week). 
Every 4 weeks for the first 2 cycles or the first 4 cycles (if you received bevacizumab 
previously), then every 8 weeks: 
• You will have a brain MRI scan or CT scans to check the status of the disease. 
• You will complete the quality-of-life questionnaire which will take about 5 minutes. 
At any time during the study, extra tests may be performed if the doctor thinks they are needed 
for your safety.  The study doctor will tell you more about any extra tests. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 5 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
When you are finished taking the drugs 
At the end of the study, give any study medicine or empty containers you still have to your study 
doctor or nurse.   
After you stopped taking the study drugs, the study staff will call you every 3 months to check 
how you are doing.  Each phone call will take about 5 minutes. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice a highly effective method of birth control before starting study treatment, 
during study treatment, and for 8 weeks after you finish study treatment. Highly effective 
contraceptive methods are also required for female partners of male patients who are sexually 
active and may become pregnant.  If you think that you or your partner is pregnant, you should 
tell your study doctor or nurse at once.   
Please discuss with your Study Doctor the most appropriate birth control method for you that 
also respect your cultural and religious situation.  
Highly effective contraception methods are one of the following: 
• Total abstinence 
• Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine 
system (IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
• Female sterilization: have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment. 
• Male sterilization: The vasectomized male partner should be the sole partner for that 
subject with the appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate. 
 
If you become pregnant or suspect being pregnant during study treatment or within 8 weeks after 
completing study treatment, you must inform the Study Doctor immediately, and you have to 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 6 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
stop ongoing study treatment immediately. You will not be allowed to continue study treatment 
if you are pregnant. Your Study Doctor will medically follow your pregnancy until delivery to 
monitor you and your child`s safety.  
 
As a male participant in the study you must agree to use a condom during intercourse and not 
father a child during the study and for the period of 8 weeks following stopping of study 
treatment. In addition, it is advised that your female partner uses a highly effective form of birth 
control method (contraception) if she is sexually active and may become pregnant.  
In case you father a child while in this study you will be asked to report the pregnancy to the 
Study Doctor. Consent from your partner will be needed to allow your Study Doctor to medically 
follow this pregnancy until delivery to monitor the mother`s and child`s safety. 
Risks or Discomforts of Participation 
While on this study, you are at risk for side effects.  These side effects will vary from person to 
person. The more commonly occurring side effects are listed in this form, as are rare but serious 
side effects.  You should discuss these with the study doctor. You may also want to ask about 
uncommon side effects that have been observed in small numbers of patients but are not listed in 
this form.  Many side effects go away shortly after treatment is stopped, but in some cases, side 
effects may be serious, long-lasting or permanent, and may even cause death. 
Tell the study staff about any side effects that you may have, even if you do not think they are 
related to the study drugs. 
Sorafenib and everolimus each may cause low blood cell counts (red blood cells, platelets, and/or 
white blood cells): 
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. You 
may need a blood transfusion. 
• A low platelet count increases your risk of bleeding (such as nosebleeds, bruising, stroke, 
and/or digestive system bleeding). You may need a platelet transfusion. 
• A low white blood cell count increases your risk of infection (such as pneumonia and/or 
severe blood infection). Infections may occur anywhere and become life-threatening. 
Symptoms of infection may include fever, pain, redness, and difficulty breathing. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 7 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Sorafenib Side Effects 
Likely (occurring in more than 20% of patients) 
• fatigue 
• skin rash 
• skin peeling 
• shedding of skin 
• hand-foot syndrome 
(palms of hands/soles of 
feet having pain, 
swelling, and blistering) 
• hair loss (partial or total) 
• abnormal salts, minerals, 
and/or acids in the blood 
(possible weakness, 
swelling, fatigue, low 
blood pressure, organ 
failure, heart problems, 
changes in mental status, 
and/or seizure) 
• abnormal digestive blood 
tests (possible pancreas 
damage) 
• diarrhea 
• abdominal pain 
• weight loss 
• loss of appetite 
• nausea 
• increased risk of bleeding 
• low blood cell counts (red/ 
white/platelets) 
 
Less Likely (occurring in 3-20% of patients) 
• high blood pressure 
• decreased blood supply to 
the heart 
• heart attack 
• nerve damage (loss of 
feeling) 
• headache 
• itching 
• dry skin 
• skin redness 
• vomiting 
• constipation 
• liver problems 
• pain (muscle/joint) 
• weakness 
• difficulty breathing 
• cough 
 
Exact frequency unknown but occurring in between 1 and 10% of patients: 
• flushing 
• depression 
• fever 
• acne 
• shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
• loss of appetite 
• upset stomach 
• difficulty swallowing 
• tongue pain 
• inflammation of the 
mucous membranes 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• dry mouth 
• impotence 
• low red blood cell counts 
• abnormal liver tests 
(possible liver damage) 
• kidney failure 
• hoarseness 
• flu-like symptoms 
 
Rare but serious (occurring in fewer than 3% of patients) 
• irregular heartbeat 
• heart failure 
• low blood levels of 
sodium (possible 
• nosebleeds 
• build-up of fluid around 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 8 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• heart attack 
• tear of the main artery of 
the heart 
• severe increase in blood 
pressure (possible stroke) 
• bleeding in the brain 
• brain damage that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision 
loss) 
• blood clot blocking a 
blood vessel (possibly in 
the heart and brain) 
• temporary stroke 
symptoms 
• very severe blistering skin 
disease (loss of large 
portion of skin) 
• very severe blistering skin 
disease (with ulcers of 
the skin and digestive 
tract) 
• tissue swelling 
• underactive thyroid gland 
(possible weight gain, 
heart failure, and/or 
constipation) 
• overactive thyroid gland 
(possible weight loss, 
heart rate changes, and/or 
sweating) 
headache, confusion, 
seizures, and/or coma) 
• dehydration 
• bleeding in the digestive 
system 
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen) 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• gallbladder inflammation 
(possible abdominal pain) 
• jaundice (yellowing of 
skin and/or eyes 
• liver failure 
• liver damage due to 
inflammation 
• bone destruction (jaw 
bone) 
• breakdown of muscle 
tissue (possible kidney 
failure) 
• decreased kidney function 
(possible kidney failure 
• bleeding in the esophagus 
the lungs 
• bleeding in the airways 
• lung inflammation 
(possible difficulty 
breathing) 
• allergic reaction (such as 
skin reaction and/or 
hives) 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 
• infection 
• preeclampsia-like 
syndrome (high blood 
pressure and increased 
proteins in the urine 
[possible kidney 
damage]) 
• pain at the tumor site 
• breakdown products of the 
cancer cells entering the 
blood stream (possible 
weakness, low blood 
pressure, muscle cramps, 
kidney damage, and/or 
other organ damage) 
• delayed wound healing 
Sorafenib may cause you to develop another type of cancer (such as skin cancer and lung 
cancer). 
Everolimus Side Effects 
Likely (occurring in more than 20% of patients) 
• swelling (arm/leg) 
• high blood pressure 
• fatigue 
• low blood sugar 
• abnormal salts, minerals, 
and/or acids in the blood 
• abnormal taste 
• low blood cell counts (red, 
white, platelets) 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 9 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• fever 
• headache 
• seizure 
• anxiety 
• aggression 
• behavioral disturbance 
• skin rash and/or itching 
• acne 
• nail changes 
• high blood levels of fat 
(possible heart disease 
and/or stroke) 
• high blood sugar (possible 
diabetes) 
(possible weakness, 
swelling, fatigue, low 
blood pressure, organ 
failure, heart problems, 
changes in mental status, 
and/or seizure) 
• mouth blisters/sores 
• loss of appetite 
• weight loss 
• diarrhea 
• constipation 
• abdominal pain 
• nausea 
• vomiting 
• increased risk of bleeding 
• abnormal liver test 
(possible liver damage 
and/or yellowing of the 
skin and/or eyes) 
• weakness 
• abnormal kidney test 
(possible kidney damage) 
• cough 
• nosebleed 
• difficulty breathing 
• infection 
 
Less Likely (occurring in 3-20% of patients) 
• chest pain (possibly due to 
heart trouble) 
• fast heartbeat 
• chills 
• migraine 
• dizziness 
• difficulty sleeping 
• depression 
• dry skin 
• skin peeling, redness, 
and/or sores 
• breaking of nails 
• eczema (skin 
inflammation) 
• hair loss (partial or total) 
• hand-foot syndrome 
(palms of hands/soles of 
feet having pain, 
swelling, and blistering) 
• diabetes 
• abnormal blood levels of 
fat 
• dry mouth 
• upset stomach 
• inflammation of the 
stomach and/or intestines 
• hemorrhoids 
• difficult and/or painful 
urination 
• blood in the urine 
• uterine and/or vaginal 
bleeding 
• changed, painful, heavy, 
or stopped menstrual 
cycle 
• pain (jaws/joint/arm/leg/ 
back) 
• muscle spasms 
• tremors 
• abnormal sensation (such 
as pins and needles) 
• swelling (eyelid) 
• red eyes 
• kidney failure 
• build-up of fluid around 
the lungs 
• lung inflammation 
(possible difficulty 
breathing) 
• stuffy/runny nose 
• difficulty swallowing 
• sore throat 
• life-threatening allergic 
reaction (such as 
difficulty breathing, 
flushing, chest pain, 
and/or tissue swelling) 
 
Frequency unknown but possibly occurring in 1-10% of patients 
• low blood pressure 
• high blood levels of uric 
• weakening or loss of bone 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 10 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
(possible 
dizziness/fainting) 
• irregular heartbeat 
• swelling 
• blood clots in a vein 
(possible pain, swelling, 
and/or redness) 
• fainting 
• agitation 
• hallucinations (seeing or 
hearing things that are 
not there) 
• weakness on one side of 
the body 
• hair growth 
• opening of a wound 
• dehydration 
• sweating/night sweats 
• change in body 
appearance due to high 
levels of steroid hormone 
• overactive thyroid gland 
(possible weight loss, 
heart rate changes, and/or 
sweating) 
acid (possible painful 
joints and/or kidney 
failure) 
• vomiting of blood 
• paralysis of the intestines 
• swelling of the scrotum 
• abdominal pain 
• gas 
• heartburn 
• thickened gums 
• abdominal wall 
inflammation 
• inability to urinate 
• frequent urination 
• urge to urinate 
• impotence 
• ovarian cysts (fluid-filled 
lump) 
• increase in 
• infection-fighting cells 
• lymph node swelling 
• high blood platelet count 
(possible increased 
clotting) 
• bone destruction 
strength (possible broken 
bones) 
• inflammation of bone in 
the spine 
• painful joint inflammation 
• pain (muscle/joint) 
• joint swelling 
• blurry vision 
• cataracts (clouding of the 
lens of the eye) 
• back-up of urine into the 
kidney 
• kidney inflammation 
(possible kidney 
damage/failure) 
• blood clot in an artery to 
the kidney (possible 
kidney damage or loss of 
function) 
• decreased kidney function 
• fluid in the lung (possible 
difficulty breathing) 
• wheezing 
 
Rare but serious (occurring in fewer than 3% of patients) 
• heart failure 
• sudden stopping of the 
heart 
• multiple blood clots 
possible organ 
dysfunction and/or 
failure) 
• blood clot at the site of a 
graft 
• decreased brain function 
(possible paralysis and/or 
coma) 
• wound healing problems 
• abnormal blood clotting in 
small blood vessels 
(possible stroke and/or 
other organ damage) 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• low sperm count 
• slowing or stoppage in the 
normal flow of bile 
(possible body yellowing   
• and/or abdominal pain) 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 11 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Everolimus may rarely cause you to develop another type of cancer (such as lymphoma [a type of 
lymph node cancer] and/or skin cancer [such as melanoma]).  It could also cause thickening in the 
lining of the uterus and uterine fibroids. 
If you have had hepatitis (liver inflammation) in the past, taking everolimus may rarely cause the 
hepatitis to come back, which may cause death. 
You must not drink grapefruit juice or eat grapefruit products while taking everolimus. 
For those patients receiving Everolimus in combination with Sorafenib, there is a rare complication 
of  muscle weakness, muscle cramps, stiffness and spasm, muscle pain in the shoulders, thighs, or 
lower back; trouble moving arms and legs; and dark red or brown urine or decreased urination.   
Symptoms may occur in one area of the body or affect the whole body. This complication may 
occur in both early and later stages of treatment.  The severity of the symptoms will vary and in 
rare cases, it can lead to death. 
Using the study drugs together may cause side effects that are not seen when each is given alone. 
The study drug combination may also increase the frequency and/or severity of the side effects 
listed above. 
Other Risks 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or develop an 
infection with redness and irritation of the vein at the site where blood is drawn. Frequent blood 
collection may cause anemia (low red blood cell count), which may create a need for blood 
transfusions. 
Questionnaires may contain questions that are sensitive in nature.  You may refuse to answer any 
question that makes you feel uncomfortable.  If you have concerns about completing the 
questionnaire, you are encouraged to contact your doctor or the Principal Investigator. 
This study may involve unpredictable risks to the participants. 
Potential Benefits of Participation 
Are there benefits to taking part in this study? 
The aim of this study is to determine a safe dose and to see if this experimental treatment will 
cause your tumors to shrink.   We do not know if you will receive personal medical benefit from 
taking part in this study.  These potential benefits could include shrinking of your tumor or 
lessening of your symptoms, such as pain, that are caused by the cancer.  Because there is not 
much information about the drug’s effect on your cancer, we do not know if you will benefit from 
taking part in this study, although the knowledge gained from this study may help others in the 
future who have cancer.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 12 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Alternative Approaches or Treatments 
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if your disease comes back during treatment 
• if you become pregnant while on study therapy 
• if you have side effects from the treatment that your doctor thinks are too severe 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Brain Tumor Trials 
Collaborative (BTTC), Novartis (drug supplier) and its authorized agents, and Bayer 
Pharmaceuticals or designated representatives. If you withdraw your consent and leave the trial, 
any samples of yours that have been obtained for the study and stored at the NCI can be 
destroyed upon request. However, any samples and data generated from the samples that have 
already been distributed to other researchers or placed in the research databases cannot be 
recalled and destroyed. 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 13 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• Brain Tumor Trials Collaborative (BTTC), Novartis (drug supplier) and its authorized 
agents, and Bayer Pharmaceuticals 
• Governmental agencies in other countries where the study drug may be considered for 
approval 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
Research Related Injury 
If you are injured while participating in this study, principal investigator will provide you with 
treatment per the NIH Clinical Center Research Injury Policy (Item # 2 on page 16).  Novartis 
(drug supplier) will not pay any money to you or your medical bills. 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 14 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using drugs developed 
by Novartis (drug supplier) and by Bayer Pharmaceuticals through a joint study with your 
researchers and the company.   The company also provides financial support for this study.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research 
Study 
STUDY NUMBER: 16-C-0011 
CONTINUATION: page 15 of 17 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  16-C-0011 
 
CONTINUATION: page 16 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action.  
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Mark Gilbert, M.D., Building 82, Room 235A, Telephone:  240-760-
6023. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  16-C-0011 
 
CONTINUATION: page 17 of 17 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby 
consent to take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to 
discuss it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ 
Guardian 
Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
 
 
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JULY 28, 2020 THROUGH JULY 27, 2021.  
 
  
 
 
  
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name