Clinical trial NCT00436215
Conditions: Ovarian Neoplasm Fallopian Tube Cancer Primary Peritoneal Cancer
Keywords: Sorafenib Ovarian Cancer Fallopian Cancer Bevacizumab Peritoneal Cancer Fallopian Tube Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2006-12-12; Completion date: 2014-09-27
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Sorafenib and bevacizumab are anti-cancer drugs that work by targeting the blood vessels that allow tumors to grow. Using the two drugs together may more effectively block the formation of blood vessels that feed tumors.
* Sorafenib and bevacizumab both are approved by the Food and Drug Administration for use in other cancers but have not ovarian cancer. In a preliminary trial of this drug combination, however, tumors in 6 of 14 patients with ovarian cancer shrank.

Objectives:

* To determine the safety and activity of the combination of sorafenib and bevacizumab for treating patients with ovarian, fallopian and peritoneal cancer.
* To determine how sorafenib and bevacizumab may affect the cancer by measuring amounts of different proteins in small biopsy samples of tumor taken before starting treatment and after 6 weeks.

Eligibility:

* Females 18 years of age and older with ovarian, fallopian, or peritoneal cancer whose disease has not responded to standard treatment or for which no standard treatment is available.
* Patients must have not been previously treated with bevacizumab or must have had their disease worsen while taking bevacizumab-based therapy.

Design:

* Patients take 200 mg of sorafenib by mouth twice a day Monday through Friday each week and 5 mg/kg of bevacizumab through a vein every 2 weeks.
* Tumor biopsies and imaging scans (magnetic resonance imaging (MRI) and positron emission tomography (PET) are done before treatment, 3 days after beginning treatment, and 6 weeks into therapy.
* Computed tomography (CT) or other imaging tests are done every 8 weeks to evaluate response to treatment.
* History, physical examinations, blood and urine tests are done periodically during treatment for health checks and research purposes.
* About 74 patients are to be enrolled in the trial.

Detailed description:
Background:

Sorafenib is an inhibitor of wild-type and mutant proto-oncogene BRaf (B-Raf) and proto-oncogene c-Raf (c-Raf) kinase isoforms in vitro, but it also inhibits mitogen-activated protein kinase (p38), proto-oncogene c-kit (c-kit), vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor (PDGFR)-Beta affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf.

Bevacizumab is a humanized immunoglobulin G 1 (IgG1) monoclonal antibody (MAb) that binds all biologically active isoforms of human vascular endothelial growth factor (vascular endothelial growth factor (VEGF), or VEGF-A) with high affinity (kd = 1.1nM).

Phase I trial of sorafenib and bevacizumab administered concurrently showed activity of the combination in patients with refractory ovarian cancer.

Objectives:

Determine the activity and tolerability of the combination bevacizumab and sorafenib in patients with refractory or recurrent epithelial ovarian, fallopian, or peritoneal cancer in patients who are bevacizumab-naive or bevacizumab-resistant.

Eligibility:

Adults with histologically documented refractory or recurrent epithelial ovarian, fallopian, or peritoneal cancer.

Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks.

Patients must have an Eastern Cooperative Oncology Group (ECOG) of 1 or less.

Patients must have disease that is amenable to biopsy.

Patients must have not been previously treated with bevacizumab or must have progressed on prior bevacizumab-based therapy.

Design:

Patients will be stratified on entrance to the trial based on their previous exposure to bevacizumab to either strata A (bevacizumab-naive patients) or strata B (patients previously treated with bevacizumab).

Patients will receive oral sorafenib 200 mg twice daily 5 out of 7 days each week and intravenous bevacizumab 5 mg/kg every two weeks.

Tumor biopsies will be obtained from patients before treatment and six weeks into therapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and fludeoxyglucose 18F-positron emission tomography (FDG-PET) will be obtained from patients before treatment, on day 3 of treatment, and six weeks into therapy.

Patients will be evaluated for response every 8 weeks using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Approximately 74 patients will be needed to achieve the objectives of the trial.

Arms: arm 1: BAY 43-9006 (sorafenib) + Bevacizumab
Interventions: intervention 1: Bevacizumab intervention 2: BAY 43-9006
Intervention descriptions: intervention 1: bevacizumab 5 mg/kg intravenous (IV) every two weeks intervention 2: BAY 43-9006 200 mg po (by mouth) twice daily 5 out of 7 days each week (Mon-Fri)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
  
 
 
1 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
CC Protocol #: 07-C-0058 N 
 
 
 
 
 
 
               
Version Date: 10/03/2018 
CTEP # 7358: Closed with CTEP as of 02/28/2013 
NCT Number: NCT00436215 
 
A Phase II Study of Sorafenib and Bevacizumab in Epithelial Ovarian, Fallopian, and Peritoneal 
Cancer 
 
NCI Principal Investigator 
Christina Annunziata, M.D., Ph.D.,  
 
WMB/CCR/NCI/NIH 
10 Center Drive, Building 10/3B43C 
Bethesda, MD 20892  
Phone: 240-760-6125 
 
Email: ca180n@nih.gov 
 
NIH Collaborator 
 
Laura Elnitski, Ph.D., TFGB, NHGRI F 
 
 
Investigator Roles 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing coded (linked) data or specimens for research purposes 
G. Some/all research activities performed outside NIH  
 
Commercial Agents: none 
 
Investigational Agents:     
 
Drug Name: 
BAY 43-9006 
Bevacizumab 
IND Number: 
69896 
7,921 
Sponsor: 
CTEP (complete 09/04/14) 
CTEP (complete 09/04/14) 
Manufacturer: 
Bayer Health Care 
Corporation 
Genentech 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 2 
PRÈCIS ........................................................................................................................................... 5 
1. 
OBJECTIVES ......................................................................................................................... 6 
1.1 
Primary Objective ............................................................................................................ 6 
1.2 
Secondary Objectives ....................................................................................................... 6 
2. 
BACKGROUND .................................................................................................................... 6 
2.1 
Sorafenib (BAY 43-9006) ................................................................................................ 6 
2.2 
Bevacizumab (rhuMAb) ................................................................................................. 13 
3. 
PATIENT SELECTION ....................................................................................................... 25 
3.1 
Eligibility Criteria .......................................................................................................... 25 
3.2 
Exclusion Criteria ........................................................................................................... 28 
3.3 
Inclusion of women and minorities ................................................................................ 29 
3.4 
Baseline evaluation ........................................................................................................ 30 
3.5 
Patient Registration ........................................................................................................ 31 
4. 
TREATMENT PLAN ........................................................................................................... 31 
4.2 
Supportive Care Guidelines ........................................................................................... 33 
4.3 
Duration of Therapy ....................................................................................................... 34 
4.4 
Reassessment .................................................................................................................. 34 
5. 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................. 36 
5.1 
Bevacizumab and sorafenib dosing modifications - Specific adverse events ................ 36 
6. 
PHARMACEUTICAL INFORMATION ............................................................................. 42 
6.1 
BAY 43-9006 (Sorafenib, NSC 724772, IND 69896) ................................................... 42 
6.2 
Bevacizumab .................................................................................................................. 44 
6.3 
Pyridoxine hydrochloride (CAS registry No.58-56-0) ................................................... 46 
7. 
CORRELATIVE/SPECIAL STUDIES ................................................................................ 48 
7.1 
Tissue and sample acquisition and processing ............................................................... 48 
7.2 
Pharmacoproteomic analysis .......................................................................................... 54 
7.3 
Correlative imaging studies ............................................................................................ 55 
7.4 
Angiogenesis studies ...................................................................................................... 56 
7.5 
Ras/Raf mutation identification ..................................................................................... 56 
8. 
STUDY CALENDAR .......................................................................................................... 57 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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9. 
MEASUREMENT OF EFFECT........................................................................................... 58 
9.1 
Definitions ...................................................................................................................... 58 
9.2 
Guidelines for Evaluation of Measurable Disease ......................................................... 60 
9.3 
Response Criteria ........................................................................................................... 61 
9.4 
Confirmatory Measurement/Duration of Response ....................................................... 64 
10. SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
65 
10.1 
Definitions ...................................................................................................................... 65 
10.2 
NCI-IRB and Clinical Director Reporting ..................................................................... 67 
10.3 
Expedited Adverse Event Reporting to Sponsor ............................................................ 68 
10.1 
Routine Adverse Event Reporting.................................................................................. 70 
10.2 
Secondary Malignancy ................................................................................................... 70 
10.3 
Second Malignancy ........................................................................................................ 71 
10.4 
CAEPR for Bevacizumab............................................................................................... 71 
10.5 
CAEPR for Sorafenib ..................................................................................................... 77 
10.6 
Data Reporting ............................................................................................................... 81 
11. COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
[CRADA/CLINICAL TRIALS AGREEMENT (CTA)] .............................................................. 81 
12. STATISTICAL CONSIDERATIONS.................................................................................. 83 
12.1 
Study Design/Endpoints ................................................................................................. 83 
12.2 
Sample Size/Accrual Rate .............................................................................................. 86 
12.3 
Stratification Factors ...................................................................................................... 86 
12.4 
Analysis of Secondary Endpoints .................................................................................. 87 
12.5 
Reporting and Exclusions............................................................................................... 87 
13. HUMAN SUBJECTS PROTECTIONS ............................................................................... 87 
13.1 
Rationale for subject selection ....................................................................................... 87 
13.2 
Participation of Children ................................................................................................ 88 
13.3 
Evaluation of Benefits and Risks/Discomforts: ............................................................. 88 
13.4 
Risks/Benefits Analysis: ................................................................................................ 89 
13.5 
Consent and Assent Process and Documentation: ......................................................... 89 
14. DATA AND SAFETY MONITORING PLAN ................................................................... 90 
15. REFERENCES ..................................................................................................................... 91 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
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16. APPENDIX A: PERFORMANCE STATUS CRITERIA .................................................... 95 
17. APPENDIX B: NCI/FDA PROTEOMICS PROGRAM STANDARD OPERATING 
PROCEDURE FOR TISSUE CORE COLLECTION – NEEDLE BIOPSY – 
CRYOPRESERVATION IN OCT ............................................................................................... 96 
18. APPENDIX C: STUDY DIARY .......................................................................................... 98 
19. APPENDIX D: CYTOCHROME P450 3A4 METABOLIZED DRUGS ............................ 99 
20. APPENDIX E: FACT-O QUALITY OF LIFE TOOL ....................................................... 101 
21. APPENDIX F: BLOOD PRESSURE CHECK FORM ...................................................... 104 
 
 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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PRÈCIS   
Background: 
x Sorafenib is an inhibitor of wild-type and mutant B-Raf and c-Raf kinase isoforms in 
vitro, but it also inhibits p38, c-kit, VEGFR-2 and PDGFR-E affecting tumor growth as 
well as possibly promoting apoptosis by events downstream of c-Raf.   
x Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all 
biologically active isoforms of human vascular endothelial growth factor (VEGF, or 
VEGF-A) with high affinity (kd = 1.1nM) 
x Phase I trial of sorafenib and bevacizumab administered concurrently showed activity of 
the combination in patients with refractory ovarian cancer 
Objectives: 
x Determine the activity and tolerability of the combination bevacizumab and sorafenib in 
patients with refractory or recurrent epithelial ovarian, fallopian, or peritoneal cancer in 
patients who are bevacizumab-naïve or bevacizumab-resistant 
Eligibility: 
x Adults with histologically documented refractory or recurrent epithelial ovarian, 
fallopian, or peritoneal cancer 
x Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or 
biological therapy for at least 4 weeks. 
x Patients must have an ECOG of 1 or less. 
x Patients must have disease that is amenable to biopsy 
x Patients must have not been previously treated with bevacizumab or must have 
progressed on prior bevacizumab-based therapy 
Design: 
x Patients will be stratified on entrance to the trial based on their previous exposure to 
bevacizumab to either strata A (bevacizumab-naïve patients) or strata B (patients 
previously treated with bevacizumab). 
x Patients will receive oral sorafenib 200 mg twice daily 5 out of 7 days each week and 
intravenous bevacizumab 5 mg/kg every two weeks 
x Tumor biopsies will be obtained from patients before treatment and six weeks into 
therapy. DCE-MRI and FDG-PET will be obtained from patients before treatment, on 
day 3 of treatment, and six weeks into therapy. 
x Patients will be evaluated for response every 8 weeks using the RECIST criteria.  
x Approximately 74 patients will be needed to achieve the objectives of the trial.  
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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1. 
OBJECTIVES 
1.1 
Primary Objective 
Determine the objective response rate of the combination of sorafenib (BAY 43-9006) and 
bevacizumab in patients with relapsed or refractory epithelial ovarian cancer (EOC), primary 
peritoneal cancer or fallopian tube cancer in patients who are bevacizumab-naïve or 
bevacizumab-resistant. 
 
1.2 
Secondary Objectives 
x Determine progression-free survival 
x Determine biochemical changes in the Ras-Raf-MAPK and VEGF signal transduction 
pathways in tumor and stromal cells in EOC in response to treatment with sorafenib and 
bevacizumab. 
x Characterize the toxicity of the combination of sorafenib and bevacizumab in patients 
with epithelial ovarian cancer 
x Evaluate correlations between biochemical pathway alterations and clinical events. 
x Examine genetic mutations in raf in EOC and evaluate correlations with clinical events. 
x Measure changes in VEGF and other angiogenic cytokines in plasma and fluids (when 
available) and evaluate correlation with clinical outcomes. 
x Apply DCE-MRI and FDG-PET technology to determine changes in tumor vascularity 
and metabolism during treatment. 
x Evaluate Quality of Life during treatment. 
 
2. 
BACKGROUND 
2.1 
Sorafenib (BAY 43-9006) 
Sorafenib represents a novel class of anticancer agents known as bi-aryl ureas.  It is a potent 
inhibitor of wild-type and mutant B-Raf and c-Raf kinase isoforms in vitro.  In addition, this 
agent also inhibits p38, c-kit, VEGFR-2 and PDGFR-E affecting tumor growth and possibly 
promotes apoptosis by events downstream of c-Raf.  At this time, over 500 patients have been 
treated with this drug with tolerable side effects [1].   


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
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Activation of the Ras oncogenic signaling pathway is considered to be an important mechanism 
by which human cancer develops.  Raf kinase is a protein involved in the Ras signal transduction 
pathway. Ras regulates several pathways which synergistically induce cellular transformation, 
including the Raf/MEK/ERK cascade and the Rac and Rho pathways [2, 3]. The Ras pathway 
has multiple activators, including the EGFR tyrosine kinases.   In turn, Ras activates the 
Raf/MEK pathway by first localizing Raf to the plasma membrane, where Raf initiates a mitogen 
activated kinase cascade.  Activated Raf phosphorylates and activates MEK which in turn 
phosphorylates and activates ERK.  Activated ERK then translocates from the cytoplasm into the 
nucleus and modulates gene expression via the phosphorylation of transcription factors.  Thus 
activation of Raf kinase, via activation of Ras, is thought to play an important role in 
carcinogenesis. 
B-Raf, a serine/threonine kinase, has been shown to be activated in a number of human tumor 
types including melanoma, ovarian and papillary thyroid carcinomas [1, 4-9].  A survey of 43 
cancer cell lines showed that all B-Raf mutations resided in exons 11 or 15.  Remarkably, 80% 
of these B-Raf mutations represent a single nucleotide change of T-A at nucleotide 1796 
resulting in a valine to glutamic acid change at residue 599 (V599E, exon 15) in the CR3 domain 
(ATP binding and substrate recognition) which in turn confers constitutive kinase activity [5, 6]. 
 
In Vitro Activity 
The ability of BAY 43-9006 to inhibit a number of kinases was evaluated [1].  The in vitro 
biochemical and cellular profile of BAY 43-9006 is summarized below: 
Biochemical Assay 
IC50 (μM) 
c-Raf b 
0.002/0.006 
b-Raf  wild-type 
0.025 
b-Raf V599E mutant 
0.038 
VEGFR-2 (human) 
0.090 
VEGFR-2 (murine) 
0.006 
VEGFR-3 (murine) 
0.010 
PDGFR-E (murine) 
0.028 
Flt-3 
0.058 
c-KIT 
0.068 
FGFR-1 
0.580 
p38D 
0.038 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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Cellular Mechanismc 
IC50 (μM) 
MDA-MB-231 MEK phosphorylation 
(Human Breast) 
0.04 
BxPC-3 MEK phosphorylation (Human 
Pancreatic) 
1.00 
LOX ERK phosphorylation (Human 
Melanoma) 
0.80 
b-Raf ER MEK activation (Human 
Chimera, 3T3 cells) 
2.30 
VEGFR-2 phosphorylation (Human, 3T3 
cells) 
0.03 
VEGFR-3 phosphorylation (Mouse, 293 
cells) 
0.10 
PDGFR-E phosphorylation (Human, 
AoSMC)d 
0.02 
Cellular Proliferation 
IC50 (μM) 
MDA-MB-231 (10% FCS)e 
2.60 
MDA-MB-231 (0.1% FCS) 
0.10 
VEGF-HUVEC (2.0% FCS)f 
3.00 
PDGFR-β AoSMCd (0.1%  BSA)g 
0.23 
a Recombinant enzyme assay 
b Raf kinase activated with Lck (truncated/full length c-Raf) 
c Mechanistic cellular assays all performed in 0.1% BSA 
d Human aortic smooth muscle cells 
e Fetal calf serum 
f  Human umbilical vein endothelial cells 
g Bovine serum albumin 
 
In vitro kinase assays demonstrated that BAY 43-9006  is a potent inhibitor of wildtype and 
mutant (V599E) B-Raf and c-Raf Kinase isoforms in vitro  [1].  In addition, BAY 43-9006 did 
not inhibit human EGFR or Her2 kinases at 10 PM.  Nor were PKC-D, PKC-E, PKC-J, and PKA 
(rat, rabbit and bovine sources) kinase activity inhibited in vitro.  BAY 43-9006 demonstrated an 
IC50 of 780 nM against p59 (bovine) Fyn kinase (Src family of protein tyrosine kinases).  In non-
kinase targets BAY 43-9006 had moderate potency against the adenosine A3, dopamine D1, and 
muscarinic M3 receptors with IC50 of 1.6 PM, 2.0 PM, and 3.1 PM, respectively.  BAY 43-9006 
did not directly inhibit MEK-1, ERK-1, EGFR, HER2/neu, c-met, PKA, PKB, Cdk-1/cyclin B, 
pim-1, GSK 3-b, CK-2, PKC-D (r), PKC-E (r), PKC-J at concentrations as high as 10 μM.   
In summary, BAY 43-9006 showed ≥100-fold more selectivity for Raf kinase relative to other 
target proteins.  BAY 43-9006 also inhibited in vitro several receptor tyrosine kinases (RTKs) 
that are involved in tumor progression; human VEGFR-2, murine VEGFR-2, murine VEGFR-3, 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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murine PDGFR-E, Flt-3, c-KIT, and p38D (MAPK family).  In cellular assays, BAY 43-9006 
was found to be a potent inhibitor of human and murine VEGFR-2, murine VEGFR-3, and 
murine PDGFR-D receptor phosphorylation [1].  
VEGF and PDGF receptors are involved in the mechanism of tumor angiogenesis [10, 11].  
PDGF receptors may also play a role in patients with chronic myeloproliferative cancers [12].  
Flt-3 is important in acute myelogenous leukemia [8] and c-Kit plays a critical role in 
gastrointestinal stromal tumors [13]. 
 
In Vivo Activity 
BAY 43-9006 has demonstrated in vivo anti-tumor efficacy as a single agent against a broad 
range of human tumor xenografts as summarized in the following table.  The models evaluated 
include HCT-116 and DLD-1 colon tumor xenografts, MX-1 mammary tumor xenograft, NCI-
H460 and A549 NSCLC xenografts, MiaPaCa-2 pancreatic tumor xenografts, and SK-OV-3 
ovarian tumor xenografts. In this table, compound efficacy is expressed as percent tumor growth 
inhibition (TGI) and is calculated as ((1-(T/C)) *100, where T and C represent the mean tumor 
size in the Treated and Control groups respectively at the first measurement after the end of 
treatment. 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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BAY 43-9006 Demonstrates Broad Spectrum Anti-Tumor 
Efficacy in Preclinical Xenograft Models 
 
Tumor Type 
Model 
Dose (mg/kg/dose 
free base equiv.)1 
Percent TGI 
((1-(T/C))*100) 
Colon 
HCT-116 
10 
30 
100 
45 
64 
68 
Colon 
DLD-1 
15 
30 
60 
31 
66 
75 
NSCLC 
NCI-H460 
10 
30 
27 
56 
NSCLC 
A549 
30 
60 
60 
68 
Mammary 
MX-1 
30 
60 
51 
67 
Pancreatic 
Mia-PaCa-2 
10 
30 
100 
45 
66 
73 
Ovarian 
SK-OV-3 
10 
30 
100 
58 
64 
81 
1  Compound dosed as BAY 43-9006 or equivalent dose levels of tosylate salt, BAY 54-9085 
The majority of the initial anti-tumor efficacy evaluations in vivo were conducted in the HCT116 
colon tumor model since the tumorigenicity of this cell line was previously shown to be 
dependent on K-Ras activation. Additional studies indicated that prolonged anti-tumor efficacy 
could be attained by extending the duration of treatment.   In this tumor model, BAY 43-9006 
was able to arrest tumor growth even if therapy was initiated against a substantially greater 
tumor burden. 
BAY 43-9006 also showed significant oral activity against two additional human tumor 
xenograft models that contain K-Ras mutations: MiaPaCa-2 pancreatic carcinoma and H460 
non-small cell lung carcinoma. The anti-tumor efficacy of BAY 43-9006 was also evaluated 
against the human SKOV-3 ovarian tumor cell line that contains a wild-type Ras but over-
expresses both the EGF and Her2 growth factor receptors.  These receptors also signal through 
the Ras/Raf/MEK pathway.  Bay 43-9006 was shown to inhibit tumor growth in that ovarian cell 
line as well. 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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In human tumor xenografts, MDA-MB-231 (breast) and Colo-205 (colon), there was a dramatic 
reduction of tumor neo-vascularization [1]. Recent data also indicated that inhibition of c-Raf 
may promote cell death in endothelial cells as a downstream event of VEGFR-2 stimulation [14]. 
Taken together, data suggests that BAY 43-9006 may be of therapeutic value not only in human 
tumors containing Ras gene mutations, but also in tumors over-expressing growth factor 
receptors in the Ras/Raf/MEK pathway, and by inhibiting tumor angiogenesis or neo-
vascularization through inhibition of VEGFR-2, VEGFR-3, and/or PDGFR-E. 
The ability of BAY 43-9006 (or its tosylate salt, BAY 54-9085) to be combined with paclitaxel, 
irinotecan, gemcitabine, or cisplatin was evaluated in preclinical in vivo models.  In these studies, 
the focus was to evaluate if the co-administration of BAY 43-9006 would adversely affect the 
tolerance or anti-tumor efficacy of the ‘standard of care’ agent. The general health of mice was 
monitored and mortality was recorded daily. Tumor dimensions and body weights were recorded 
twice a week starting with the first day of treatment. Treatments producing greater than 20% 
lethality and/or 20% net body weight loss were considered ‘toxic’.  The results of these 
combinability analyses are summarized below: 
Combinability of Concurrent Treatment with BAY 43-9006 and 
Clinically Established Agents 
Combination Agent 
Tumor Model 
Combinability 
Y/N 
Paclitaxel 
NCI-H460 NSCLC 
MX-1 Mammary 
Yes 
Yes 
Irinotecan 
DLD-1 Colon 
    Yes 
Gemcitabine 
MiaPaCa-2 Pancreatic 
Yes 
Cisplatin 
NCI-H23 NSCLC 
Yes 
 
BAY 43-9006 can be safely combined with a variety of standard cytotoxic cancer chemotherapy 
agents, including paclitaxel, irinotecan, gemcitabine and cisplatin with no significant increase in 
the toxicity associated with those agents and without diminishing their anti-tumor efficacy in 
preclinical models. 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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Clinical Experience 
BAY 43-9006 has been evaluated in multiple Phase 1 and Phase 2 studies in a variety of tumor 
types.  To date, over 750 patients have been treated with single agent BAY 43-9006. The Phase 1 
single agent clinical plan focused on characterizing the safety and pharmacokinetic profile BAY 
43-9006 in several different dosing regimens. All completed Phase 1 trial patients (197 patients) 
had a variety of advanced refractory solid tumors, and some of the patients stayed on trial for 
more than one year.  Four different regimens have been tested: continuous treatment, 4 weeks 
on/ 1 week off, 3 weeks on /1 week off, and 1 week on/ 1 week off.   Patients have received 
doses ranging from 50 mg once weekly to 1600 mg daily of BAY 43-9006 on intermittent and 
continuous schedules.  The 800 mg bid continuous administration cohort has exceeded maximum 
tolerated dose (MTD) in all tested schedules. The 600 mg bid cohort exceeded the MTD in all 
but the less dose intensive regimen of 1 week on / 1 week off.  The most frequent drug-related 
adverse events were hand-foot skin reaction, dermatitis, rash, fatigue, anorexia and diarrhea.  
There was an increase in the number of serious adverse events, discontinuations due to adverse 
events, and a number of skin toxicities at the higher dose levels ≥ 600 mg bid. Therefore, 400 mg 
bid was selected as the recommended dose for Phase 2.   
In general, available information from the ongoing Phase 2 studies reveals toxicities that are 
similar to the Phase 1 data.  Again, the five most frequent drug-related toxicities observed 
include hand-foot skin reaction, rash, anorexia, diarrhea, and fatigue. When all available data 
from the various studies/schedules are combined, the incidence of greater than grade 3 treatment 
emergent skin toxicity (e.g. hand-foot syndrome and “dermatology/skin reaction”) for an initial 
dose of 400 mg bid and 600 mg bid, was 0% and 30%, respectively.  
Hypertension has also been an observed toxicity for BAY 43-9006. In the phase II trial of 
sorafenib in renal cell carcinoma, only 5% of patients receiving multiple cycles required dose 
reduction due to toxicity [37].  The phase III trial of sorafenib in renal cell carcinoma presented 
at ASCO at the annual meeting in 2005 had 25% of patients being dose-reduced, 78% of these 
due to toxicity [38]. 
A recent study designed to track the incidence of hypertension in 20 patients treated with 
sorafenib 400 mg po bid found a median increase of systolic blood pressure (SBP) of 20 mmHG, 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
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with 60% of patients having an increase in SBP of 20 mmHg and 75% having an increase in SBP 
by 10 mmHg. Two patients (10%) required new or increased BP medication [41].  
Anti-tumor activity was observed in both Phase 1 and 2 studies.  Phase 2 results in renal cell 
carcinoma have shown a 50% progression-free survival at 24 weeks compared to 18% on the 
placebo arm.  Phase 3 studies are proceeding using sorafenib in hepatocellular and renal cell 
carcinomas [37].   On interim reporting, phase 3 data in renal cell carcinoma showed a 
progression –free survival of 79% versus 50% on the placebo arm [38]. 
 
Pharmacokinetics 
Pharmacokinetic studies in humans shows that BAY 43-9006 undergoes metabolism to a few 
primary metabolites, some of which may be active [1].  No data are available at this writing to 
describe the pharmacokinetics of repetitive dosing of BAY 43-9006 in patients.  However, up to 
36 hours after a single dose, BAY 43-9006 continues to be the predominant species detected.  In 
vitro liver microsomal degradation studies data indicate that BAY 43-90006 is primarily 
metabolized by CYP 3A4.  Ongoing studies are being pursued by the Sponsor to evaluate drug-
drug interaction potential of BAY 43-9006 with agents that alter function of CYP2C19, 
CYP2D6, and CYP3A4.   
 
2.2 
Bevacizumab (rhuMAb) 
Background 
 
Bevacizumab (rhuMAb) is a recombinant humanized anti-VEGF monoclonal antibody 
composed of human IgG1 framework regions and antigen-binding complementarity-determining 
regions from a murine monoclonal antibody (muMAb VEGF A.4.6.1) which blocks the binding 
of human VEGF to its receptors. Approximately 93% of the amino acid sequence, including 
most of the antibody framework, is derived from human IgG1, and ~7% of the sequence is 
derived from the murine antibody.  
Preclinical data 
In cynomolgus monkeys, twice weekly IV treatments with bevacizumab (doses of 2, 10 and 50 
mg/kg) for 4, 13 or 26 weeks were well tolerated, with no overt signs of acute toxicity [15, 16]. 


 
 
 
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Animals with open growth plates showed physeal dysplasia as well as focal to diffuse chondroid 
necrosis and linear fissuring of the cartilaginous growth plate. Females treated with 10-50mg/kg 
twice weekly had decreased ovarian and uterine weights, which were associated with absence of 
corpora lutea. These findings were expected, considering the known role of VEGF in formation 
of the corpora lutea and of the growing bone [17]. A further study using a similar treatment 
regimen, in the recovery period the physeal dysplasia and ovarian and uterine changes induced 
by rhuMAb VEGF were partially reversible. No antibodies against bevacizumab were detected. 
Phase I Clinical studies  
Two phase I studies have been performed. Study AVF0737g was a dose escalation trial of single 
and multiple intravenous (IV) administration of rhuMAb in patients with advanced malignancies. 
Five dose levels were evaluated (0.1, 0.3, 1.0, 3.0, and 10mg/kg). rhuMAb VEGF was 
administered as a 90-minute infusion on days 0, 28, 35 and 42 [18]. The second study, 
AVF0761g, evaluated multiple doses of rhuMAb VEGF 3 mg/kg weekly for up to 8 weeks in 
combination with one of three cytotoxic chemotherapy regimens (5-fluorouracil/leucovorin, 
carboplatin/paclitaxel, or doxorubicin) in subjects with advanced solid malignancies [19]. 
rhuMAb VEGF was administered weekly at 3mg/kg for eight doses. 
In both studies, rhuMAb VEGF appeared to be well tolerated. In AVF0737g, 3 of 25 patients 
treated experienced tumor-related hemorrhagic events, possibly related to the administration of 
rhuMAb VEGF. In two cases the event was considered serious: an intracranial hemorrhage (at an 
occult cerebral metastasis) in a patient with hepatocellular carcinoma and bleeding at the tumor 
site in a 38-year-old woman with a slowly progressing sarcoma of the thigh. No patient in 
AVF0761g reported serious bleeding. No dose limiting toxicity was reached in either study. No 
antibodies to rhuMAb VEGF were detected after therapy in either study.  
Pharmacokinetics 
In study AVF0737g, the pharmacokinetics of rhuMAb VEGF appeared to be linear for doses t 
1mg/kg with a half-life of approximately 15-21 days. Comparable pharmacokinetic data was 
seen in study AVF0761g. Co-administration of rhuMAb and cytotoxic chemotherapy did not 
appear to result in a change in the systemic concentration of the cytotoxic agents. 


 
 
 
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Phase II Clinical Studies   
Bevacizumab has been shown to be effective in the therapy of metastatic renal cell carcinoma.  
Yang et al. [20] completed a randomized, double-blind, phase 2 trial comparing placebo to 
bevacizumab at doses of 3 and 10 mg/kg given every 2 weeks.  There was a statistically 
significant increase in time to progression with the high-dose group compared to placebo. 
Study AVF0776g is an ongoing Phase II trial in patients with metastatic breast cancer who have 
progressed following at least one conventional cytotoxic chemotherapy regimen for metastatic 
disease. Eighteen patients have enrolled in the 3mg/kg dose level every other week and 41 
patients at the 10mg/kg every other week dose level.  All 59 patients have completed the study 
and 16 subjects have recently been enrolled at the 20mg/kg dose level. Twenty patients have 
experienced a total of 25 serious adverse events; 5 of 18 at 3mg/kg, 9 of 41 at 10mg/kg and 6 of 
16 at 20mg/kg. Nine patients experienced serious adverse events that were considered possibly 
or probably related to rhuMAb VEGF. One patient developed hypertension and nephrotic 
syndrome within one month of starting therapy. Four additional subjects (1 at 3mg/kg, 2 at 
10mg/kg and 1 at 20mg/kg) developed hypertension which was reported as a serious adverse 
event but was easily treated and did not require discontinuation of rhuMAb VEGF therapy. Four 
patients treated at 20mg/kg developed headache, nausea and vomiting, which resulted in study 
discontinuation for one patient. Hypertension has been reported as an adverse event in an 
additional 9 subjects (2 at 3mg/kg, 7 at 10mg/kg; non-serious adverse events at 20mg/kg are not 
available). Proteinuria has resulted in a study discontinuation for 3 patients (one at each dose 
level). One patient has developed a deep venous thrombosis; there have been no significant 
bleeding episodes.  
Tumor assessment available for 3mg/kg and 10mg/kg dose groups include 1 partial response in a 
cervical lymph node in the 3mg/kg group and 4 objective responses (One complete response in a 
supraclavicular node and three partial responses in lymph node, skin and liver disease). Eight of 
41 patients (20%) had either stable disease or an ongoing response at the final tumor assessment 
at Day 154.  
In Study AVF0757g, rhuMAb VEGF administered at a dose of 15mg/kg every 3 weeks in 
combination with carboplatin and paclitaxel showed a non-significant trend towards increased 


 
 
 
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response rates and time to progression compared with chemotherapy alone. There was no 
significant difference in either parameter between chemotherapy and rhuMAb VEGF 7.5mg/kg 
and chemotherapy alone.  
In Study AVF0780g, patients with metastatic colon cancer were treated with either 5-
FU/leucovorin (500mg/m2 5-FU and 500mg/m2 leucovorin administered weekly for six weeks, 
with courses repeated every eight weeks) alone or in combination with rhuMAb VEGF 5mg/kg 
or 10mg/kg every two weeks. Response rates were 17%, 40% (p=. 03) and 24%(p=. 23), 
respectively. A prolonged time to disease progression was seen in patients treated with rhuMAb 
VEGF 5mg/kg in combination with chemotherapy (9.0 months p=. 005) compared with those 
who received rhuMAb VEGF 10mg/kg (7.2 months p= .217) or chemotherapy alone (5.2 
months).  
The GOG phase 2 trial of bevacizumab treated patients with recurrent ovarian or peritoneal 
cancer and < 3 prior therapies with bevacizumab (15 mg/kg q3wks).  The trial found a 38.8% 6 
month progression-free survival and a 17% response rate [39].  In the California Cancer 
Consortium phase 2 trial of low-dose oral cyclophosphamide (50 mg po qd) and bevacizumab 
(20 mg/kg qwk x 3 then q2wk), interim analysis has shown a 47% progression-free survival in 
patients with recurrent ovarian or peritoneal cancer [40].   
 
Toxicities   
Life threatening toxicities seen in clinical trials to date with rhuMAb VEGF have included 
hemorrhage, thrombosis, and gastrointestinal perforation.   Less severe toxicities have included 
proteinuria, hypertension, fever, chills, rash, headache, infection, epistaxis and mouth ulceration. 
 
a) Hemorrhage - Life threatening hemorrhage was seen in a Phase I trial (AVF0737g) in the form 
of an intracranial hemorrhage (at an occult cerebral metastasis) in a patient with hepatocellular 
carcinoma and in the Phase II study (AVF0757g) in the form of massive hemoptysis or 
hematemesis. There were 6 life-threatening hemorrhages among 66 patients receiving rhuMAb 
VEGF-treated patients of which four of these events were fatal. An analysis of possible risk 
factors for life-threatening bleeding identified squamous cell histology as a risk factor (4 of 6 


 
 
 
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bleeds occurred in patients with squamous cell histology whereas only 13 of 66 rhuMAb VEGF-
treated patients had squamous histology). A number of investigations were performed on two of 
the patients with pulmonary hemorrhage and in eight patients in AVF0780g receiving rhuMAb 
VEGF including platelet count, prothrombin time, activated prothrombin time, fibrinogen, 
bleeding time, euglobulin clot lysis, d-dimer, alpha2-antiplasmin, PFA-100 (a platelet function 
assay) and these were all within normal range (Novotny,W. Genentech Inc personal 
communication).  
 
b) Thrombosis- In Study AVF0780g in metastatic colorectal cancer, venous and arterial 
thrombosis were seen more frequently than in patients treated with rhuMAb VEGF plus 5-
FU/leucovorin than in patients treated with 5-FU/leucovorin alone: 3 of 35 patients in the control 
arm, 9 of 35 patients in the 5mg/kg rhuMAb VEGF arm and 4 of 32 patients in the 10mg/kg 
rhuMAb VEGF arm. One event was fatal (a pulmonary embolism in the 10mg/kg arm) and three 
events required study discontinuation (a pulmonary embolism and a superior mesenteric vein 
occlusion in the 5mg/kg arm and a cerebrovascular event in the 10mg/kg arm). Cancer patients 
are known to be at high risk for thromboembolism owing to a number of factors including 
intrinsic tumor pro-coagulant activity, immobilization, indwelling catheters and the pro-
thrombotic effects of chemotherapy. The incidence of thrombosis among patients with breast 
cancer receiving chemotherapy is approximately 5-10% being higher in patients on tamoxifen 
and in patients with metastatic disease [21]. In the first 59 patients with metastatic breast cancer 
treated with rhuMAb VEGF monotherapy, two patients have developed a subclavian/axillary 
deep venous thrombosis on the side of the indwelling central line. 
In the AVF2107 study, there was a 1% incidence of arterial thromboembolic (TE) events (which 
include myocardial infarction, transient ischemic attack, cerebrovascular accident/stroke, and 
angina/unstable angina) in the IFL + placebo arm versus 3% in the ILF + bevacizumab arm.  A 
pooled analysis of the rate of arterial TE events from 5 randomized studies showed that treatment 
with bevacizumab increased the risk of these events two- to three- fold (up to 5%).  Furthermore, 
certain baseline characteristics, specifically age > 65 years and prior arterial TE event, conferred 
additional risk. 
 


 
 
 
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c) Hypertension- Hypertension has been seen in all rhuMAb VEGF clinical trials to date. There 
has been one reported case of hypertensive encephalopathy in a patient receiving 3mg/kg of 
rhuMAb VEGF on Study AVF0776g. In addition, 12 other patients have developed either new 
hypertension (7 patients) or worsening existing hypertension (5 patients) for which 10 of these 
patients required medical therapy (3 patients in 3mg/kg rhuMAb arm (n=18) and 7 in the 
10mg/kg (n=41), no data available from 20mg/kg arm). 
After 10 weeks of treatment, the mean change in blood pressure for all subjects compared with 
baseline was as follows (mean systolic change/mean diastolic change); 3mg/kg rhuMAb VEGF 
+10.5mmHg/+8.5mmHg and 10mg/kg rhuMAb VEGF +18.5mmHg/+8.2mmHg. In Study 
AVF0780g (colorectal cancer), using NCI-CTC Grade 3 or 4 events, there were four events in 
the control arm (n=35), four events between 2 patients in the 5mg/kg rhuMAb VEGF (n=35) and 
nine-events among 5 subjects in the 10mg/kg rhuMAb VEGF (n=32). The most commonly used 
therapies to treat this hypertension have been angiotensin converting enzyme inhibitors and 
calcium channel blockers. 
VEGF has been shown to induce nitric oxide-mediated vasodilatation and hypotension [22]. In a 
recent study, VEGF has been shown to govern endothelial nitric oxide synthase expression via a 
KDR/flk-1 receptor and protein kinase C signaling pathway, which suggests a possible 
mechanism for rhuMAb VEGFs induction of hypertension [23]. 
 
d) Proteinuria - Proteinuria by dipstick analysis has been seen in all rhuMAb VEGF clinical trials 
and has ranged in severity from clinically silent trace proteinuria to nephrotic syndrome. In study 
AVF0776g, 8 of 59 (12%) subjects treated with 3mg/kg or 10mg/kg have developed some 
degree of proteinuria (detected by dipstick) during the study to date. Three of these patients have 
also developed hypertension. Two patients were discontinued from study because of proteinuria; 
one patient (10mg/kg arm) had >2.5g/24 hr which decreased to 0.7mg/24 hr within 4 weeks with 
a normal serum creatinine and a second patient in the 20mg/kg arm who developed >5g/24hr. 
Another patient (3mg/kg arm) developed hypertensive encephalopathy, which was followed by 
the development of nephrotic syndrome (5g/24hr). This patient died of progressive disease soon 
thereafter and renal biopsy was not performed.  A recent study has shown that VEGF mediates 


 
 
 
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glomerular repair, which suggested a possible mechanism for rhuMAb VEGF-associated 
proteinuria [24]. 
 
e) Congestive Heart Failure- Two patients with metastatic breast cancer in study AVF0776g who 
had been treated previously with doxorubicin developed congestive heart failure while on 
rhuMAb VEGF, one patient after one year at 10 mg/kg and the second patient after two doses at 
20 mg/kg.  
 
f) Dyspnea/hypoxia-  In study AVF2107g, an ongoing trial with bevacizumab with 
5FU/leucovorin in metastatic colon cancer, one patient on this study developed dyspnea and 
pneumonitis requiring intubation eleven days after receiving her fifth infusion of bevacizumab 
with irinotecan and 5-FU.  Two other patients on this study also developed grade IV respiratory 
failure felt to be related to end-of-life events and not directly related to the drug.  In study 
AVF0757g, for stage IIIb and IV non-small cell lung cancer, 3 patients had grade IV dyspnea 
events, the etiology of which is unclear but at least partially attributable to their underlying 
disease.  No other grade IV dyspnea events were reported in other trials.   
There has been a recent report of an ovarian cancer patient who developed hypoxia of unclear 
etiology while on the phase II Bevacizumab in Ovarian Cancer study.  Twenty-three incidences 
of hypoxia have been reported out of 6031 patients enrolled on NCI-sponsored IND trials using 
bevacizumab. 
 
g) Perforation – The Genentech sponsored trial of bevacizumab in recurrent ovarian cancer was 
terminated early due to a greater than expected incidence of bowel perforations (11%).  Patients 
were dosed at 15mg/kg q3wks as compared to our likely dosing of 5 mg/kg q2wks.  Previous 
studies of bevacizumab in colon cancer had an incidence of bowel perforation of between 4-6%.   
At the recent January 2006 GOG meeting, an analysis of all ovarian cancer patients receiving 
bevacizumab in CTEP sponsored trials, approximately 150 patients, had only a 4.8% 
perforation/fistula rate, much closer approximating the incidence seen in colon cancer.  Further 
analysis is ongoing to ascertain the true risk of bowel perforation in ovarian cancer patients 
receiving bevacizumab. 


 
 
 
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h) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar leukoencephalopathy 
syndrome – RPLS or clinical syndromes related to vasogenic edema of the white matter have 
rarely been reported with bevacizumab therapy (<1%). Clinical presentations are variable and 
may include altered mental status, seizure, and cortical visual deficit.  HTN is a common risk 
factor and was present in most (though not all) patients on bevacizumab who developed RPLS.  
MRI scans are key to diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 
and FLAIR images and hypointensity in T1 images) predominantly in the white matter of the 
posterior parietal and occipital lobes; less frequently, the anterior distributions and the gray 
matter may also be involved.  RPLS should be in the differential diagnosis in patients presenting 
with unexplained altered mental status change, visual disturbances, seizure or other CNS 
findings.  RPLS is potentially reversible, but timely correction of the underlying causes, 
including control of blood pressure and interruption of the offending drug, is important in order 
to prevent progression to irreversible tissue damage. 
 
2.3 
Epithelial Ovarian Cancer (EOC) 
Ovarian cancer is the fifth leading cause of death from cancer in American women and is the most 
common cause of death from a gynecologic malignancy in the United States [6].  Although over 70% of 
women with advanced disease respond to optimal debulking surgery followed by platinum-taxane based 
chemotherapy, duration of response is short and relapse is common [7]. In the GOG 158 trial, median 
progression free survival for newly diagnosed optimally debulked stage III ovarian cancer treated with 
carboplatin/paclitaxel was 20 months [42]. Only 20-30% of relapsing patients have long unmaintained 
remissions because their tumors become resistant to chemotherapy [7]. Several recent studies have 
suggested that the median length of remission, based on the extent of disease at the start of initial 
chemotherapy, ranges between 15 and 24 months but subsequent responses are less than 6 months [8]. 
At relapse, patients are considered platinum sensitive if their relapse is >6 months from their last 
platinum treatment. The standard of care in these patients consists of a platinum-containing doublet per 
the sentinel ICON4 trial and median progression-free survival is 13 months [43].  In platinum-resistant 
ovarian cancer, many other agents have minimal efficacy with response rates in the <10% range, 
including taxanes, gemcitabine, liposomal doxorubicin, etoposide, topotecan, and hormonal agents; they 


 
 
 
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can be administered in any order. Sorafenib/bevacizumab can be considered by all relapsed/refractory 
patients.   
 
2.3.1 EOC and molecular targets 
Raf-kinase is important in cellular differentiation and proliferation.  Recently, attention has been given 
to the role of Raf in ovarian cancer.  Increased levels of c-Raf were found in a majority of EOC tumor 
samples in one series and had a significant correlation with poor survival (p=0.002)   Antisense 
oligodeoxynucleotides to c-Raf reduced its levels and inhibited cellular proliferation, suggesting a 
possible therapeutic benefit in targeting Raf in EOC [31].  VEGF and VEGFR have been found to be 
upregulated in ovarian cancer than in benign and normal ovarian tissue [32], making that pathway a 
reasonable target in EOC as well. Sorafenib is also an inhibitor of VEGFR and PDGFR. Our hypothesis 
behind combining it with bevacizumab includes sequential targeting of the VEGF pathway.  
 
2.3.2 Sorafenib and EOC 
Sorafenib targets Raf-kinase affecting the Ras-Raf-MAPK pathway which is recognized as important for 
tumor cell proliferation and differentiation.  It also inhibits other tyrosine kinases involved in 
angiogenesis and tumor progression including VEGFR-2, VEGFR-3, PDGFR-E, Flt3, c-kit, p38-D.  
Mutations in key signaling molecules in the Ras-Raf-MAPK pathway, particularly K-Ras and B-Raf 
mutations, are known to be important in tumor development in a variety of cancer types [33].  These 
mutations have a high incidence in borderline serous neoplasms and low grade serous malignancies in 
the ovary but are relatively rare in high grade ovarian serous carcinomas [34]. However, even in the 
absence of genetic mutations, this Ras-Raf-MAPK pathway is activated by the overexpression and 
activation of upstream growth factors and their receptors, including EGFR.  Phase I trials of BAY 43-
9006 have included patients with epithelial ovarian cancer, showing some activity [35].  The 
Gynecologic Oncology Group (GOG) has opened a phase II trial of sorafenib (GOG 0170F) in ovarian 
cancer that has not been analyzed yet.  
      
2.3.3 Bevacizumab and EOC 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody which blocks the binding of 
human VEGF to its receptors.  VEGF is upregulated in most human tumors and is produced by both 


 
 
 
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tumor cells and stroma [17].  Increased levels of VEGF are seen in ovarian cancer cells when compared 
to both normal ovary and benign ovarian disease [32].  Clinically, high serum VEGF levels in ovarian 
cancer patients are associated with a poor prognosis and may be a marker for persistent disease [36].  
Therefore, inhibiting VEGF and angiogenesis is a logical strategy to target ovarian cancer.  Because 
both sorafenib and bevacizumab affect the VEGF-VEGFR pathway, overlapping clinical activity is 
expected.  The GOG has completed a phase II study of bevacizumab describing an 18% response rates 
in recurrent ovarian cancer patients [39].  The Genetech trial of ovarian cancer was suspended after the 
development of perforations in multiple patients, as described in section 2.2. Bevacizumab has also been 
studied in ovarian cancer patients in combination with oral cyclophosphamide (50 mg po qd) and a 
response rate of 21% and median PFS of 5.8 months was observed [40]. 
 
2.4 
Combination of Sorafenib and Bevacizumab 
Despite the promise of signal transduction and angiogenesis inhibitors, these drugs have met with mixed 
results in clinical trials.  While these drugs clearly have activity in certain tumors models, they are only 
rarely effective as single agents.  We propose that inhibition of multiple targets may be necessary for 
more significant clinical effects.  Sorafenib and bevacizumab inhibit two pathways that are commonly 
activated in ovarian cancer and related malignancies.  There are significant interactions of these 
signaling pathways in both tumor cells and endothelial cells.   
 
2.4.1 Overlapping activity of sorafenib and bevacizumab 
BAY 43-9006 was designed to inhibit Raf and is also known to inhibit other kinases including 
VEGFR2, VEGFR3, PDGFR-E, Flt3, c-KIT, and p38D [1]. Moreover, BAY 43-9006 appears to 
have antiangiogenic properties which may be mediated through the direct inhibition of these 
kinases.  The drug may also downregulate the VEGF pathway via blockade of Raf kinase which 
leads to decreased VEGF production. Thus targeting of the VEGF pathway as a component 
effect of BAY 43-9006 may be important in its clinical activity and is an important testable 
molecular event. 
VEGF is one of the most potent and specific angiogenic factors identified.  VEGF is upregulated 
in most human tumors and is produced by both tumor cells and stroma [25].  Bevacizumab is a 
recombinant humanized anti-VEGF monoclonal antibody which blocks the binding of human 


 
 
 
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VEGF to its receptors.  Recent findings using bevacizumab suggest some overlap in clinical 
activity with BAY 43-9006.  Bevacizumab has been shown to delay progression in renal cell 
carcinoma as a single agent and increase survival in colon cancer in combination with 
chemotherapy [20, 26].  These findings support the preclinical data of complementary 
mechanisms.  This also argues that combining these drugs is a promising strategy.   
Interestingly, there is notable interaction between the Ras-Raf-MAPK pathway and VEGF.  The 
VEGF mitogenic signal in endothelial cells utilizes Ras-Raf-MAPK [25].  In addition, activation 
of the Ras-Raf-MAPK pathway induces VEGF expression.  Thus, inhibition of Raf kinase may 
block the VEGF angiogenic stimulus in two independent ways.  As a result, BAY 43-9006 may 
augment the antiangiogenic effects of bevacizumab. 
 
2.4.2 Clinical experience combining sorafenib and bevacizumab 
There is limited clinical experience with the combination of sorafenib and bevacizumab.  At this 
time, our group is completing a phase I trial of sorafenib and bevacizumab in solid tumors (05-C-
0022).  Thus far, 48 patients have been treated for greater than 344 cycles with each cycle lasting 
4 weeks.  Nineteen of these patients are ovarian cancer patients.  Dose level 1 (DL1) consisted of 
treatment with sorafenib 200 mg by mouth twice daily with bevacizumab 5 mg/kg IV q2wk.  
DL1 was the MTD and administered in cohort 2 (N=27).  Dose-limiting toxicity in DL2 was 
grade 3 proteinuria and thrombocytopenia.  Dose level 2 (DL2) consisted of sorafenib 200 mg 
bid with bevacizumab increased to 10 mg/kg IV q2wk.  A single DLT was seen at DL1 in a 
patient with extensive intrabdominal tumor masses who had also undergone multiple bowel 
resections.  With rapid tumor shrinkage, the patient developed an enterocutaneous fistula and 
fluid collection that appeared to be an abscess.  The most common DL1 adverse events (AEs) 
that were t grade 2 were hypertension (6/6) and hand-foot syndrome (HFS; 4/6). Infection was a 
late grade 3 AE on DL1.  Its attribution to drug remains unclear. DLT was reached at DL2 when 
2/6 patients developed grade 3 proteinuria (4, 5 gm/24 hr) and one grade 3 thrombocytopenia.  
Dose reduction of bevacizumab to 5 mg/kg q2weeks on DL2 was not associated with recurrence 
of the proteinuria or the thrombocytopenia.  Several DL2 patients later had sorafenib dose 
reduction for HFS.  Dose reduction on daily sorafenib (DL1 and DL2) occurred for 11/12 pts at a 
median of 2 cycles.  


 
 
 
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Preliminary data were published in the Journal of Clinical Oncology (Azad et al. 2008 [44]). 
Table of Grade 2 to 5 Toxicity by Maximum Grade per Patient (N=39)* 
 
Toxicity Grade (No. of Patients) 
Grade 2 
Grade 3 
Grade 4 
Toxicity 
DL1 
DL2 
DL1 
DL2 
DL1 
DL2 
Diarrhea 
1 
1 
4 
1 
0 
0 
Fatigue 
10 
2 
3 
0 
0 
0 
Fistula 
1 
1 
0 
0 
0 
0 
Hand-foot 
syndrome 
18† 
4 
0 
1 
0 
0 
Hypertension 
12 
1 
8 
4 
1 
0 
Perforation 
0 
0 
1 
0 
0 
0 
 
Proteinuria 
3 
1 
0 
2‡ 
0 
0 
Thrombocytopenia 
1 
0 
0 
1‡ 
0 
0 
Thrombosis 
0 
0 
2 
0 
1 
0 
Transaminitis 
9 
0 
3 
0 
1 
0 
*Cohort 2 (translational) patients enrolled on DL1 dosage (N=24). 
†Recurrent grade 2 hand-foot syndrome was the DLT in DL1. 
‡DLT in DL2. 
Gastrointestinal fistulae occurred in two ovarian cancer patients, occurring within 4 weeks of 
initiation of therapy, all in areas of measurable tumor regression.  One patient with cervical 
cancer experienced a rectovaginal fistula after 18 weeks of therapy, in an area of previous 
radiation therapy.  One patient with melanoma was taken off trial after presenting with a 
perforated appendix that possibly could be attributed to bevacizumab.  Toxicities did not appear 
to be cumulative.    
DLTs did occur on DL4, an intermittent dosing schedule of sorafenib 200 mg by mouth twice 
daily on days 1-5 each week with bevacizumab 5 mg/kg IV on day 1 then every other week, has 
completed accrual.  DL4 was determined to be the MTD.  3/7 patients required dose reduction on 
the intermittent schedule (DL4) and they were delayed.   


 
 
 
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DL5A, sorafenib 200 mg by mouth twice daily on days 1-5 each week with bevacizumab 10 mg/kg IV 
on day 1 every other week, and DL5B, sorafenib 400 mg by mouth twice daily on days 1-5 each week 
with bevacizumab 5 mg/kg IV on day 1 every other week were added.   
Four of the 6 patients treated on DL1, 3 of 6 patients on DL2, and 3 of 7 patients on DL4, 2 of 5 on 
DL5A, and 1 of 5 on DL5B are ovarian cancer (EOC) patients.  In addition, five of the patients on the 
expansion cohort have EOC.  Even at dose level 1, we observed sufficient clinical activity in all 4 
patients with EOC leading us to believe that this combinatorial strategy may be efficacious.  Responses 
were seen despite our patients being heavily pre-treated with cytotoxic agents with minimal responses.   
Seven of 19 patients (36%) with EOC have been on treatment for greater than 6 months.  Six of 19 
patients (31.5%) have a PR and 15 of 19 (79%) have SD or PR (duration of treatment ranges from 4 to 
37 months.  From this group we have 6 PRs by RECIST criteria and one with a 20% tumor shrinkage 
after 2 cycles.  All patients report at least subjective benefit from therapy.  Although this is a small 
cohort of ovarian cancer patients, the results are sufficiently encouraging to warrant investigation of 
these agents in a larger cohort of patients with ovarian cancer. 
One other combination study is a phase 1/2 trial in renal cell carcinoma out of Vanderbilt 
University, based on the 1/12/06 CTEP meeting detailing the 63 NCI sponsored sorafenib 
studies.  That study administers the sorafenib daily at 200-400 mg bid and bevacizumab 5-10 
mg/kg q2wks.  It is focusing on maximizing doses of both agents whereas our focus is minimum 
therapeutic dosing of both agents.  Data are too early to report. 
 
3. 
PATIENT SELECTION 
3.1 
Eligibility Criteria 
3.1.1 Histopathologically documented recurrent/refractory epithelial ovarian cancer, 
primary peritoneal cancer or fallopian tube cancer from a previous biopsy verified by 
the Laboratory of Pathology, NCI. 
3.1.2 Recurrent/refractory disease defined as progression within 6 months of upfront 
platinum-containing therapy or progression after subsequent therapy in previously 
relapsed patients. 


 
 
 
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3.1.3 Disease amenable to percutaneous or skin biopsy as determined by an associate 
investigator and a member of the interventional team. 
3.1.4 Patient willingness to have biopsies performed. 
3.1.5 Measurable disease defined as tumor t 1 cm. 
3.1.6 Age ≥ 18 years. 
3.1.7 Life expectancy of more than 3 months. 
3.1.8 Performance status of 0 to 1 according to the ECOG criteria. 
3.1.9 Adequate organ function as defined below: 
Laboratory Test 
Required value 
Leukocytes 
>3,000/PL 
Absolute neutrophil count 
>1,200/PL 
Platelets 
>100,000/PL 
total bilirubin  
≤1.5 X institutional upper limits of normal 
AST(SGOT) and ALT(SGPT) 
<2.5 X institutional upper limit of normal 
creatinine 
 
OR 
Creatinine clearance 
≤1.5 mg/dL 
 
>45 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
Activated partial thromboplastin 
time (PTT) 
< 1.5 x institutional upper limits of normal 
Prothrombin Time (PT)/INR 
< 1.5 x institutional upper limits of normal 
Amylase and Lipase 
Less than institutional upper limits of normal 
 
3.1.10 Patients must have a urine protein/creatinine ratio (UPC) < 1.0 for enrollment 
3.1.11 No surgery, radiation therapy, chemotherapy, immunotherapy, biotherapy, or 
hormonal therapy (exception raloxifene for bone health) within four weeks (6 weeks 
for mitomycin C, carboplatin, or nitrosoureas);  
3.1.12 No metabolically active complimentary or alternative therapy for at least 1 week, 
defined as any ingested or administered chemical substances including herbal 
medications, but not including acupuncture, hypnosis, meditation, or other non-
chemical treatments. 
3.1.13 No monoclonal antibody therapy for at least 6 weeks. 


 
 
 
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3.1.14 Patients must have recovered from any acute toxicity related to prior therapy, 
including surgery.  Toxicity should be ≤ grade 1 (as defined by CTCAE v4) or 
returned to baseline.  Peripheral neuropathy ≤ grade 2 will be allowed as this patient 
population has universally been treated with platinum-based chemotherapy with 
residual neuropathy being a common occurrence. 
3.1.15 No other invasive malignancies within the past two years (with the exception of non-
melanoma skin cancers, non-invasive bladder cancer, stage I endometrial cancer or 
cervical cancer synchronous to the ovarian cancer diagnosis and cured by surgical 
resection).  
3.1.16 Ability to understand and sign an informed consent form. 
3.1.17 Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin), 
NSAIDs, and other maintenance medications prior to study entry will be allowed to 
continue their supportive therapies. 
3.1.18 Ability to tolerate orally administered medications. 
3.1.19 Contraception is not a consideration as these patients have all had surgical removal of 
their reproductive organs. Pregnant women are excluded from this study because 
BAY 43-9006 and bevacizumab are agents with the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with BAY 43-9006 
and/or bevacizumab, breastfeeding should be discontinued if the mother is treated 
with BAY 43-9006 and/or bevacizumab. 
3.1.20 There is no limit on the number of prior regimens with which a patient has been 
treated 
3.1.21 Patients who have been treated with bevacizumab previously are eligible for the trial 
if they have progressed while on bevacizumab-based therapy 
3.1.21.1 Disease progression on bevacizumab therapy will be defined as documented 
increase in disease based on imaging while the patient is receiving bevacizumab 
or within six months of their last dose of bevacizumab. 


 
 
 
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3.1.21.2 Patients must be at least 6 weeks from their last dose of bevacizumab prior to 
being enrolled on study 
3.1.21.3 Patients who have a healed fistula greater than 28 days prior to enrollment are 
eligible (refer to section 3.2.15 for patients who have had prior bevacizumab) 
3.2 
Exclusion Criteria 
3.2.1 Serious non-healing wounds (including wounds healing by secondary intention), 
acute or non-healing ulcers, or bone fractures within 3 months of enrollment. 
3.2.2 Moderate or massive hemoptysis or surgery within 28 days of enrollment 
3.2.3 Ongoing treatment with any other investigational agents. 
3.2.4 Brain metastases 
3.2.4.1 Patients with CNS metastases within the past 2 years are ineligible.  Patients 
who have had CNS disease curatively treated and without recurrence for 2 years 
may be eligible. but any CNS disease that has not undergone curative therapy 
with radiation, gamma knife, and/or surgical therapy are ineligible 
3.2.4.2 CNS imaging will not be mandated for all patients.  However, if there is clinical 
suspicion of CNS involvement, a contrast CT or MRI of the brain will be 
required. 
3.2.4.3 Patients with CNS metastases may not be on steroids for the purpose of CNS 
disease or edema control 
3.2.4.4 Patients with CNS disease must be on an anti-seizure medication and that 
medication cannot be a CYPP4503A modulating agent  
3.2.5 Thrombotic or embolic events within the past 6 months such as a cerebrovascular 
accident (including transient ischemic attacks), pulmonary embolism, unstable 
angina, or myocardial infarction.  Fully treated deep vein thrombosis no longer 
requiring anticoagulation will be allowed. 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure (AHA Class II or worse), unstable 


 
 
 
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angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements. 
3.2.6.1 Patients with evidence of active infection will become eligible for 
reconsideration 7 days after completing antibiotic therapy. 
3.2.7 HIV-positive patients receiving combination anti-retroviral therapy are excluded from 
the study because of possible pharmacokinetic interactions with sorafenib, 
bevacizumab, and/or the combination.   
3.2.8 Hypertension defined as systolic blood pressure >150 mmHg or diastolic pressure > 
90 mmHg despite optimal medical management. 
3.2.9 Therapeutic anticoagulation with coumadin, heparins, or heparinoids. 
3.2.10 Evidence of a bleeding diathesis. 
3.2.11 History of high grade varices or arteriovenous malformations. 
3.2.12 Patients previously treated with sorafenib will not be eligible for this trial. 
3.2.13 Fistula or bowel obstruction or perforation in the 28 days prior to enrollment 
3.2.14 Patients must not be taking the CYP450 enzyme-inducing drugs phenytoin, 
carbamazepine, phenobarbital, St. John’s wort, or rifampin. 
3.2.15 For patients who have been previously treated with bevacizumab, any severe toxicity 
associated with bevacizumab while the patient was being treated with the agent will 
make the patient ineligible for the trial.  This includes bevacizumab-induced 
hypertensive crisis, arterial thromboembolic events (including cardiac ischemia or 
cerebrovascular ischemia or other arterial thrombosis), nephrotic syndrome, 
gastrointestinal perforation, serious hemorrhage, and fistulas (unless the fistula 
completely resolved while the patient was still on bevacizumab or it has been 
surgically corrected). 
3.3 
Inclusion of women and minorities 
Women of all races and ethnic groups are eligible for this trial.   
 


 
 
 
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3.4 
Baseline evaluation 
3.4.1 Complete history and physical examination (including height, weight, vital signs 
including blood pressure, and ECOG performance score) with documentation of 1) 
measurable disease, detailed sites of tumor, 2) narcotic use and pain assessment and 
3) prior therapies (hormonal, surgical, radio therapeutic and cytotoxic) 4) prior bowel 
perforations, obstructions, or fistulas will be conducted prior to starting therapy.  A 
complete medication history will be obtained prior to starting including over the 
counter medications, homeopathic remedies, vitamins, and alternative therapies 
3.4.2 Medically Indicated Imaging Studies (Baseline) - Every patient must have a baseline 
CT scan of chest, abdomen and pelvis areas of known or suspected disease 
involvement prior to receiving treatment to be used to monitor response.  In some 
patients an MRI, PET, or ultrasound may be more appropriate and may be ordered or 
requested in addition the baseline CT scan. This must be completed within 16 days 
prior to enrollment. 
3.4.3 An EKG should be obtained within 16 days prior to enrollment. 
3.4.4 Laboratory Evaluation [baseline is to be obtained within 4 days prior to enrollment. 
3.4.4.1 Hematological Profile: CBC with differential and platelet count, prothrombin 
time, activated partial thromboplastin time  
3.4.4.2 Biochemical Profile: electrolytes, BUN, creatinine, glucose, AST, ALT, 
alkaline phosphatase, bilirubin, calcium, phosphorous, albumin, magnesium, 
amylase, lipase 
3.4.4.3 CA-125 and TSH within 4 days prior to enrollment. 
3.4.4.4 Serum beta-hCG for female patients of childbearing age and anatomic ability.  
For those women who have undergone hysterectomy this will not be a 
requirement. 
3.4.4.5 Urinalysis and Spot UPC for protein and creatinine. 


 
 
 
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3.4.4.6 A block of primary tissue (or 10 unstained sections on charged slides) from the 
time of diagnosis will be required from each patient.  Tissue blocks from a 
known recurrence will be accepted if original tumor samples are unavailable. 
3.4.5 Baseline blood pressure will be documented on physical exam on initial screening 
and confirmed by blood pressure reading on the day of starting therapy. 
3.4.6 Baseline quality of life assessment using FACT-O tool (see APPENDIX E: FACT-O 
QUALITY OF LIFE TOOL). 
3.5 
Patient Registration 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and faxed to 301-
480-0757.  After confirmation of eligibility at Central Registration Office, 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. A recorder is available during non-working hours. 
 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
faxed to 301-480-0757. 
 
 
4. 
TREATMENT PLAN 
The doses on this trial will be bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg PO 
twice daily for five days of every seven for a cycle length of 28 (+/- 2-3 days to allow for clinic 
and scheduling variations around holidays or availability of biopsy or imaging facilities), which 
is based on the results of our phase I study.  
 
At the outset of the study, the patient may be admitted to the inpatient service to complete 
research studies including biopsies.  Otherwise, treatment will be administered on an outpatient 
basis.  For cycle 1, dosing of sorafenib and bevacizumab will not begin until after the completion 


 
 
 
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of the biopsy and pre-treatment imaging.  This cycle may be foreshortened  to 25 days due to this 
scheduling. 
 
4.1 
Drug administration 
 
4.1.1 Sorafenib administration 
Treatment will be administered on an outpatient basis with the exception of admissions for the 
purpose of facilitating research studies.  Reported adverse events and potential risks are 
described in Section 6.  Appropriate dose modifications for sorafenib and bevacizumab are 
described in Section 5.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient’s malignancy. 
 
Sorafenib is supplied as 200-mg tablets. Patients will self-administer one tablet orally twice a 
day on days 1-5 of 7 each week (except for cycle 1 week 1, treatment may be less than 5 days for 
facilitation of biopsies and imaging studies). Patients are to swallow the tablets whole with 
approximately 250 ml (8 oz.) of water, each morning and evening (i.e., 12-hourly). Cycles will 
be 28 days long.  Patients will be asked to administer the drug at approximately 08:00 and 20:00 
hours. When sorafenib is given with a moderate fat meal, bioavailability was similar to that in the 
fasted state. With a high fat meal, sorafenib’s bioavailability was reduced by 29% compared to 
administration in the fasted state. Thus, it is recommended that BAY 43-9006 be taken on an 
empty stomach (at least 1 hour before or 2 hours after eating). Patients will be asked to maintain a 
diary to document consumption of sorafenib as outlined in sections 6 and 4.1.1. 
 
4.1.2 Bevacizumab administration 
4.1.2.1 
On the day of bevacizumab administration, a review of systems pertinent to 
bleeding and thrombosis, a spot urine protein/creatinine ratio, and a measurement of 
blood pressure should be performed.  Dose timing adjustments are listed in Section 5 
4.1.2.2 
Bevacizumab will be administered intravenously every 2 weeks (+/- 2 days) on an 
outpatient basis with the exception of admissions for the purpose of facilitating 
research studies.  The dose of bevacizumab to be given is 5 mg/kg (to be adjusted as 
our phase I study matures). 


 
 
 
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4.1.2.3 
Vials contain no preservatives and are intended for single use only.  Place the 
calculated dose in 100 mL of 0.9% sodium chloride for injection. Administration will 
be as a continuous IV infusion. The initial bevacizumab dose will be delivered over 
90 r 10 minutes as a continuous IV infusion. If the first infusion is tolerated without 
infusion-associated adverse events (fevers and/or chills), the second infusion maybe 
delivered over 60 r 10 minutes. If the 60 minute infusion is well tolerated, all 
subsequent infusions maybe delivered over 30 minutes. 
4.1.2.4 
In the event of an infusion-related event, the infusion of bevacizumab should be 
stopped and held until resolution of acute symptoms.  The PI or AI will be notified of 
the infusion-related event at the time of the occurrence.  Upon resolution, the infusion 
should be restarted at a rate to increase the total infusion time by 30 minutes beyond 
the current time.  For example, if an infusion related event occurs when the dose is 
planned to run for 60 minutes (i.e. a rate of 1.7 cc/hr), the drug should be held.  When 
the event is resolved, the rate should be lowered to 1.1 cc/hr.   
 
4.2 
Supportive Care Guidelines 
4.2.1 Patients will be allowed continued use of erythropoietin or analogs initiated prior to 
entry.   
4.2.2 No concomitant use of alternative, complementary therapies or over-the-counter 
agents will be allowed without prior approval of the PI.   
4.2.3 Treatment Plan: Patients who have experienced substantial clinical benefit in the form 
of tumor reduction resulting in manageable, but increased toxicity that would 
otherwise require cessation of therapy, will be allowed to continue on therapy at the 
discretion of the associate investigator physician or PI, after approval by 
CTEP/sponsors as described in section 5.  The patients will remain officially on study 
and their responses will be analyzed as such. 
4.2.4 Management of toxicities that are likely relating to the investigational agents are 
found in section 5. 
 


 
 
 
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4.3 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
x Disease progression 
x Intercurrent illness that prevents further administration of treatment 
x Unacceptable adverse event(s).  Specifically, CTC toxicity grades 3 or 4 that do not 
resolve to grade 1 or baseline with a maximum of 3 weeks drug holiday.  
Bevacizumab may be held for up to 8 weeks for proteinuria. 
x Gastrointestinal perforation 
x Patient decides to withdraw from the study, or 
x General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
x Subject death 
Serious noncompliance with sorafenib, supportive care agents, or explicit health care-related 
instructions, as determined by the judgment of the investigator. 
 
4.4 
Reassessment 
4.4.1 Patients will be seen at least every 4 weeks in clinic.  For the first two cycles, patients 
will be seen every two weeks.  A history and physical with vital signs and a review of 
systems that documents coagulopathy-related events must be charted in the medical 
record for each visit. 
4.4.2 In the absence of intercurrent illness or adverse events, no clinic visit is required for 
d15 bevacizumab after the first 2 cycles, patients provided that no toxicities 
attributable to either drug requiring modification of therapy have been encountered. 
4.4.3 Medically indicated CT scans will be obtained and reviewed approximately every 8 
weeks (or 2 cycles of therapy) to monitor disease response.  Measurable disease will 
be monitored as described below in section 9.3. 
4.4.4 CA-125 should be obtained approximately every 4 weeks; however, no biochemical 
criteria will be used to describe disease progression. 


 
 
 
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4.4.5 Routine laboratory studies will be obtained every 4 weeks, to include, but not limited 
to, CBC with differential and platelet count, and Biochemical Profile: electrolytes, 
BUN, creatinine, glucose, AST, ALT, alkaline phosphatase, bilirubin, calcium, 
phosphorous, albumin, magnesium 
4.4.6 Treatment for each odd number cycle, starting with cycle 3, cannot be given prior to 
restaging imaging. 
4.4.7 From Cycle 3 onward, the mid-cycle (Day 15) evaluation will include: blood 
pressure, UPC, and a review of systems focused on bleeding.  This will be 
documented in the electronic medical record. 
4.4.8 Blood pressure monitoring will be based on our current and successful experience in 
our phase 1 trial. Each patient will receive a sphygmomanometer to use to measure 
blood pressures at home when outside of the clinical center.  Blood pressures will be 
measured daily for the first 8 weeks of therapy (at least once per week in a 
physician’s office, see APPENDIX F: BLOOD PRESSURE CHECK FORM).  The 
patient’s sphygmomanometer will be calibrated against the clinical center blood 
pressure machines at each visit.  If there is a discrepancy between the measurements 
from the patient’s sphygmomanometer and the clinical center blood pressure machine 
of greater than or equal to 10 points, it will be documented in the patient’s medical 
record.   The manual blood pressure reading with properly sized cuff will be the 
reading of record from which therapeutic decisions will be made.  The PI will be 
notified for any abnormal measurement (any systolic BP over 160 or diastolic BP > 
100).  Treatment will be determined by the BP on the clinic visit day surrounding the 
treatment. 
4.4.9 Patients will have their quality of life assessed every two cycles and when they come 
off study using the FACT-O Quality of Life tool (see APPENDIX E: FACT-O 
QUALITY OF LIFE TOOL). 


 
 
 
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5. 
DOSING DELAYS/DOSE MODIFICATIONS 
Toxicities will be described using CTCAE v4.  The following adjustment will only apply if the 
toxicities reported are attributed by the investigator to be related to sorafenib and/or 
bevacizumab therapy. 
 
Dose reduction of sorafenib below 200 mg by mouth qd will not be allowed.  
Dose reduction of bevacizumab below 3 mg/kg will not be allowed. 
 
Sorafenib dose reductions 
 
Patients experiencing unexpected NCI/CTEP grade 3 or 4 non-hematologic toxicity will have 
interruption of treatment of the likely offending agent and will be evaluated individually for 
intervention and resolution of toxicity, and safety for further treatment.  Reporting of adverse 
events will be according to section 10. 
5.1 
Bevacizumab and sorafenib dosing modifications - Specific adverse events 
5.1.1 Hypertension 
Bevacizumab should be held for systolic BP (SBP) > 160 or diastolic BP (DBP) > 100. 
Bevacizumab should be held for symptomatic hypertension of any grade, and should be 
discontinued for G4 hypertension.  If pressure exceeds either of the above parameters, it should 
Grade Occurrence 
Immediate Action 
Resumption of Therapy 
1 
1st 
None 
no interruption 
2 
1st 
Investigator’s discretion 
to hold therapy until 
Grade ≤ 1 
No change in dose, but initiate appropriate 
medical therapy 
Subsequent 
Hold therapy until Grade 
≤ 1 
Reduce sorafenib to 200 mg qd 
3 
1st 
Hold therapy until Grade 
≤ 1 
Initiate appropriate medical therapy and re-
challenge with reduced sorafenib dose (200 
mg qd) 
4 
1st 
Stop therapy 
Terminate therapy with experimental 
agent(s).  Follow patient until 
resolution/stabilization of toxicity 


 
 
 
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be rechecked no sooner than 30 minutes with a manual sphygmomanometer which has been 
appropriately calibrated.  Bevacizumab should not be administered if the above parameters are 
exceeded.  Antihypertensive therapy should be initiated and/or modified until parameters are met 
for at least 2 days.  After 2 days, therapy may be restarted following the guidelines below. 
 
 
 
Table: Sorafenib adjustments for hypertension 
 
5.1.2 Hemorrhage/Bleeding  
Bevacizumab administration is contingent upon assessment of any persistent bleeding.  Active 
bleeding such as new petechiae, epistaxis, CNS bleed, intermittent minimal hemoptysis or nasal 
secretions, or other grade 1 or greater bleeding events (excluding dipstick positive urine without 
red blood cells by microscopic exam) will require additional workup and subsequent risk 
assessment.   
Grade 2 hemorrhage:  Bevacizumab will be held for any grade 2 or greater bleeding event until 
resolution to a grade 0.  At that time, reassessment of risk must be made. If bleeding of grade 2 
or worse recurs, the patient will be taken off study. 
Grade 3 or 4 hemorrhage: The patient will be taken off study without rechallenge. 
Grade of Event 
(CTCAE v.4) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Sorafenib Dose Modification 
grade 1 
None 
Routine 
No change 
grade 2 
asymptomatic 
Initiate monotherapy 
(suggest ACE-
inhibitors or 
angiotensin receptor 
blockers) 
Reinstitute daily BP 
monitoring and qweek 
by health care 
professional 
No changes 
grade 2 
(symptomatic/ 
persistent) 
OR 
diastolic BP ≥ 
110 mm Hg 
OR 
grade 3 
Add agents: K+ 
channel opener, beta-
blocker, thiazide 
diuretic), Ca++ 
blocker 
Increase frequency of 
monitoring (by health 
care professional) every 
2 days until stabilized; 
continued q2d 
monitoring to 
stabilization after dosing 
restarted. 
Hold sorafenib until 
symptoms resolved and 
diastolic BP ≤ 100 mmHg 
Resume treatment at reduced 
dose. 
grade 4 
 
 
Discontinue protocol therapy 


 
 
 
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5.1.3 Proteinuria 
A spot UPC ratio should be performed prior to each bevacizumab dose.  Repeat testing within 24 
hours may be performed at the investigator’s discretion to rule out spurious results.  If the UPC is 
still elevated (≥ 1), the dose delays/modifications outlined in the table below will be followed. 
 
UPC ratio 
Bevacizumab dose modification 
<1 
Continue bevacizumab 
≥1-3.5 
Hold bevacizumab and recheck UPC in one week.  
UPC must resolve to < 1.0 in order to resume 
bevacizumab.   
>3.5  
Hold bevacizumab.  Collect 24 hr urine and recheck 
UPC in one week.  UPC must resolve to < 1.0 in 
order to resume bevacizumab.  When restarted, dose 
reduction of bevacizumab to 3 mg/kg IV q2weeks 
will be required 
 
If bevacizumab is delayed for more than 8 weeks due to proteinuria, discontinue bevacizumab. 
 
Sorafenib will not be held when bevacizumab is held for proteinuria. 
 
5.1.4 Surgical or periodontal procedures 
If there is need for a major surgical or serious periodontal procedure, bevacizumab should be 
held for 4 weeks prior to the procedure and must not be resumed before 4 weeks after the 
surgical procedure.  Longer delays may be necessary if clinically indicated in order to insure that 
adequate healing has taken place prior to bevacizumab resumption.  Minor oral or periodontal 
procedures or surgical procedures may be done with no delay at the discretion of the PI. 
5.1.5 Thrombosis 
5.1.5.1 Arterial Thrombosis 
Patients will be taken off study in the event of arterial thrombosis.  Arterial thrombosis include 
CNS ischemia, cardiac ischemia, and any visceral or peripheral artery thrombosis. 


 
 
 
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5.1.5.2  Venous Thrombosis 
For venous thrombosis requiring systemic anticoagulation, the patient may continue on 
monotherapy with bevacizumab while on systemic anticoagulation (sorafenib must be 
discontinued). If bevacizumab is continued as a single agent, the following guidelines should be 
followed regarding bevacizumab and anticoagulation administration: 
 
Venous Thrombosis  
 
 
[Note:  Patients with lung cancer requiring therapeutic 
anticoagulation should discontinue bevacizumab] 
Grade 3 
OR 
asymptomatic 
Grade 4 
 
 Hold bevacizumab treatment.  If the planned 
duration of full-dose anticoagulation is 
<2weeks, bevacizumab should be held until 
the full-dose anticoagulation period is over. 
 If the planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab 
may be resumed during the period of full-dose 
anticoagulation IF all of the criteria below are 
met: 
- The subject must have an in-range INR 
(usually   2-3) on a stable dose of warfarin, 
or on stable dose of heparin prior to 
restarting bevacizumab. 
- The subject must not have pathological 
conditions that carry high risk of bleeding 
(e.g. tumor involving major vessels or other 
conditions) 
- The subject must not have had hemorrhagic 
events while on study 
 If thromboemboli worsen/recur upon 
resumption of study therapy, discontinue 
bevacizumab 
Grade 4 
(symptomatic) 
Discontinue bevacizumab 
 
5.1.6 Coagulopathy 
Patients with grade 3-4 coagulopathy must hold bevacizumab until the coagulopathy 
resolves to grade 1 if sorafenib is continuing.  


 
 
 
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5.1.7 LFT abnormality (SGOT/SGPT, bilirubin) 
First appearance of Grade 3 or 4:  hold sorafenib until < grade 1 or baseline.  If there is 
no recovery in 3 weeks, discontinue sorafenib. 
Recurrent grade 3 or 4:  discontinue sorafenib. 
5.1.8 Thrombocytopenia (plts < 50,000- grade 3 or greater) 
Bevacizumab and sorafenib should be held until platelets are grade 1 or better (>75,000).  
If held for more than 3 weeks, discontinue therapy. 
5.1.9 Allergic reactions and cytokine release syndrome (acute infusion reaction): 
Patients who develop grade 2 allergic reactions with bronchospasm or any grade 3/4 
allergic/ infusional reactions should have bevacizumab discontinued. 
Grade 2/3 cytokine release syndrome can be rechallenged 24 hours later after 
premedication with methylprednisolone 60 mg IV or dexamethasone 20 mg IV 30 
minutes before the infusion.  The infusion rate should be increased to 3 hours.  If 
tolerated, the subsequent dose can be given with 50% of the steroid dose and then tapered 
to 25% of steroid dose with a decreased duration of each infusion from 3 hourso90 
minuteso60 minuteso30 minutes. 
5.1.10 RPLS 
Bevacizumab should be held in patients with signs and symptoms suggestive of 
reversible posterior leukoencephalopathy syndrome (RPLS), pending work-up and 
management, including control of blood pressure.  Bevacizumab should be discontinued 
upon diagnosis of RPLS. 
If bevacizumab is terminated due to toxicity, patients cannot continue on monotherapy 
with sorafenib. 
5.1.11 Hand-Foot Syndrome 
Prior to or upon initiating therapy, patients will begin pyridoxine 100 mg by mouth bid.  
Upon detection of any dryness, redness, or discomfort in the hands or feet, treatment with 
topical emollients (such as Aquaphor) should begin. These agents should be applied at 
least 2-4 times daily.  In addition, pyridoxine dosage will be increased to a maximum 


 
 
 
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dosage of 1000 mg a day.  Topical steroids agents may be used with PI/AI approval. Use 
of antihistamine agents is acceptable when appropriate. 
 
5.1.12 Neuropathy 
Neuropathy (grade 1 and 2) was a common finding at dose levels 1 and 2 in the phase I 
study.  It is often difficult to distinguish from pain associated with hand foot syndrome.  
In the setting of discomfort in the hands and feet the associate investigator or PI must 
make a determination of whether the symptoms are related to hand-foot syndrome or 
neuropathy as needed.  In the setting of neuropathy, therapy with gabapentin 100 mg-300 
mg by mouth qHS may be initiated.  Doses should be escalated as needed. 
 
5.1.13 Antiemetic therapy 
Patients with chemotherapy-induced nausea should be treated initially with a 
phenothiazine (prochlorperazine 10 mg q8h PO prn or promethazine 25 mg IV q6h prn).  
If this is inadequate, a benzodiazepine, ondansetron, or steroid should be added until 
acute nausea is controlled or a steroid may be added (e.g. dexamethasone 4 mg q6h prn).  
After acute nausea has resolved, consideration should be given to prophylactic therapy. If 
nausea recurs despite reasonable medical intervention dose reduction should be 
considered. 
 
5.1.14 Rhinorrhea 
Rhinorrhea is an expected toxicity.  Use of pseudoephedrine is discouraged due to the 
likelihood of worsening hypertension.  Antihistamine therapy is allowed. 
 
5.1.15 Perforations/Fistulas 
Any patient who has a visceral perforation shall be taken off both drugs, and thus off 
study.  If a patient experiences a fistula, bevacizumab will be held pending evaluation of 
the fistula.  If the fistula is non-complicated with no signs or likelihood of perforation 
based on radiologic appearance and/or consultation with subspecialty services as 
appropriate, patients may be conservatively managed with watchful waiting and continue 
on therapy with both drugs. 
 
 


 
 
 
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6. 
PHARMACEUTICAL INFORMATION 
6.1 
BAY 43-9006 (Sorafenib, NSC 724772, IND 69896)   
6.1.1 Source 
The investigational agent BAY 43-9006 will be supplied by the Bayer Health Care 
Corporation and distributed by CTEP 
6.1.2 Chemical name and identification 
Chemical Name: 4–{4-[3-(4-chloro-3-trifluoromethyl-phenyl) ureido]-phenoxy}-pyridine-2 
carboxylic acid methylamide-4-methylbenzensulfonate. 
Other Names: BAY 54-9085 is the tosylate salt of BAY 43-9006; sorafenib, Nexavar®. 
Classification: Kinase inhibitor (Raf, VEGF-R, and PDGF-R) 
Mechanism of Action: The Ras/Raf signaling pathway is an important mediator of responses to 
growth signals and angiogenic factors. This pathway is often aberrantly activated in human 
tumors due to presence of activated Ras, mutant b-Raf, or over expression of growth factor 
receptors.  
BAY 43-9006 is a potent inhibitor of c-Raf, and wild-type and mutant b-Raf in vitro. 
Additionally, further characterization of BAY 43-9006 tosylate revealed that this agent inhibits 
several receptor tyrosine kinases (RTKs) that are involved in tumor progression (VEGF-R, 
PDGF-R, Flt3, and c-KIT) and p38D, a member of the MAPK family. 
Molecular Formula: C12H16CIF3N4O3 X C7H8O3S  
M.W.: BAY 43-9006 tosylate: 637 Daltons; BAY 43-9006 (free base): 465 Daltons  
Approximate Solubility: 0.19 mg/100 mL in 0.1 N HCl, 453 mg/100 mL in Ethanol, and 2971 
mg/100 mL in PEG 400.  
How Supplied: BAY 43-9006 tosylate is supplied as an immediate-release film-coated, round, and 
salmon color tablet containing 200 mg of the free base, BAY 43-9006, and the excipients 
croscarmellose sodium, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium lauryl 
sulfate, and magnesium stearate. The film-coat consists of hydroxypropylmethyl cellulose, 
polyethylene glycol, tiranium dioxide and red iron oxide. The film coating has no effect on the rate 
of release of the active BAY 43-9006 tosylate.  


 
 
 
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BAY 43-9006 tosylate 200 mg tablets are supplied in bottles of 140 tablets. 
Storage: Store at controlled room temperature (15ºC – 25ºC). Storage conditions should not exceed 
25ºC. 
Stability: Stability studies with the 200 mg dosage form are ongoing. The current shelf life is 36 
months when stored at controlled room temperature.  
Route of Administration: Oral 
Reported Adverse Events and Potential Risks:   
Full CAEPR listed in section 10.5 
Method of Administration:  
Method of Administration: Following oral administration, BAY 
43-9006 tosylate’s mean relative bioavailability is 38-49%. When given with a moderate fat meal, 
bioavailability was similar to that in the fasted state. With a high fat meal, BAY 43-9006 tosylate’s 
bioavailability was reduced by 29% compared to administration in the fasted state. Thus, it is 
recommended that BAY 43-9006 be taken on an empty stomach (at least 1 hour before or 2 hours 
after eating) and with at least 250 mL of water. 
Potential Drug Interactions: BAY 43-9006 tosylate is neither a clinically meaningful inhibitor 
nor a clinically meaningful inducer of CYP2C19, CYP2D6 and CYP3A4 isoenzymes and is not 
expected to significantly increase or decrease the exposure of coadministered compounds 
metabolized by these pathways.   However, concomitant administration of BAY 43-9006 tosylate 
and CYP3A4 inducers, such as phenytoin, carbamazepine, phenobarbital, rifampin, or St. Johns 
Wort should be avoided. 
Availability: BAY 43-9006 is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
Agent Ordering: NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designees) at each participating institution.  Pharmaceutical Management Branch 
(PMB) policy requires that the agent be shipped directly to the institution where the patient is to 
be treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  Completed Clinical Drug Requests (NIH-986) should be 


 
 
 
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submitted to the PMB by fax (301) 480-4612 or mailed to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI, 9000 Rockville Pike, EPN Rm. 7149, Bethesda, MD 20892. 
Agent Accountability: The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the inventory and disposition of all drugs received from DCTD 
using the NCI Drug Accountability Record Form (DARF).   BAY 43-9006, as an oral self-
administered investigational agent, will be properly accounted for, handled, and disposed in 
accordance with CCR Policy # Clin-1 “Policy on Documenting, Handling and Disposing of Oral 
Investigational Agents that are Self-Administered by NCI CCR patients.”  The Standard 
Operating Procedure # Clin-1 “Standard Operating Procedure for Conducting and Documenting 
Drug Accountability for Oral Investigational Agents that are Self Administered by Patients at the 
CCR” identifies all activities associated with drug accountability for orally self administered 
investigational agents.  Study drug may be repackaged by the Clinical Center Pharmacy Dept. 
and dispensed in light-resistant HDPE containers that contain up to a 28-day supply of BAY 43-
9006.  Patients will be instructed to document on a study diary the daily intake of BAY 43-9006, 
including the time the dose is taken, and whether or not any doses are missed.  They will bring 
the study diary and any unused drug to their clinic appointments.  Clinic staff will (1) collect all 
“old” [i.e., empty bottle(s), partial bottle(s) or full bottle(s)] of study drug; (2) perform a pill 
count and record the results on the approved CCR Pill Count Case Report Form which is to be 
maintained in the research record; (3) dispense the partial and full bottle(s) of BAY 43-9006 to 
the patient.  Unused study drug is to be returned to the research nurse who will dispose of it 
according to the SOP. 
 
6.2 
Bevacizumab  
6.2.1 Source 
Bevacizumab will be supplied by Genentech and distributed by CTEP.  The bevacizumab to be 
supplied for this protocol is intended for clinical trial use only and is not the commercially 
available Avastin.  Investigational bevacizumab and commercially available Avastin may be 
produced at separate facilities and some difference may exist between the two products, although 
both are required to meet similar product testing criteria and are expected to be very similar in 


 
 
 
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safety and activity.  For further details and molecule characterization, see the updated 
bevacizumab Investigator Brochure. 
6.2.2 Chemical name and identification 
Chemical Name:  
 
Other Names: Recombinant humanized monoclonal anti-VEGF antibody (rhuMAB VEGF, 
Avastin®) 
Classification: Recombinant humanized monoclonal antibody 
Mechanism of Action: Inhibition of vascular endothelial growth factor (VEGF) resulting in 
inhibition of angiogenesis. 
How Supplied: Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid ready for 
parenteral administration in two vial sizes: 
o Each 100 mg (25 mg/mL – 4 mL fill) glass vial contains bevacizumab with phosphate, 
trehalose, polysorbate 20, and Sterile Water for Injection, USP. 
o Each 1000 mg (25mg/ml – 40 mL fill) glass vial contains bevacizumab with phosphate, 
trehalose, polysorbate 20, and Sterile Water for Injection, USP. 
. 
Storage: Upon receipt, bevacizumab should be refrigerated (2 to 8º C).  Do not freeze.  Do not 
shake. 
Stability: Shelf-life studies of rhuMAb VEGF are ongoing.  The sterile single use vials contain  
no antibacterial preservatives.  Therefore, vials should be discarded 8 hours after initial entry. 
Once diluted in 0.9% sodium chloride, solutions of bevacizumab must be administered within 8 
hours.  
Preparation:  Vials contain no preservatives and are intended for single use only.  Place the 
calculated dose in 100 mL of 0.9% sodium chloride for injection. 
Route of Administration:  Intravenous 
Reported Adverse Events and Potential Risks:   
Full CAEPR listed as in section 10.4 


 
 
 
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Method of Administration:  rhuMAb VEGF will be administered intravenously through a 
secondary IV set piggybacked above the infusion control device (pump) into a primary IV set 
containing 0.9% NaCl. When the rhuMAb VEGF drug product container is empty, 0.9% NaCl 
from the primary line should be used to flush the secondary set to complete rhuMAb VEGF 
delivery.  0.9% NaCl infusion should be continued to flush the primary IV set with a volume of 
fluid at least equal to the tubing priming volume, thus insuring complete drug delivery. Note that 
this flush is not included in the infusion times below. 
The loading dose should be administered over a minimum of 90 minutes. If no adverse reactions 
occur, the second dose should be administered over a minimum of 60 minutes. Again, if no 
adverse reactions occur, the third and subsequent doses should be administered over a minimum 
of 30 minutes. If infusion-related adverse reactions occur, subsequent infusions should be 
administered over the shortest period that was well tolerated. 
 
6.3 
Pyridoxine hydrochloride (CAS registry No.58-56-0) 
6.3.1 Source 
Pyridoxine HCl is available generically in a variety of formulations for oral use, including: 
prompt-release tablets containing 25mg. 50mg, 100mg, 250mg, or 500mg of the active drug.  
Pyridoxine HCl will be purchased from commercial sources by the NIH Clinical Center 
Pharmacy Department. 
6.3.2 Chemical name and identification 
Chemical Name: 
1) 3,4-pyridinedimethanol, 5-hydroxy,6-methyl-, hydrochloride 
2) Pyridoxine hydrochloride 
Other Names: Vitamin B6 
Pharmacology: Pyridoxine and two related water-soluble compounds, pyridoxal and 
pyridoxamine, have equal biologic activity and are collectively known as vitamin B6. They are 
converted in the liver primarily to pyridoxal phosphate, the active form of the vitamin; some 
conversion to pyridoxamine phosphate occurs, which is also biologically active. 


 
 
 
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Pyridoxine is absorbed by passive diffusion in the jejunum and, to a lesser extent, the ileum, and 
is converted to pyridoxal-5-phosphate in the liver and excreted mostly as 4-pyridoxic acid in the 
urine (35 – 63%). 
Pyridoxal phosphate (pyridoxal 5´-phosphate) is a coenzyme involved in numerous metabolic 
transformations of proteins and amino acids; is a cofactor for glycogen phosphorylase; is 
involved in the metabolism of neurotransmitter amines, polyunsaturated fatty acids, and 
phospholipids; and modulates the actions of steroid hormones via interaction with steroid 
receptor complexes. 
Storage: Pyridoxine HCl should be stored at <30°C (<86°F) in well-closed containers and 
protected from light 
Stability: Commercial products are labeled with the manufacturer’s expiration date. 
Route of Administration: Oral 
Reported Adverse Events and Potential Risks:   
Nausea and other gastrointestinal complaints have been reported with pharmacologic doses of 
pyridoxine. Abdominal pain, vomiting, and a loss of appetite have been reported with high doses. 
Pure sensory axonal neuropathy, with symptoms of numbness, burning, shooting, or tingling 
pain; perioral numbness, decreased sensation to touch, temperature, and vibration; paresthesia; 
clumsiness, unstable gait, and ataxia are alleged to occur after chronic daily ingestion of 75 – 
300mg pyridoxine.  Other neurologic symptoms may include depression, headache, tiredness, 
and irritability.  
Central sensory neuropathy, with ataxia, Romberg’s sign, and Lhermitte’s symptoms, may also 
be present and may account for incomplete recovery in some patients.  Muscle weakness, 
fasciculations, and diminished reflexes may accompany sensory changes.The principal effect of 
pyridoxine overdosage is a sensory axonal neuropathy. Central effects have also been described. 
Neuropathy has been most commonly reported after chronic ingestion of 200 – 6000 mg/day for 
months or years. The minimum amount acutely associated with ganglion cell destruction in 
humans is 10,000 mg in an adult (~140 mg/kg).  A reversible skin lesion similar to that of 
porphyria cutanea tarda may accompany sensory neuropathy. 


 
 
 
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Transient withdrawal symptoms (nervousness, tremors, abnormal EEG) were described in three 
of eight adult males following cessation of doses of 200 mg/day for 33 days.Pyridoxine use has 
been reported to cause photosensitivity. 
Maternal supplementation with up to 20 mg pyridoxine daily may decrease lactation.  Breast 
soreness and breast enlargement have been reported rarely with pharmacologic doses of oral 
pyridoxine during therapy of premenstrual syndrome. 
Low serum folic acid concentrations have been reported in patients with homocystinuria who 
received pyridoxine 500 – 1500 mg daily. 
In overuse: Patients who receiving 2000 – 7000 mg/day (or greater than 200 mg/day for >2 
months) have developed sensory neuropathy with associated ataxia and numbness of the hands 
and feet.  Symptoms decrease after pyridoxine is discontinued; however, it may take 6 months 
for sensation to normalize. 
Drug Interactions: Drugs that may result in vitamin B6 deficiency include the vitamin B6 
antagonists: isoniazid, cycloserine, penicillamine, hydralazine, and estrogen. Urinary excretion 
of 4-pyridoxic acid <0.1 mg/24 hours is suggestive of vitamin B6 deficiency. 
Concurrent use of altretamine and pyridoxine should be avoided. Data from a randomized trial 
evaluating altretamine and cisplatin ± pyridoxine in the treatment of ovarian cancer found that 
pyridoxine administration adversely affected the duration of response to chemotherapy. 
7. 
CORRELATIVE/SPECIAL STUDIES 
 
7.1 
Tissue and sample acquisition and processing 
Table 1: Laboratory studies by techniques 
Tissue lysates 
arrays (TLA) 
Immunohistochemistry 
(IHC) 
Tumor Biopsies 
Archival tissue re-cuts 
 
Tumor biopsies 
Cytokine 
profiling 
Genotyping 
Serum 
Whole blood 
Plasma 
Tumor biopsies 
 


 
 
 
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7.1.1 Rationale 
In the context of this study, patients will undergo serial biopsies of tumors to characterize the 
effects that sorafenib and bevacizumab have upon the biology of both the tumor and the stroma.  
Serial tumor biopsies will be obtained through Interventional Radiology if considered minimal 
surgical risk.  
The two studies during cycles 1 and 2 have specific translational purposes.  The pretreatment 
biopsy is necessary to have baseline analysis of the patients’ tumors. The purpose of the day 42 
(C2D15) biopsy is to determine long-term post-treatment changes in the tumor and corresponds 
to biopsy date in the phase I trial, so there will be a large cohort of patient samples biopsied at 
the same time during their treatment to evaluate the effect of sorafenib/bevacizumab treatment 
and can be correlated with PET/MRI results.  The final biopsy (again completely voluntary) will 
be to ascertain if patient’s tumors change when they become refractory to treatment.  Detailed 
molecular profiling will be used to evaluate target pathways as well as related pathways.  
Completed and ongoing studies have shown that both sorafenib and bevacizumab affect their 
intended targets; further detailed molecular analysis of tumor and stroma will lead to an 
understanding of the mechanisms mediating clinical response, tumor progression, and toxicities.  
In addition, the combination of these drugs may lead to molecular events that do not occur with 
either drug alone.  Pathway profiling will be done in both tumor and stroma using LCM to 
selectively procure each.  We have extended our tissue lysate arrays to allow assessment of 
stroma and angiogenesis.   
7.1.2 Tumor Biopsies  
7.1.2.1 Timing 
Biopsies will be performed at the following times (the biopsy should be obtained prior to the 
day’s dosing of both sorafenib and bevacizumab- doses should be held if needed): 
o after consent, prior to treatment on C1D1 
o C2D15 after 1.5 months of treatment if the patient consents (optional) 
o Off-study if the patient consents (optional) 


 
 
 
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Patients who choose not to undergo optional biopsies will remain on study and continue to 
receive treatment. 
7.1.2.2 At least two core biopsies, not less than 18-gauge in diameter and at least 1cm 
in length will be obtained.  Inability to get tissue with a reasonable attempt will 
not preclude treatment and the patient will remain eligible for all other 
translational components, including imaging.  A reasonable attempt is defined 
as one attempt prior to the procedure being deemed unsuccessful.  The use of 
imaging to facilitate biopsies will be decided upon by members of the 
interventional radiology team.  Should CT scans be needed for biopsy, a limit of 
10 scans for each procedure will be observed to minimize radiation exposure to 
the patient. 
7.1.2.3 The biopsies are to be immediately embedded and frozen on site according to 
SOP (APPENDIX B: NCI/FDA PROTEOMICS PROGRAM STANDARD 
OPERATING PROCEDURE FOR TISSUE CORE COLLECTION – NEEDLE 
BIOPSY – CRYOPRESERVATION IN OCT). The schedule for the biopsies 
will be made with Special Procedures (Dr. Brad Wood) or for surgery with Dr. 
Steven Libutti. Annunziata’s lab (10/B1B40, (301) 496-9336, beeper 102-
11155), will be on call to receive and embed biopsies.   
7.1.2.4 Each patient sample set will be assigned a unique patient identifier upon receipt 
and storage in Annunziata’s lab. The protocol scientific investigator(s) handling 
the samples will be blinded as to the patient identification, patient data and 
outcome.  Samples from sets of at least three patients will be grouped for 
scientific analysis.   
7.1.2.5 Frozen biopsies will be sectioned, stained, and subjected to microdissection of 
tumor cells and stromal cells according to optimized SOP (see APPENDIX B: 
NCI/FDA PROTEOMICS PROGRAM STANDARD OPERATING 
PROCEDURE FOR TISSUE CORE COLLECTION – NEEDLE BIOPSY – 
CRYOPRESERVATION IN OCT).  Dissected cells will be lysed and tissue 


 
 
 
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lysates arrays printed for prosecution with a panel of antibodies as described 
below.  
7.1.2.6 If a site is deemed appropriate for biopsy with minimal risk to the patient by 
agreement between the investigators and interventional radiology, an attempt at 
biopsy will be made. Minimal risk indicates a biopsy that is deemed safe by the 
performing service, either interventional radiology, general surgery, or the 
appropriate subspecialty service performing the procedure (pulmonary, 
gastroenterology, etc.) If the attempt is unsuccessful, the patient will still be 
eligible for treatment and other non-biopsy procedures and the subsequent 
biopsies will be foregone. 
7.1.2.7 Biopsy material will be prioritized for tissue proteomics.  The remaining tissue 
will be released for additional testing prioritized to raf-mutation analysis, 
microvessel density measurements, and immunohistochemistry.  The archival 
material requested at the outset of the study will be used for the remainder of the 
requested tests 
7.1.3 Blood samples:  Serum and plasma samples will be collected for cytokine analysis 
and archived for other lab analyses related to angiogenesis, molecular targets, and 
signaling targets to be determined as described below.  Note: Blood samples will no 
longer be collected each cycle after 04/11/14 (Amendment J). 
7.1.3.1 One 7 ml EDTA (purple top) tube will be drawn at the beginning of each cycle, 
maintained on wet ice and transported to the Annunziata’s lab. Plasma will be 
separated immediately upon receipt and aliquots frozen at –800C (no greater 
than 500 Pl aliquots).  Sample pickup can be requested by paging the 
Annunziata’s Lab at 102-11155.   
7.1.3.2 The same unique patient identifier linked to the tumor biopsies will be used to 
shield the archived blood samples. 
7.1.4 Archival material.  A block of archival tumor material will be requested from each 
patient.  A recent resection sample or a block of tissue from the original resection are 


 
 
 
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requested.  Where a block cannot be released by the governing Pathology department, 
10 x 8um re-cuts on charged slides will be requested.   
7.1.5 Samples, and associated data, will be stored permanently unless the patient withdraws 
consent. If researchers have samples remaining once they have completed all studies 
associated with the protocol, they must be returned to Dr. Annunziata’s laboratory.” 
7.1.6 The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. a broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if 
they are lost in transit between facilities or misplaced by a researcher.  Dr. 
Annunziata’s laboratory will report any freezer problems, lost samples or other 
problems associated with samples to the IRB, the NCI Clinical Director, and the 
office of the CCR, NCI.” 
7.1.7 DNA methylation profiling in plasma samples of ovarian cancer patients 
We have implemented a pipeline to assess DNA methylation levels at one locus in the 
human genome, ZNF154, which has been identified as a pan-cancer marker (Sanchez-
Vega, et al. Epigenetics 2013). 
 
Briefly the protocol involves extracting cell free DNA from plasma samples, bisulfite 
conversion of the DNA (using 20 ng up to 1 ug), PCR amplification of the target 
region, annealing adapters and barcodes for sequencing, and sequencing on a MiSeq 
platform. Subsequent computational analyses will identify the extent and patterns of 
DNA methylation in the sequencing reads, for characterization of tumor vs normal 
status. Assays are typically run in a 96 well plate, all samples are run in duplicate and 
only one locus is examined in the genome. No DNA mutations are assessed in this 
analysis and the results do not give personally identifiable information. 
 
We will assess samples covering time points over the course of treatment from the 
same individual, as available. The analysis will address the sensitivity of our assay to 
detect circulating tumor DNA carrying specific DNA methylation patterns that are 


 
 
 
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unique to tumor samples, from the data of earliest clinical contact through a treatment 
regime. We anticipate that the detectable signal will vary over the stage and severity 
of disease, with decreases in signal reflecting response to treatment. As this is a 
preliminary project, we anticipate testing the sensitivity and specificity of the method 
when the diagnosis is known for each plasma sample, rather than a blinded study. 
 
A minimum of 1 mL of plasma is needed per time point, up 2mL. Any unused DNA 
will be returned to the Annunziata lab. Comparisons will be between time points of 
the same individual, or across affected vs unaffected individuals, where normal 
plasma samples can be obtained. These normal samples may ultimately come from a 
commercial source, matched for age, BMI, smoking history and/or any other patient 
characteristics that are available. All current assays are being conducted on samples 
obtained from these commercial sources. 
 
Collaborator: 
Dr. Laura Elnitski 
Senior Investigator, Genomic Functional Analysis Section 
Translational and Functional Genomics Branch, National Human Genome Research 
Institute 
Building 5625FL, Room 5N-01R 
5625 Fishers Lane 
Rockville, MD 20892 
Tel:  301-451-0265 
Fax:  301-435-6170 
Email:  elnitski@mail.nih.gov 
 
Dr. Elnitski identified the ZNF154 site as a pan-cancer marker and developed the 
pipeline for bisulfite sequence analysis. She will oversee all aspects of the data 
analysis. The results will be published as a collaborative effort between Drs. 
Annunziata and Elnitski. 
 


 
 
 
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7.2 
Pharmacoproteomic analysis 
7.2.1 The primary targets of pharmacoproteomic modulation to be measured were defined 
based upon the preclinical signaling data.  They are listed below 
Survival/Proliferation 
Angiogenesis 
Apoptosis 
AKT 
p-AKT 
ENOS 
p-eNOS 
PARP 
Cleaved-PARP 
ERK 1 / 2 
p-ERK 1 / 2 
p-VEGFR-
2 
CD31 
Caspase 3 
Cleaved Caspase-3 
Cyclin D1 
Myb-1 
 
 
 
 
 
7.2.2 Should additional tissue or TLA arrays be available, the following targets will be 
characterized. These will include but are not limited to the following: 
Survival/Proliferation 
Angiogenesis 
Apoptosis 
mTOR 
p-mTOR 
-smooth muscle actin 
p53 
EGFR 
p-EGFR 
Pyk2 
p-Pyk2 
GSK3ß 
p-GSK3ß 
Src 
p-Src 
VEGFR-2 
p-bad 
NFkB 
p-NFkB 
Integrin E3 
p-Bcl-2/bcl-2 
STAT1 
p-STAT1 
 
Caspase 9 
IkB 
p-IkB 
 
Cleaved Caspase-9 
p38 
Phospho-p38 
 
 
Jak1 
p-Jak1 
 
 
 
7.2.3 Provided that the following antibodies be validated for usage and adequate tissue or 
TLA arrays be available, the following additional targets will be characterized: 
Survival/Proliferation 
Fos  
Raf 
Ras 
CREB 
Jun 
p-Jun 
 
 
 


 
 
 
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7.3 
Correlative imaging studies 
We will use functional tumor imaging with dynamic contrast enhanced (DCE) MRI and PET to 
evaluate changes in vascularity and quality of index lesions for research purposes only.  These 
modalities may provide early indications of treatment effect even before changes in size can be 
perceived on CT.  Moreover, they may provide data on the additive effect of BAY 43-9006 and 
bevacizumab on angiogenesis regulation.  PET may provide additional information on tumor 
metabolism as well as the effects of treatment on GLUT-1 transporter function. Together, these 
modalities should provide a unique window on the single and combined effects of BAY 43-9006 
and bevacizumab. 
Index lesions will be selected for serial measurement based on size (at least 1 cm in largest 
diameter for biopsy and imaging studies at the discretion of the collaborative imager) and 
relative immobility.  The same lesion will be evaluated by Dynamic Contrast Enhanced MRI 
(DCE-MRI) and PET.  Scans will be obtained on the same schedule as the tumor biopsies.   They 
will not be used to assess disease response and continuation on the protocol. 
7.3.1 DCE-MRI 
Patients will undergo DCE-MRI using the following parameters.  Conventional T1 and T2 
weighted images of the target lesion will be obtained and a T1 map will be generated.  This will 
be followed by a series of 3D gradient echo T1 weighted dynamic sequence which will be 
acquired before, during and after the administration of 0.1mmol/kg of a gadolinium chelate.  
Data will be analyzed using a general kinetic model by the Clinical Imaging Processing Service 
(CIPS) in the Diagnostic Radiology Department.  This model generates two parameters K_trans 
and kep (permeability terms) which will be used as continuous outcome variables in the analysis.  
Vascular fraction may also be assessed.  Color maps based on these parameters will also be 
generated. 
7.3.2 PET 
Patients will undergo a FDG PET after fasting for 6 hours (patient may have water and oral 
medications) on C1d1.  Approximately 1 hour following injection of 15 mCi FDG a whole body 
PET will be obtained. For each patient, we will select and measure one lesion that is greater than 
1 cm and is the same mass being analyzed by DCE MRI.  Standardized Uptake Values (SUV) 
will be obtained from the target lesion and used as a continuous outcome variable.   On C1d3 


 
 
 
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andC2d15, repeat PETs following the same procedure listed above will be obtained to ascertain 
if PET response following treatment is predictive of response. SUV values will be compared 
between patients and across time for changes in tumor activity, as well as compared with 
eventual patient tumor response to therapy using standard statistical methods. 
7.4 
Angiogenesis studies 
7.4.1 Cytokine profiling 
Cytokine production has been shown to be regulated by the Ras/Raf/MAPK pathways and 
downstream of VEGFR signaling.  Serial plasma samples will be collected during the course of 
the study.  These will be batched and the analyzed by commercially available ELISA.  The 
following will be measured:  VEGF, IL-6. IL-8 or others as indicated by pilot results in phase I 
Sorafenib/bevacizumab (work in progress). 
7.4.2 Biopsy analysis/microvessel staining 
Re-cuts of tumor biopsies where available and/or archival materials will be stained and analyzed 
for microvessel density (MVD) using standard immunohistochemical assays.   Quantification of 
MVD will be assessed using the method of Weidner et al. using CD31 expression.  Sections will 
then be screened to determine the most vascular area of the tumor (hot spot).  Within the hot spot 
area, the stained microvessels will be counted as a single high-power (x 400) field.   
 
7.5 
Ras/Raf mutation identification 
It has recently been found that B-Raf is commonly mutated in human tumors.  To determine if 
BAY 43-9006 preferentially inhibits tumors with mutant B-Raf, mutational analysis of B-Raf 
will be done using the following paradigm:  
Initial screening for B-Raf mutation will be executed by protein lysate array analysis.  The most 
frequently observed mutation in B-Raf yields the V599E [29] amino acid substitution.  Dr. 
Meltzer’s group in the NCI’s Genetics Branch has developed a monoclonal antibody specific to 
this mutation (unpublished data).  Lysate arrays will be optimized with this monoclonal antibody 
and then will be used to assess expression of this B-Raf mutation.  Detection of this protein 
product will prompt allele specific PCR of the tumor genome using a recut from the tumor 
biopsies obtained for the protocol.  No germline analysis will be done.  Additionally, once a 


 
 
 
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57 
cohort of responders has been identified, genomic DNA will be extracted from tissue blocks for 
allele specific PCR in the other commonly mutated regions, for which a specific antibody does 
not yet exist. 
8. 
STUDY CALENDAR 
Schedules shown in the Study Calendar below are provided as an example and should be 
modified as appropriate (+/- 2-3 days to allow for clinic and scheduling variations around 
holidays or availability of biopsy or imaging facilities). 
 
Baseline physical examinations are to be conducted within 1 week prior to administration of 
protocol therapy. Laboratory evaluations should be within 48 hours prior to initiation of the next 
cycle of therapy. 
 
 
 
Pre- 
Treatment 
C1D
1 
C1D
3 
C1D1
5 
C2D
1 
C2D1
5 
C3D
1 
Q 2 
weeks 
Q 
month 
Q 2 
months 
Off 
Studyc 
Bevacizumab therapy 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
Sorafenib therapy 
 
Xh  
 
Xh 
Xh 
 
Xh 
 
Xh 
 
Xh 
 
Xh 
Xh 
 
Xh 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Concurrent meds 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Diary reviewf 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
Physical exam 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Daily blood pressure 
(See 
APPENDIX 
F: 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Vital signs 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Performance status 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Quality of life 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
CBC w/diff, plts 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
Serum chemistrya 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
PT/PTT 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
CA 125 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
TSH 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 


 
 
 
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58 
Tumor Measurement 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
UPC 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
Adverse event evaluation 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
B-HCG 
Xb  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Bloods 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Xg 
 
Tumor Biopsy 
Xe 
 
 
 
 
 
 
 
 
 
Xg 
 
 
 
 
 
 
 
Xg 
 
FDG-PET  
X e 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
DCEMRI 
Xe 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
CT Chest/Abdomen/Pelvis 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
a: electrolytes, BUN, creatinine, glucose, AST (SGOT), ALT (SGPT), bilirubin, calcium, phosphorous, albumin, 
magnesium, alkaline phosphatase, amylase, lipase 
b: Serum pregnancy test (women of childbearing potential only). 
c: Off-study evaluation.  If the patient is unable to return to the clinical center for evaluation, a follow-up phone call 
will be made. 
d: prestudy tests should be completed within 4 days of enrollment 
e: the initial biopsy and DCEMRI should be performed within a period of 7 days prior to starting drug therapy 
f: A study diary will be assigned to each patient.  It will be reviewed every cycle with the research nurse to monitor 
compliance and a copy will be placed in the research record. 
g: If patient is willing h:  Sorafenib will be taken orally twice daily for 5 days every week 
 
 
9. 
MEASUREMENT OF EFFECT 
For the purposes of this study, patients should be reevaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be 4 weeks following initial 
documentation of objective response. 
 
9.1 
Definitions 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 92(3):205-
216, 2000].  Changes in only the largest diameter (unidimensional measurement) of the tumor 
lesions are used in the RECIST criteria.  Note:  Lesions are either measurable or non-measurable 


 
 
 
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59 
using the criteria provided below. The term “evaluable” in reference to measurability will not be 
used because it does not provide additional meaning or accuracy. 
9.1.1 Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, 
x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
9.1.2 Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
9.1.3 Target Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response. 
9.1.4 Non-target Lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline.  Non-target lesions include measurable lesions that exceed the maximum 
numbers per organ or total of all involved organs as well as non-measurable lesions.  
Measurements of these lesions are not required but the presence or absence of each should be 
noted throughout follow-up.  
 


 
 
 
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9.2 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and 
neck tumors and those of extremities usually require specific protocols. 
 
Ultrasound (US).  When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 


 
 
 
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Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation 
has not yet been fully and widely validated.  Their uses in this specific context require 
sophisticated equipment and a high level of expertise that may only be available in some centers.  
Therefore, the utilization of such techniques for objective tumor response should be restricted to 
validation purposes in reference centers. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
CA-125.  CA-125 alone will not be used to assess response.  If CA-125 is initially above the 
upper normal limit, it must normalize for a patient to be considered in complete clinical 
response.  
 
9.3 
Response Criteria 
Response will be evaluated by physical exam every four weeks and/or noninvasive imaging 
using techniques that demonstrate lesions and tumor markers where appropriate.  Response and 
progression will be evaluated in this study using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee [30].  Changes in only the 
largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST 
criteria.   
 


 
 
 
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9.3.1 Evaluation of Target Lesions 
 
 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference 
the baseline sum LD 
Progressive Disease (PD): 
 
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest sum 
LD recorded since the treatment started or the 
appearance of one or more new lesions 
Stable Disease (SD):  
 
 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment 
started 
 
9.3.2 Evaluation of non-target Lesions 
 
Complete Response (CR): 
 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
 
Incomplete Response/  
  
 
 
Stable Disease (SD):  
 
 Persistence of one or more non-target lesion(s) 
or/and maintenance of tumor marker level above the 
normal limits 
Progressive Disease (PD): 
 
Appearance of one or more new lesions and/or  
unequivocal progression of existing non-target 
lesions 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail, and the progression status should be 
confirmed at a later time by the review panel (or study chair). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 


 
 
 
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9.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria (see section 9.3.1). 
 
 
 
 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete 
response status. 
 


 
 
 
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64 
9.4 
Confirmatory Measurement/Duration of Response 
9.4.1 Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when 
reporting the outcome of such studies that the responses are not confirmed. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate.  
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the 
study protocol see section 9.3.3 
 
9.4.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
9.4.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  Disease 
must show an absence of progression for a period of at least 4 weeks as verified by serial CT 
scans to be classified as stable disease. 
 
9.4.4 Reporting of Results 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). 
 


 
 
 
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65 
All of the patients who met the eligibility criteria should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered as failing to respond to 
treatment (disease progression).  Thus, an incorrect treatment schedule or drug administration 
does not result in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific. 
 
All conclusions should be based on all eligible patients. 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for 
whom major protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol deviations, etc.).  However, these subanalyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported.   
The 95% confidence intervals should be provided. 
 
10. 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
10.1 Definitions 
10.1.1 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.  
 
10.1.2 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. 
10.1.3 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 


 
 
 
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66 
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. 
10.1.4 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. 
10.1.5 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: 
x 
Death, 
x 
A life-threatening adverse drug experience 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x 
A congenital anomaly/birth defect. 
x 
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. 
10.1.6 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
10.1.7 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. 
10.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol. 


 
 
 
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67 
10.1.9 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.  
10.1.10 
Unanticipated Problem 
Any incident, experience, or outcome that: 
x  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 
x Is related or possibly related to participation in the research; AND 
x 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. 
10.2 NCI-IRB and Clinical Director Reporting 
10.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
x All deaths, except deaths due to progressive disease  
x All Protocol Deviations 
x All Unanticipated Problems 
x All non-compliance 
 
Reports must be received within 7 days of PI awareness via iRIS. 
10.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
The protocol 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 


 
 
 
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68 
3. A tabular summary of the following adverse events: 
x 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
x 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
x 
All Grade 5 events regardless of attribution;  
x 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
10.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
 
10.3 Expedited Adverse Event Reporting to Sponsor 
Expedited adverse event (AE) reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System ), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
which can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  These requirements 
are briefly outlined in the tables below (Section 10.3.1). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting beginning 
January 1, 2011.  All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0.  A list of adverse events that have occurred or might occur (Reported Adverse 
Events and Potential Risks) can be found in Section 6 (Pharmaceutical Information).  A copy of 


 
 
 
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69 
the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/ctc.html).   
 
Expedited reports are submitted to CTEP via the secure CTEP-AERS application accessed via 
the CTEP web site (http://ctep.cancer.gov) and to the NCI IRB.  Those AEs that do not require 
expedited reporting must be reported in routine (CDUS) study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
 
 
10.3.1 Expedited Reporting Guidelines 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  CTEP-AERS Reporting 
Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of the 
Investigational Agent 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days 
after the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
x Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
x Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
x Grade 5 expected events 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table. 
December 15, 2004 
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 


 
 
 
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x 
Expedited AE reporting timelines defined: 
¾ “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 5 calendar days of the initial 24-hour report. 
¾ “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted 
within 10 calendar days of the investigator learning of the event.  
x 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of 
attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
x 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
x 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
x 
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497, only when 
Internet connectivity is disrupted.  Once Internet connectivity is restored, a 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original 
submitter at the site 
x All expedited AE reports must also be sent to the local IRB according to local IRB policy 
and procedure 
 
10.1 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
10.2 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  


 
 
 
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CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS)  
x Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.3 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
10.4  CAEPR for Bevacizumab 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 3540 patients. Below is the CAEPR for 
bevacizumab (rhuMAb VEGF). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 


 
 
 
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Version Date:  10/03/2018 
 
72 
Version 2.3, August 1, 20131 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Blood and lymphatic system 
disorders - Other (renal 
thrombotic microangiopathy) 
  
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Acute coronary syndrome2 
  
 
Cardiac disorders - Other 
(supraventricular 
arrhythmias)3 
 
 Cardiac disorders - Other 
(supraventricular arrhythmias)3 (Gr 3) 
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction2 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Colitis 
 
 Colitis (Gr 3) 
 
Constipation 
 
 Constipation (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula4 
  
 
Gastrointestinal 
hemorrhage5 
 
 Gastrointestinal hemorrhage5 (Gr 2) 
 
 Gastrointestinal obstruction6  
  
 
 
Gastrointestinal perforation7 
  
 
 
Gastrointestinal ulcer8 
  
 
Ileus 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Infusion related reaction 
 
 Infusion related reaction (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 3) 
 
Pain 
 
 Pain (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection9 
 
 Infection9 (Gr 3) 
 
 
Infections and infestations - 
Other (necrotizing fasciitis) 
  


 
 
 
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73 
 
Infections and infestations - 
Other (peri-rectal abscess) 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Injury, poisoning and procedural 
complications – Other 
(anastomotic leak)10 
  
 
Wound complication 
 
 Wound complication (Gr 2) 
 
Wound dehiscence 
 
 Wound dehiscence (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Cardiac troponin I increased  
  
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 3) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased  
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Musculoskeletal and 
connective tissue disorder -  
Other (bone metaphyseal 
dysplasia)11 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Osteonecrosis of jaw12 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular2 
  
 
Peripheral sensory 
neuropathy13 
 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
Syncope 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Hematuria 
 
 Hematuria (Gr 3) 
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (Nephrotic Syndrome) 
  
 
 
Urinary fistula 
 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
Reproductive system 
and breast disorders - 
 
 
  


 
 
 
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74 
Other (ovarian 
failure)14 
 
 
Vaginal fistula 
  
 
Vaginal hemorrhage 
 
 Vaginal hemorrhage (Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 3) 
 
 
Bronchopleural fistula 
  
 
 
Bronchopulmonary hemorrhage   
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 3) 
 
Hoarseness 
 
 Hoarseness (Gr 3) 
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 3) 
 
 
Vascular disorders - Other 
(arterial thromboembolic 
event)2,15 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in patients 
with a history of diabetes. 
 
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and atrial flutter. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Gastric 
fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, 
Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Oral 
hemorrhage, Rectal hemorrhage, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal obstruction, Ileal 
obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Jejunal perforation, Rectal perforation, Small intestinal perforation, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 


 
 
 
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Version Date:  10/03/2018 
 
75 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large intestinal 
anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic 
leak 
 
11Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
12Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with bevacizumab 
treatment, the majority of whom had received prior or concomitant treatment with i.v. bisphosphonates. 
 
13Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab and 
chemotherapy compared to chemotherapy alone.  
 
14Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) 
elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX compared to 
mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses and an FSH level 
<30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term effects of bevacizumab exposure on 
fertility are unknown. 
 
15Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart attack and 
stroke. 
 
 
Also reported on bevacizumab (rhuMAb VEGF) trials but with the relationship to bevacizumab (rhuMAb 
VEGF) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(idiopathic thrombocytopenia purpura); Bone marrow hypocellular; Disseminated intravascular coagulation; 
Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac arrest; 
Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane perforation); 
Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye 
disorders - Other (floaters); Eye disorders - Other (ischemic CRVO); Eye disorders - Other (macular pucker); Eye 
disorders - Other (transient increased IOP > or =30 mm Hg); Eye disorders - Other (vitreous hemorrhage); Eye pain; 
Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; Retinal tear; Retinopathy; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Chelitis; Colonic stenosis; Dry mouth; Dysphagia; Enterocolitis; 
Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral pain; 
Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis;Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; Edema 
limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site reaction; Localized 
edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic failure; 
Hepatic necrosis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; Dermatitis 
radiation; Fracture 


 
 
 
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76 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone abnormal; 
CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; Electrocardiogram 
QT corrected interval prolonged; Forced expiratory volume decreased; GGT increased; INR increased; Lipase 
increased; Lymphocyte count decreased; Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Chest 
wall pain; Fibrosis deep connective tissue; Generalized muscle weakness; Head soft tissue necrosis; Joint effusion; 
Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - Other 
(aseptic necrotic bone); Musculoskeletal and connective tissue disorder - Other (myasthenia gravis); 
Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); Neck pain; Pain in extremity; 
Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; Cerebrospinal fluid 
leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; 
Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; Leukoencephalopathy; Memory 
impairment; Nervous system disorders - Other (increased intracranial pressure); Paresthesia; Peripheral motor 
neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; Renal 
and urinary disorders - Other (dysuria); Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; 
Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular 
menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Pulmonary hypertension; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal disorders - 
Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; Pain of 
skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and subcutaneous tissue disorders - Other (skin 
breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis  
 
 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
 
 


 
 
 
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Version Date:  10/03/2018 
 
77 
10.5 CAEPR for Sorafenib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Sorafenib (BAY 43-9006, NSC 724772) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2157 patients. Below is the CAEPR for 
sorafenib (BAY 43-9006). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.4, December 21, 20111 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006) 
 (CTCAE 4.0 Term) 
[n= 2157] 
 
  Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
 
(formerly known as ASAEL) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
  
CARDIAC DISORDERS 
  
 
 
Acute coronary 
syndrome 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Anal mucositis 
 
  
 
Ascites 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Gastrointestinal 
 
 Gastrointestinal hemorrhage2  


 
 
 
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78 
hemorrhage2 
(Gr 3) 
 
 
Gastrointestinal 
perforation3 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Rectal mucositis 
 
  
 
Small intestinal mucositis  
  
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Non-cardiac chest pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INVESTIGATIONS 
  
 
Activated partial 
thromboplastin time 
prolonged 
 
 Activated partial 
thromboplastin time prolonged 
(Gr 2) 
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase 
increased 
 
 
 Alkaline phosphatase increased 
(Gr 3) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased (Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased (Gr 
3) 
 
Cholesterol high 
 
  
Creatinine increased 
 
 
 Creatinine increased (Gr 3) 
 
GGT increased 
 
  
INR increased 
 
 
 INR increased (Gr 2) 
 
Investigations - Other 
(bicarbonate, serum-low) 
 
  
Lipase increased 
 
 
 Lipase increased (Gr 3) 
Lymphocyte count 
decreased 
 
 
 Lymphocyte count decreased  
(Gr 3) 
 
Neutrophil count 
decreased 
 
 Neutrophil count decreased    
(Gr 4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
Serum amylase increased 
 
 
 Serum amylase increased (Gr 
3) 
Weight loss 
 
 
 Weight loss (Gr 2) 
White blood cell decreased  
 
 White blood cell decreased (Gr 
4) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia (Gr 3) 


 
 
 
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79 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 3) 
 
Hypernatremia 
 
  
 
Hyperuricemia 
 
  
Hypoalbuminemia 
 
 
 Hypoalbuminemia (Gr 3) 
Hypocalcemia 
 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 3) 
Hyponatremia 
 
 
 Hyponatremia (Gr 3) 
Hypophosphatemia 
 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Back pain 
 
 Back pain (Gr 3) 
 
Bone pain 
 
  
 
Musculoskeletal and 
connective tissue disorder 
-  Other (muscle spasms) 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
 
 Pain in extremity (Gr 3) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage   
 
Peripheral sensory 
neuropathy 
 
  
 
 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Hematuria 
 
  
 
Renal hemorrhage 
 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Hematosalpinx 
 
  
 
Ovarian hemorrhage 
 
  
 
Prostatic hemorrhage 
 
  
 
Spermatic cord 
hemorrhage 
 
  
 
Testicular hemorrhage 
 
  
 
Uterine hemorrhage 
 
  
 
Vaginal hemorrhage 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Bronchopulmonary 
hemorrhage 
 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
  


 
 
 
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80 
 
Laryngeal mucositis 
 
  
 
Pharyngeal mucositis 
 
  
 
Tracheal mucositis 
 
  
 
Voice alteration 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Alopecia 
 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 3) 
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
 
Stevens-Johnson 
syndrome 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
 
4Includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
Also reported on sorafenib (BAY 43-9006) trials but with the relationship to sorafenib (BAY 43-9006) still 
undetermined: 
 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Chest pain - cardiac; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Extraocular muscle paresis  
GASTROINTESTINAL DISORDERS - Abdominal distension; Dyspepsia; Dysphagia; Flatulence; Ileus; 
Pancreatitis; Rectal fistula; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Flu like 
symptoms; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Fibrinogen decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypermagnesemia; Hypertriglyceridemia; 
Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Generalized muscle weakness 


 
 
 
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81 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Ischemia cerebrovascular; Memory 
impairment; Syncope 
PSYCHIATRIC DISORDERS - Confusion; Depression 
RENAL AND URINARY DISORDERS - Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Hypoxia; Pleural effusion; Pneumonitis; 
Pneumothorax 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Hyperhidrosis; Purpura; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (non-life threatening squamous cell carcinoma of skin:  keratoacanthoma 
type); Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypotension; Vasculitis 
 
Note: Sorafenib (BAY 43-9006) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
10.6 Data Reporting 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means (NCI C3D).  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for submitting data 
using the CDUS can be found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
 
11. 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
[CRADA/CLINICAL TRIALS AGREEMENT (CTA)] 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as Collaborator(s)) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
Intellectual Property Option to Collaborator contained within the terms of award, apply to the 
use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
investigational Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI.  If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 


 
 
 
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82 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
a. 
NCI must provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NIH, the design of the proposed combination protocol, and the existence 
of any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary to 
allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own investigational Agent. 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own investigational Agent. 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order. 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 


 
 
 
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5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to 
submission for publication.  Collaborator(s) will have 30 days from the date of receipt for 
review.  Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and proprietary 
data, in addition to Collaborator(s)’s intellectual property rights, are protected.  Copies of 
abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review 
as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings. Press releases 
and other media presentations must also be forwarded to CTEP prior to release. Copies of 
any manuscript, abstract and/or press release/ media presentation should be sent to: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@ctep.nci.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
 
publication, manuscript or other form of public disclosure shall contain any of  
 
Collaborators confidential/ proprietary information. 
 
NOTE:  The trial was completed with CTEP September 4, 2014. 
 
12. 
STATISTICAL CONSIDERATIONS 
12.1 Study Design/Endpoints 
The primary objective of this study is to determine if the clinical response rate of this 
combination is sufficiently high to warrant further evaluation in patients with ovarian cancer. 
The clinical outcome will be defined as complete response (CR) or partial response (PR). 


 
 
 
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Secondary objectives include evaluation of progression free survival at greater than or equal to 6 
cycles, toxicity, as well as a variety of biologic markers to determine if treatment impacts these 
parameters, and to see if the changes may be associated with clinical outcome. These studies will 
include characterization of effects on survival/proliferation, apoptotic, and angiogenic signaling 
cascades; identification of genetic mutations in raf to determine if this is a potentially important 
factor in disease response, apply real-time assessments of tumor vascularity and metabolism to 
characterization of response; and assessment of angiogenic effects of this combination. 
 
Eligible patients will be stratified upon enrollment according to whether they have received prior 
bevacizumab or not.  
 
In patients with no prior exposure to Bevacizumab, a Simon two-stage optimal design 
(1) will be used to determine whether the combination of bevacizumab and sorafenib is 
able to rule out a 20% response rate (p0=0.20) in favor of a more desirable 40% 
response rate (p1=0.40). Using alpha=0.10 and beta=0.10, initially 17 evaluable patients 
will be enrolled and receive treatment. If there are 0-3 clinical responses (CR+PR), then 
no further patients will be enrolled onto this arm of the trial, and this combination will 
be considered insufficiently active for further consideration in this disease.  After 17 
patients have been enrolled in this stratum, we will halt accrual until this analysis of the 
first stage is completed.  If 4 or more clinical responses are identified in the first 17 
patients enrolled in this stratum, then accrual will continue until a total of 37 patients are 
enrolled. If 3 to 10 clinical responses are noted in 37 patients, then the agents will not be 
considered sufficiently active in this disease for this stratum, while 11 or greater 
responses in 37 patients in this stratum will warrant further investigation in subsequent 
trials. Under the null hypothesis of 20% response rate, the probability of early 
termination in this stratum is 55%. 
In patients with prior exposure to Bevacizumab, a Simon two-stage optimal design (1) 
will be used to determine whether the combination of bevacizumab and sorafenib is able 
to rule out a 5% response rate (p0=0.05) in favor of a more desirable 20% response rate 
(p1=0.20). Using alpha=0.05 and beta=0.10, initially 21 evaluable patients will be 
enrolled and receive treatment. If there are 0-1 clinical responses (CR+PR), then no 


 
 
 
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further patients will be enrolled onto this arm of the trial, and this combination will be 
considered insufficiently active for further consideration in this disease.  After 21 
patients have been enrolled in this stratum, we will halt accrual until this analysis of the 
first stage is completed.  If 2 or more clinical responses are identified in the first 21 
patients enrolled in this stratum, then accrual will continue until a total of 41 patients are 
enrolled. If 2 to 4 clinical responses are noted in 41 patients, then the agents will not be 
considered sufficiently active in this disease for this stratum, while 5 or greater 
responses in 41 patients in this stratum will warrant further investigation in subsequent 
trials. Under the null hypothesis of 5% response rate, the probability of early termination 
in this stratum is 72%. 
Additional patients will be accrued to replace any patient who is entered on trial but 
does not complete the 2 cycle time period for evaluation of the primary endpoint, 
response (i.e. uncontrolled intercurrent illness, voluntary self-withdrawal, toxicity 
precluding continuation).  Demonstration of progressive disease within that period will 
not require replacement as it is an outcome response.  Any and all adverse events that 
occur during the time of drug exposure will be counted.  Three replacement patients per 
stratum will be allowed. 
A variety of markers will be evaluated at baseline as well as at cycle 2, day 1 of treatment. 
Changes from baseline will be determined in either absolute or relative terms as appropriate, and 
evaluated for statistical significance, as well as to determine if the changes or the actual values at 
a time point are associated with clinical response. Paired comparisons with baseline will be done 
using a paired t-test or Wilcoxon signed rank test as appropriate, and, if accrual is able to 
continue onto the second stage, the changes will be compared between responders (CR +PR) and 
non-responders (SD+PD) using a two sample t-test or Wilcoxon rank sum test as appropriate. As 
a minimum, for a given stratum, even if 10 markers were evaluated compared to baseline, with 
20 patients there would be 88% power to declare a given marker change from baseline to be 
significant at the 0.05 level after adjusting for multiple comparisons by the Bonferroni 
procedure, although less stringent adjustments may be made in practice as these would be 
secondary endpoints. 


 
 
 
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PET and MRI parameters will also be obtained at the same time points, and changes in these 
parameters will also be compared in a similar fashion, both with respect to the changes 
themselves and with respect to any association with clinical response.  In all such cases, these 
analyses will be considered exploratory and not formally adjusted for multiple comparisons. 
However, to ensure proper interpretation in the context of a potentially large number of 
explorations being performed, only p-values <0.01 will be interpretable as being associated with 
statistical significance.  
 
Kaplan-Meier curves depicting time to progression on sorafenib + bevacizumab will be provided 
for both strata. Appropriate 95% confidence intervals will be formed. 
 
Toxicities will be tabulated and the frequency of grade 3 or greater toxicities will be calculated, 
and appropriate 95% confidence intervals will be formed. As a final exploratory analysis, results 
from both strata may be pooled if it is determined that the results from both strata are sufficiently 
similar, that is, if p>0.10 for a test to determine if any set of results differ by stratum.  Since 
patients with prior bevacizumab exposure are expected to potentially have different outcomes 
than those who do not, this combination of results will be carefully noted to be a secondary 
evaluation, not necessarily as meaningful as results from within each stratum, and will only be 
done cautiously if appropriate to do so at all.  
 
 
For those correlative studies that do not meet criteria for statistical significance, they will be used 
as exploratory analyses for hypothesis generator (please refer to section 12.4 of the protocol).   
 
12.2 Sample Size/Accrual Rate 
It is anticipated that 30 patients per year may be enrolled onto the protocol. In order to enroll 78 
evaluable patients, an accrual period of up to 3 years is expected. 
 
12.3 Stratification Factors 
Patients will be stratified based on exposure to bevacizumab. 
 


 
 
 
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12.4 Analysis of Secondary Endpoints 
Proteomic and molecular endpoints will be evaluated on the protocol in all available enrolled 
patients.  These will all be considered exploratory analyses and will not have their statistical 
results adjusted for multiple comparisons. However, all interesting findings will be carefully 
interpreted as hypothesis generating. 
12.5 Reporting and Exclusions 
 
12.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time of 
their first treatment 
 
12.5.2 
Evaluation of response.  All patients included in the study must be assessed for 
response to treatment, even if there are major protocol treatment deviations or if they are 
ineligible.  Each patient will be assigned one of the following categories:  1) complete 
response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data).  [Note:  By arbitrary convention, category 9 
usually designates the “unknown” status of any type of data in a clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered as failing to 
respond to treatment (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
13. 
HUMAN SUBJECTS PROTECTIONS 
13.1 Rationale for subject selection 
This study will be open to all women with recurrent epithelial ovarian, fallopian, and peritoneal 
cancer regardless of gender, ethnicity, or race provided that the aforementioned inclusion and 
exclusion criteria are met.  For safety reasons, only pregnant women and children are excluded 
from this study. This study will be recruited through internal referral, our local physician referral 


 
 
 
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base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-
888-624-1937).   
 
All individuals with epithelial ovarian, fallopian, and peritoneal cancer that is refractory to 
standard care are eligible according to the eligibility criteria within section 3.  This is a phase II 
study to determine the efficacy of this combination for the treatment of these cancers.  Patients 
must have failed therapy of proven efficacy for their disease. 
 
Female patients all racial /ethnic groups are eligible for this study if they meet the eligibility 
criteria outlined in section 3.  To date, there is no information that suggests that differences in 
drug metabolism or disease response would be expected in one ethnic group compared to 
another.  Efforts will be made to extend accrual to each representative population, but in this 
preliminary study, a balance must be struck between patient safety considerations and limitations 
on the number of individuals exposed to potentially toxic and/or ineffective treatments on the 
one hand and the need to explore racial/ethnic aspects of clinical research on the other hand.  If 
differences in outcome that correlate to ethnic identity are noted, accrual may be expanded, or a 
follow-up study may be written to investigate those differences more fully. 
 
13.2 Participation of Children 
Epithelial cancer of the ovary, fallopian tubes, or peritoneum in children is a exceedingly rare, 
reportable disease. Patients under the age of 18 will be excluded from study. 
 
13.3 Evaluation of Benefits and Risks/Discomforts: 
The potential benefit to a patient who enters study is a reduction in the bulk of her tumor, which 
may or may not have a favorable impact on symptoms and/or survival.  Potential risks include 
the possible occurrence of any of a range of side effects that are listed in the pharmaceutical 
section and the consent document.  The procedure for protecting against or minimizing risks will 
be to medically evaluate patients on a regular basis as described earlier, including initial 
eligibility screening prior to enrollment on the protocol. 
 


 
 
 
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13.4 Risks/Benefits Analysis: 
13.4.1 Potential Risks 
13.4.1.1 Risk of serial biopsies: All care will be taken to minimize risks that may be 
incurred by tumor sampling.  However, there are procedure-related risks (such 
as bleeding, infection and visceral injury) that will be explained fully during 
informed consent. If patients suffer any physical injury as a result of the 
biopsies, immediate medical treatment is available at the NIH’s Clinical Center 
in Bethesda, Maryland.  Although no compensation is available, any injury will 
be fully evaluated and treated in keeping with the benefits or care to which 
patients are entitled under applicable regulations. 
 
13.4.1.2 Risk of Treatment:  Details of the risk of drug therapy are detailed in section 6. 
13.4.1.3 Risks of radiation exposure:  This study incorporates serial imaging with 
radioactive substances related to the PET scans and CT scans for biopsy 
guidance (where needed) in the study.  Patients will receive 3 injections of 15 
mCi of F-18 FDG for PET.  The total effective dose is less than 5 rem.  This 
study is approved by the NIH Radiation Safety Committee. 
 
13.5 Consent and Assent Process and Documentation: 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
treatment plan, research objectives and follow-up of this trial.  The patient will be provided an 
IRB-approved consent for review and signature and his/her questions will be answered.  After a 
decision is made to enroll into the study, a signature will be obtained from the patient at a 
subsequent visit.  A copy of the signed informed consent will be placed in the patient's medical 
record and the original held in the Protocol Office. 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
 


 
 
 
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14. 
DATA AND SAFETY MONITORING PLAN 
Patients are reviewed weekly in team meetings and response data will be reviewed on a quarterly 
basis as well. All unexpected or serious adverse drug reactions will be reported to the NCI 
Institutional Review Board (IRB) within 10 working days of the date of occurrence. Safety 
information from patients enrolled onto the study will be gathered and reported.  Any unusual 
toxicity will be explored for possible causative mechanisms.  The safety of the repetitive biopsy 
procedure will also be determined and reported. 
Any unanticipated or unknown treatment- or drug-related toxicity(ies) and life-threatening and 
lethal toxicity(ies) must follow the guidelines described in section 10.  Clinical Associates and/or 
senior staff should notify the Principal Investigator at 301-402-2726 (Dr. Annunziata’s), 
Bldg.10, Rm 12N226 of the occurrence of such toxicity.  
A summary of the ongoing study will be submitted to the NCI’s Institutional Review Board at 12 
month intervals and a final report will be sent within six months of study completion at the 
request of the Institutional Review Board using the CTEP study summary form.  The status 
reported will be submitted and presented at upcoming NCI meetings as requested. 


 
 
 
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15. 
REFERENCES 
1. Singer, G., et al., Mutations in BRAF and KRAS characterize the development of low-grade 
ovarian serous carcinoma. J Natl Cancer Inst, 2003. 95(6): p. 484-6. 
2. Campbell, S.L., et al., Increasing complexity of Ras signaling. Oncogene, 1998. 17(11 
Reviews): p. 1395-413. 
3. Chong, H., H.G. Vikis, and K.L. Guan, Mechanisms of regulating the Raf kinase family. Cell 
Signal, 2003. 15(5): p. 463-9. 
4. Cohen, Y., et al., BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst, 2003. 
95(8): p. 625-7. 
5. Davies, H., et al., Mutations of the BRAF gene in human cancer. Nature, 2002. 417(6892): p. 
949-54. 
6. Mercer, K.E. and C.A. Pritchard, Raf proteins and cancer: B-Raf is identified as a mutational 
target. Biochim Biophys Acta, 2003. 1653(1): p. 25-40. 
7. Pollock, P.M. and P.S. Meltzer, A genome-based strategy uncovers frequent BRAF mutations 
in melanoma. Cancer Cell, 2002. 2(1): p. 5-7. 
8. Sawyers, C.L., Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute 
myeloid leukemia. Cancer Cell, 2002. 1(5): p. 413-5. 
9. Tannapfel, A., et al., Mutations of the BRAF gene in cholangiocarcinoma but not in 
hepatocellular carcinoma. Gut, 2003. 52(5): p. 706-12. 
10. Bergers, G., et al., Benefits of targeting both pericytes and endothelial cells in the tumor 
vasculature with kinase inhibitors. J Clin Invest, 2003. 111(9): p. 1287-95. 
11. Ferrara, N., VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer, 2002. 
2(10): p. 795-803. 
12. Apperley, J.F., et al., Response to imatinib mesylate in patients with chronic 
myeloproliferative diseases with rearrangements of the platelet-derived growth factor 
receptor beta. N Engl J Med, 2002. 347(7): p. 481-7. 
13. Heinrich, M.C., et al., Inhibition of KIT tyrosine kinase activity: a novel molecular approach 
to the treatment of KIT-positive malignancies. J Clin Oncol, 2002. 20(6): p. 1692-703. 


 
 
 
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14. Alavi, A., et al., Role of Raf in vascular protection from distinct apoptotic stimuli. Science, 
2003. 301(5629): p. 94-6. 
15. Christian, B., 26-Week intravenous toxicity study with rhuMAb VEGF in cynomolgus 
monkeys with a 12 week recovery. 1999, Genetech Report: South San Francisco. p. 97-194. 
16. Ryan, A.M., et al., Preclinical safety evaluation of rhuMAbVEGF, an antiangiogenic 
humanized monoclonal antibody. Toxicol Pathol, 1999. 27(1): p. 78-86. 
17. Ferrara, N., et al., Vascular endothelial growth factor is essential for corpus luteum 
angiogenesis. Nat Med, 1998. 4(3): p. 336-40. 
18. Gordon, M.S., et al., Phase I safety and pharmacokinetic study of recombinant human anti-
vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol, 2001. 
19(3): p. 843-50. 
19. Margolin, K., et al., Phase Ib trial of intravenous recombinant humanized monoclonal 
antibody to vascular endothelial growth factor in combination with chemotherapy in patients 
with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol, 2001. 19(3): 
p. 851-6. 
20. Yang, J.C., et al., A randomized trial of bevacizumab, an anti-vascular endothelial growth 
factor antibody, for metastatic renal cancer. N Engl J Med, 2003. 349(5): p. 427-34. 
21. Levine, M.N., Prevention of thrombotic disorders in cancer patients undergoing 
chemotherapy. Thromb Haemost, 1997. 78(1): p. 133-6. 
22. Yang, R., et al., Effects of vascular endothelial growth factor on hemodynamics and cardiac 
performance. J Cardiovasc Pharmacol, 1996. 27(6): p. 838-44. 
23. Shen, B.Q., D.Y. Lee, and T.F. Zioncheck, Vascular endothelial growth factor governs 
endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase 
C signaling pathway. J Biol Chem, 1999. 274(46): p. 33057-63. 
24. Ostendorf, T., et al., VEGF(165) mediates glomerular endothelial repair. J Clin Invest, 1999. 
104(7): p. 913-23. 
25. Ferrara, N., H.P. Gerber, and J. LeCouter, The biology of VEGF and its receptors. Nat Med, 
2003. 9(6): p. 669-76. 
26. Hurwitz, H., et al. Bevacizumab (a monoclonal antibody to vascular endothelial growth 
factor) prolongs survival in first-line colorectal cancer (CRC): Results of a phase III trial of 


 
 
 
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bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-
line therapy in subjects with metastatic CRC. (Abstactr #3646). in American Society of 
Clinical Oncology Annual Meeting. 2003. Chicago, IL. 
27. Simon, R., Optimal two-stage designs for phase II clinical trials. Control Clin Trials, 1989. 
10(1): p. 1-10. 
28. Weidner, N., et al., Tumor angiogenesis and metastasis--correlation in invasive breast 
carcinoma. N Engl J Med, 1991. 324(1): p. 1-8. 
29. Pollock, P.M., et al., High frequency of BRAF mutations in nevi. Nat Genet, 2003. 33(1): p. 
19-20. 
30. Therasse, P., et al., New guidelines to evaluate the response to treatment in solid tumors. 
European Organization for Research and Treatment of Cancer, National Cancer Institute of 
the United States, National Cancer Institute of Canada. J Natl Cancer Inst, 2000. 92(3): p. 
205-16. 
31. McPhillips, F., et al. Association of c-Raf expression with survival and its targeting with 
antisense oligonucleotides in ovarian cancer. Br J Cancer. 2001 Nov 30;85(11):1753-8. 
32. Chen, H., et al. VEGF, VEGFRs expressions and activated STATs in ovarian epithelial 
carcinoma. Gynecol Oncol. 2004 Sep;94(3):630-5. 
33. Mercer, K., et al. Raf proteins and cancer: B-Raf is identified as a mutational target. 
Biochim Biophys Acta. 2003 Jun 5;1653(1):25-40. 
34. Russell, S., et al. A multistep model for ovarian tumorigenesis: the value of mutation analysis 
in the KRAS and BRAF genes. J Pathol. 2004 Jun;203(2):617-9. 
35. Strumberg, D., 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. J Clin Oncol. 2005 Feb 10;23(5):965-72. Epub 2004 Dec 21. 
36. Alvarez Secord, A., et al. The relationship between serum vascular endothelial growth 
factor, persistent disease, and survival at second-look laparotomy in ovarian cancer. 
Gynecol Oncol. 2004 Jul;94(1):74-9 
37. Ratain M. et al. Final findings from a Phase II, placebo-controlled, randomized 
discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell 
carcinoma (RCC).  ASCO Annual Meeting 2005 Abstracts. 


 
 
 
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38. Escudier B. 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).  ASCO 
Annual Meeting 2005. 
39. Burger R. et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian 
cancer (EOC) or primary peritoneal cancer (PPC): a Gynecologic Oncology Group (GOG) 
study.  ASCO Annual Meeting 2005. 
40. Garcia A. et al  Interim report of a phase II clinical trial of bevacizumab (Bev) and low dose 
metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary 
peritoneal carcinoma: A California Cancer Consortium Trial.  ASCO Annual Meeting 2005. 
41. Veronese, M.L. et al. Mechanisms of Hypertension Associated With BAY 43-9006  J Clin 
Oncol. 30 Jan 2006 Epub. 
42. Bookman, M.A. et al. Optimal therapy of advanced ovarian cancer: carboplatin and 
paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update on GOG0 182-ICON5 Int J 
Gynecol Cancer. 2003 Nov-Dec;13(6):735-40. 
43. Parmar, M.K. et al. Paclitaxel plus platinum-based chemotherapy versus conventional 
platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-
OVAR-2.2 trial.  Lancet. 2003 Jun 21;361(9375):2099-106 
44. Azad, N. S. et al. Combination targeted therapy with sorafenib and bevacizumab results in 
enhanced toxicity and antitumor activity.  J Clin Oncol. 2008 Aug:26(22):3709-14. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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16. 
APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-
disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically 
strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of 
all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking 
hours. 
3 
In bed >50% of the time.  Capable of only limited self-
care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry 
on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 


 
 
 
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17. 
APPENDIX B: NCI/FDA PROTEOMICS PROGRAM STANDARD OPERATING 
PROCEDURE FOR TISSUE CORE COLLECTION – NEEDLE BIOPSY – 
CRYOPRESERVATION IN OCT 
 
Principle: 
Core needle biopsies are used to sample tissue from a specific, defined location.  These biopsies 
may consist of normal, pre-malignant and malignant tissue due to the multi-level tissue sample 
that is obtained.  This type of sample is ideal for studying the micro-tumor environment. 
Rapid freezing of the sample is required to prevent degradation of the proteins or RNA.  Optimal 
Cutting Temperature (OCT) compound is an alcohol polymer that is liquid at room temperature 
and a solid at –20oC.  This polymer is used to cryo-protect the tissue and provide a medium for 
cryo-sectioning. 
 
Materials: 
Cryomolds  (Sakura Finetek Ca.t # 4728) 
OCT (Sakura Finetek Cat. # 4583) 
Dry ice 
Ultra cold freezer (-700 to -800C)  
Needle: 16 or 18 gauge 
Permanent marker 
Sterile forceps 
Sterile Glass slides 
Aluminum foil or 50ml Falcon tubes 
 


 
 
 
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Procedure: 
1. Prepare all supplies prior to the biopsy procedure to avoid delay once the specimen has 
been obtained. 
2. Label the handle and the front surface of the cryomold with the sample or patient’s 
identifying information. 
3. Receive core needle biopsy. 
4. Pick the core from the biopsy needle onto a sterile glass slide. 
5. Fill cryomold about 1/3 full with OCT.  Place the cryomold in dry ice to partially freeze 
the OCT.  The OCT should be jelly-like, not completely frozen. 
6. Carefully lift the core biopsy by both ends with sterile forceps. Do not stretch the biopsy 
or it will break. 
7. Lay the biopsy as straight as possible in the OCT.  Once the sample touches the OCT, 
you cannot reposition it or the sample will break apart. 
8. Quickly add OCT on top of the biopsy, completely covering the sample. 
9. Ensure the sample is level and freeze immediately in dry ice. 
10. Store wrapped in aluminum foil or in a 50ml Falcon tube at –70oC then offload to liquid 
nitrogen. 
 
Note:  
Do not lay the biopsy on frozen OCT and cover it with liquid OCT.  The OCT will not fuse and 
will split into two sections when cutting the frozen tissue sections. 
 
Frozen Section Slides 
1. Frozen sections for proteomic analysis should be cut at 5-8um on plain, uncoated glass 
microscope slides. 
2. The tissue section should be placed as close as possible to the center of the slide.  Do not 
place the frozen section at the end of the slide. 
3. Two tissue sections from the same biopsy may be placed on the same glass slide if space 
permits. 
4. Do not allow the tissue section to air on the slide.  Freeze immediately on dry ice or at –
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18. 
APPENDIX C: STUDY DIARY 
 
Patient Name:  
 
 
 
 
 
 
Day 
Please note the 
times and dose 
of sorafenib 
(BAY 43-9006) 
that was taken by 
mouth. 
Record Blood 
Pressure Daily at 
home  and have            
BP checked 
WEEKLY at Dr's 
Office during Cycles 
1 and 2. (Use 
separate form for 
Doctor’s  BP 
checks). 
Please note any side 
effects you 
experienced on this 
day 
Do not list your daily 
medications, but note any 
other medications you took on 
this day (both prescription and 
nonprescription  and the 
reason why taken) 
Monday 
 
 
 
 
Tuesday 
 
 
 
 
Wednesday 
 
 
 
 
Thursday 
 
 
 
 
Friday 
 
 
 
 
Saturday 
 
 
 
 
Sunday 
 
 
 
 
**Record entries daily.  Do not record batch entries.  If an error is made, draw a line through it and initial. 
 
 
 
Patient Signature_________________________Date_____________________ 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
99 
19. 
APPENDIX D: CYTOCHROME P450 3A4 METABOLIZED DRUGS 
 
Substrates 
Acetaminophen 
Dapsone 
Levobupivicaine 
Risperidone 
Alfentanil 
Dehydroepiandrostendio
ne 
Lidocaine 
Ritonavir** 
Alosetron 
Delavirdine 
Loratadine 
Salmeterol 
Alprazolam 
Desmethyldiazepam 
Losartan 
Saquinavir 
Amiodarone 
Dexamethasone 
Lovastatin 
Sertindole 
Amitriptyline (minor) 
Dextromethorphan 
(minor) 
Methadone 
Sertraline 
Amlodipine 
Diazepam (minor) 
Mibefradil 
Sibutramine 
Anastrozole 
Digitoxin 
Miconazole 
Sildenafil citrate  
Androsterone 
Diltiazem 
Midazolam 
Simvastatin 
Antipyrine 
Disopyramide 
Mifepristone 
Sirolimus 
Astemizole 
Docetaxel 
Mirtazapine  
Sufentanil 
Atorvastatin 
Dofetilide (minor) 
Montelukast 
Tacrolimus 
Benzphetamine 
Dolasteron 
Navelbine 
Tamoxifen 
Bepridil 
Donepezil 
Nefazodone 
Temazepam 
Bexarotene 
Doxorubicin 
Nelfinavir 
Teniposide 
Bromazepam 
Doxycycline 
Nevirapine 
Terfenadine 
Bromocriptine 
Dronabinol 
Nicardipine 
Testosterone 
Budesonide 
Enalapril 
Nifedipine 
Tetrahydrocannabinol 
Bupropion (weak) 
Erythromycin 
Niludipine 
Theophylline 
Buspirone 
Estradiol 
Nimodipine 
Tiagabine 
Busulfan 
Ethenyl estradiol 
Nisoldipine 
Tolterodine 
Caffeine 
Ethosuximide 
Nitrendipine 
Toremifene 
Cannabinoids 
Etoposide 
Omeprazole 
(sulfonation) 
Trazodone 
Carbamazepine 
Exemestane 
Ondasetron 
Tertinoin 
Cerivastatin 
Felodipine 
Oral contraceptives 
Triazolam 
Cevimeline  
Fentanyl 
Orphenadrine 
Troglitazone 
Chlorpromazine 
Fexofenadine 
Paclitaxel 
Troleandomycin 
Cimetidine 
Finasteride 
Pantoprazole 
Venlafaxine 
Cisapride 
Fluoxetine 
Pimozide 
Verapamil 
Citalopram 
Flutamide 
Pioglitazone 
Vinblastine 
Clarithromycin 
Glyburide 
Pravastatin 
Vincristine 
Clindamycin 
Granisetron 
Prednisone 
Warfarin 
Clomipramine 
Halofantrine 
Progesterone 
Yohimbine 
Clonazepam 
Hydrocortisone 
Proguanil 
Zaleplon (minor) 
Clozapine 
Hydroxyarginine 
Propafenone 
Zatoestron 
Cocaine 
Ifosfamide 
Quercetin 
Zileuton 
Codeine 
Imipramine 
Quetiapine 
Ziprasidone 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
100 
Cortisol 
Indinavir 
Quinidine 
Zolpidem\ 
Cortisone 
Isradipine 
Quinine 
Zonisamide 
Cyclobenzaprine  
Itraconazole 
Repaglinide 
 
Cyclophosphamide 
Ketoconazole 
Retinoic acid 
 
Cyclosporine 
Lansoprazole (minor) 
Rifampin 
 
Inducers 
Carbamazepine 
Nelfinavir 
Primidone 
Sulfadimidine 
Dexamethasone 
Nevirapine 
Progesterone 
Sulfinpyrazone 
Ethosuximide 
Oxcarbazepine 
Rifabutin 
Troglitazone 
Glucocorticoids 
Phenobarbital 
Rifampin 
 
Griseofulvin 
Phenylbutazone 
Rofecoxib (minor) 
 
Nafcillin 
Phenytoin 
St. John’s Wort 
 
Inhibitors 
Amiodarone 
Disulfiram 
Mibefradil 
Ranitidine 
Anastrozole 
Entacapone 
Miconazole (moderate) 
Ritonavir** 
Azithromycin 
Erythromycin 
Nefazodone 
Saquinavir 
Cannabinoids 
Ethenyl estradiol 
Nelfinavir 
Sertindole 
Cimetidine 
Fluconazole 
(weak) 
Nevirapine 
Sertraline 
Clarithromycin 
Fluoxetine 
Norfloxacin 
Troglitazone 
Clotrimazole 
Fluvoxamine 
Norfluoxetine 
Troleandomycin 
Cyclosporine 
Gestodene 
Omeprazole (weak) 
Valproic acid 
(weak) 
Danazole 
Grapefruit Juice 
Oxiconazole 
Verapamil 
Delavirdine 
Indinavir 
Paroxetine (weak) 
Zarfirlukast 
Dexamethasone 
Isoniazid 
Propoxyphene 
Zileuton 
Dimethyldithiocarbamate 
Itraconazole** 
Quinidine 
 
Diltiazem 
Ketoconazole** 
Quinine 
 
Dirithromycin 
Metronidazole 
Quinupristin and 
dalfopristin 
 
** Contraindications  
From Drug Information Handbook 8th Edition 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
101 
20. 
APPENDIX E: FACT-O QUALITY OF LIFE TOOL 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
102 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
103 
 
 
 
 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
104 
 
21. 
APPENDIX F: BLOOD PRESSURE CHECK FORM 
 
Blood Pressure Check 
Cycle 1 
 
Week 1: 
 
Name of Health Care Facility:  
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 
 
Week 2: 
 
Name of Health Care Facility___________________________ 
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 
Week 3: 
 
Name of Health Care Facility___________________________ 
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 
 
Week 4: 
 
Name of Health Care Facility___________________________ 
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 


 
 
 
Abbreviated Title: Phase II trial of Sorafenib+Bevacizumab in Ovary 
 
 
Version Date:  10/03/2018 
 
105 
Blood Pressure Check 
Cycle 2 
 
Week 1: 
 
Name of Health Care Facility:  
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 
 
Week 2: 
 
Name of Health Care Facility___________________________ 
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 
Week 3: 
 
Name of Health Care Facility___________________________ 
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 
 
Week 4: 
 
Name of Health Care Facility___________________________ 
 
 
Date ________________ 
 
B/P______________________ 
 
 
 
Done by ___________________________________________ 
 
 
 
 

ICF_001.pdf: 
 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
 
National Cancer Institute 
 
 
STUDY NUMBER: 
07-C-0058            PRINCIPAL INVESTIGATOR: Christina M. Annunziata, MD, PhD  
 
STUDY TITLE: 
A Phase II Study of Sorafenib and Bevacizumab in Epithelial Ovarian, Fallopian, and 
Peritoneal Cancer 
 
 
Continuing Review Approved by the IRB on 02/10/14 
Amendment Approved by the IRB on 05/20/2014 (J)  
 
 
Date Posted to Web: 06/06/14 
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. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.   Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
You are being asked to take part in this study because you have a cancer that has not responded 
to standard treatments or for which no standard treatments have been identified.    


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 2 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Why is this study being done? 
The purpose of this study is to determine the effectiveness of the combination of two anti-cancer 
drugs, sorafenib and bevacizumab, and to find out what effects, good and/or bad, these drugs 
may have on you and your cancer.  This study will also look at how the drugs may affect the 
cancer by measuring amounts of different proteins in small biopsy samples of your tumor taken 
before you start treatment and after different times of treatment.  Optional biopsies will be 
performed 6 weeks after treatment begins and at the completion of therapy.  
 
Using these drugs together is experimental. These drugs work by targeting the blood vessels that 
allow tumors to grow.  Our theory is that by combining two drugs that target blood vessels, we 
can more effectively block the formation of blood vessels that feed tumors.  On the phase 1 trial 
of this combination that is also being performed by our group, 6 of 14 ovarian cancer patients 
have had documented tumor shrinkage. Both of these drugs have been approved by the FDA for 
use in other cancers but have not been approved for ovarian cancer.  However, we have been 
studying the combination and believe it to be of potential value in ovarian cancer. 
 
How many people will take part in the study? 
Between 74-78 people will take part in this study.  The study will be divided into 2 groups.  One 
group will enroll patients who have received bevacizumab in the past and the other group will 
enroll patients who have not had treatment with bevacizumab.  Patients in both groups will 
receive the same treatment.  There will be no difference in dose or scheduling of the drugs 
between groups. 
 
What will happen if I take part in this research study?   
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
 
Blood tests: measurements of how your liver, kidneys and blood clotting work, measurement of 
your white blood cells, red blood cells and platelets, your blood sugar and blood electrolytes.  
Since ovarian, fallopian, and peritoneal cancer may make the protein CA-125, we ask that you 
have your CA-125 level checked as well.  These will be done during your first visit to NIH as an 
outpatient. 
• Urinalysis. 
• CT Scan (or similar imaging test) to assess where your cancer may be 
• Tissue block (pathology slides from biopsy or surgery) of the cancer to submit to the 
study doctor or a member of the research team 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 3 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
If the initial exams, tests, and procedures show that you are eligible to be in the study, you will 
have the following tests and procedures performed during your participation.  They are part of 
regular cancer care. 
 
• Clinic visit to ask how you are feeling and to evaluate you with a physical examination 
every 4 weeks while you remain on the study. 
• Blood tests: measurements of how your liver, kidneys and blood clotting work, 
measurement of your white blood cells, red blood cells and platelets, your blood sugar 
and blood electrolytes will be done every 2 weeks for one month then every 4 weeks.  A 
CA-125 measurement will also be done every 4 weeks.   
• Urinalysis.  This will be done every 2 weeks prior to receiving the bevacizumab infusion. 
 
You will need these tests and procedures that are part of regular cancer care.   They may be done 
more often because you are in this study.   
 
• Computed tomography (CT) or other imaging test such as ultrasound or MRI that can 
detect your tumor will be done every 8 weeks while you are on the study.  This is done so 
that any benefit of the study can be determined and if your cancer is not responding to the 
study drugs, the study team can advise you of this and help you to move to a different 
treatment program (discussed further below). 
• Twice weekly blood pressure measurements (for the first 8 weeks). You will be given a 
blood pressure cuff to use at home and we will ask you to record your blood pressure 
measurements and report them to us. 
 
You will need these exams and procedures that are either being tested in this study or being done 
to see how the study is affecting your body. 
 
• Research blood samples (5 tubes or about 8 teaspoons) also will be taken at every 4 week 
clinic visit. Note: Research blood samples will no longer be collected each cycle after 
04/11/14. 
• PET (Positron Emission Tomography).  This will be done before you start study drugs, 
on the third day after you start taking the medications, and 6 weeks into treatment.  A 
PET scan is used by doctors to look at how different parts of the body utilize a sugar-
nutrient called glucose.  The test works by injecting into your body a small amount of 
sugar labeled with a tiny amount of radioactivity that the PET imaging machine can 
detect. You are put in a chamber that looks like a tube while the machine performs the 
test. Cancer cells tend to consume sugar nutrients faster than normal cells and may pick 
up more signal than the normal cells. This test is being done to determine if there is any 
change in your tumor’s activity level with the addition of these two drugs.   


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 4 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Dynamic contrast-enhanced MRI or DCE-MRI. This will be done before you start study 
drugs, on the third day after you start taking the medications, and 6 weeks into treatment.  
This is a test that does not use any radiation. Instead, it uses magnetic energy to 
examining the inside of your body with a special non-radioactive dye, so that doctors can 
measure blood flow into the tumor. You are put in a chamber that looks like a tube while 
the machine performs the test. This test is being done to determine if there is any change 
in your tumor’s blood flow with the addition of these two drugs. 
• Biopsy of your tumor: This will be done before you start a study drug. In addition, there 
are 2 optional tumor biopsies 1) at 6 weeks into treatment and 2) if you are taken off this 
study because your tumor progresses or because of side effects of the treatment, These 
biopsies are not required but may help us understand these drugs work on cancer cells.  
The biopsy will be performed by an experienced, highly skilled interventional radiologist.  
The procedure is performed with a small needle directed by either ultrasound or CT scan 
This biopsy will be used for research purposes, not for diagnostic purposes.  You will not 
be allowed to undergo such a procedure if there is significant risk of harm from this 
procedure. 
• Quality of Life questionnaire:  As part of this study, you will answer a questionnaire that 
asks you questions about your symptoms and how you are feeling about the study and 
your life.  The questionnaire will be given to you just before you start the treatment and 
then every 8 weeks and when you come off study. 
 
The tumor biopsy, capture of a small piece of your cancer, is a necessary part of this trial and is 
done for research purposes. No formal pathology review of these biopsy specimens will be done 
routinely.  Trained personnel will perform the biopsy keeping your safety in mind.  All efforts 
will be made to minimize risks and discomfort involved with these biopsies.  If any complication 
occurs, we will provide the medical care as appropriate.  If, upon attempting the first biopsy, no 
tissue can be obtained or it has caused you harm, subsequent biopsies will not be done. If for any 
reason the biopsies cannot be done safely, you may still receive the study drugs.  
 
Biopsies will be done either using a small bore needle under CT guidance (looking at the needle 
location by CT scan). The CT scan helps the specialized radiologist know that the needle has 
been placed into the tumor mass.  The needle biopsy is done by inserting a needle through the 
skin into the tumor mass. Typical risks of both procedures include, but are not limited to 
bleeding, infection, pain, and scarring.  You will be counseled in more detail about the procedure 
and you will be asked to sign a separate consent that will describe the procedure and its 
associated risks at that time. Your safety is the most important thing at all times. 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 5 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
When I am finished taking sorafenib and bevacizumab? 
Your participation in this study will continue until either you or your study doctor decides that 
this medication is not beneficial to you or you wish you stop.  Your participation is voluntary; so 
you may stop taking sorafenib and bevacizumab at any time.   We ask that you speak to your 
study doctor if you are thinking about this and before you stop taking the medications.  Your 
study doctor will be monitoring you and your cancer while you are taking sorafenib and 
bevacizumab.  If your cancer is worsening, then the study doctor will suggest that you stop the 
experimental therapy and s/he will discuss other options with you.  Also, if you are experiencing 
effects from the therapy which are dangerous to your health or too difficult for you to tolerate, 
you and the study team may decide that you should stop the study drugs.  At the end of the study, 
no additional testing will be required unless you experience side effects from the study 
medications that we need to follow.  We will ask you to consider an optional biopsy that would 
be performed the same way as the previous biopsies, again performed for only research purposes.  
This biopsy is not a required procedure and you are free to choose not to have it performed. 
 
If you are taken off of sorafenib for any reason including toxicity of the drug, you may continue 
on study with treatment with bevacizumab alone, if there is not evidence to suggest that your 
tumor is resistant to bevacizumab.  You, your home physician, and your study doctor will discuss 
the option of continuing on bevacizumab alone versus other treatment options. 
 
You will be followed 4 weeks after stopping treatment with a phone call.  If additional lab tests 
need to be done, you may be asked to return to the clinic for a follow-up visit. 
 
Study Chart 
The treatment is given over 28-day periods of time called cycles.  The 28 day treatment cycle 
will be repeated as long as you are tolerating the medication and your cancer is either steady or 
getting better.  Each cycle is numbered in consecutive order.  The chart below shows what will 
happen to you during Cycles 1 and 2 and future cycles.  The left-hand column shows the day in 
the cycle and the right-hand column tells you what will happen on that day.  This schedule 
indicates what will happen to you after you sign consent and start the study.  You will be asked 
to record your usage of the study medication in a study diary.  This must be done each day for 
each dose.  You will be provided with a new diary every month. 
 
Sorafenib is a pill that is taken by mouth twice daily for 5 days out of every week; we will tell 
you which five days to take the pills.  Sorafenib should be taken on an empty stomach with 250 
cc of water (large glass).  Bevacizumab is injected into your veins once every two weeks.  
Initially it will be given to you over 90 minutes, and if you have no side effects from the 
infusion, we will gradually shorten the administration time to 30 minutes. 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 6 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Cycle 1 and 2 
Day 
 
What to do and what will happen to you 
Before 
starting 
study 
Sign informed consent. 
Fill out Quality of Life questionnaire 
Get routine blood tests. 
Check-in to the outpatient clinic. 
Have a history of how you feel taken and undergo a physical examination by a Health Care 
Provider 
PET, DCE-MRI, and tumor biopsy will be done after signing informed consent but before 
starting the study drugs. 
Cycle 1 
Day 1 
1)Begin taking sorafenib by mouth twice a day for 5 out of 7 days a week (Monday-
Friday). You will continue to take sorafenib for 5 out of 7 days for the next 4 weeks, which 
will complete cycle 1 2)Blood draws for research will be obtained on days 1 and 3 
3)Receive bevacizumab by vein on the same day sorafenib starts.  This will occur every 2 
weeks. 
4) Begin recording pill consumption daily and twice weekly blood pressure.  Record this is 
in your study diary. 
Cycle 1 
Day 3/4 
PET and DCE-MRI will be done. 
Take your sorafenib on these tests days. 
Cycle 1 
Day 15 
Routine blood work and urine testing (for protein) at the day hospital. 
If your blood and urine tests indicate everything is safe, you will receive your dose of 
bevacizumab by vein.   
Cycle 2  
Day 1 
Return to the outpatient clinic to see your Health Care Provider. Have a history of how you 
feel taken and undergo a physical examination. 
Routine blood work and urine testing for protein. 
Research bloods will be collected. 
If your exam and blood and urine tests indicate everything is safe within limits, you will 
receive your dose of bevacizumab by vein. 
Continue sorafenib twice daily 5 out of 7 days for the next 4 weeks. 
Cycle 2  
Day 15/16 
Routine blood work and urine testing for protein 
Research bloods will be collected. 
PET, DCE-MRI, and tumor biopsy (optional) will be done. 
Take your sorafenib on these days. 
If your exam and blood and urine tests indicate everything is safe within limits, you will 
receive your dose of bevacizumab by vein 
All other 
Cycles 
Day 1  
Return to the outpatient clinic to see your Health Care Provider. Have a history of how you 
feel taken and undergo a physical examination. 
Routine blood work and urine testing for protein. 
Start next cycle of sorafenib by mouth twice a day days 1-5 of 7.   


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 7 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
If your exam and blood and urine tests indicate everything is safe within limits, you will 
receive your next dose of bevacizumab by vein in the day hospital. 
All cycles 
Day 15 
Provide a urine sample for testing and have your blood pressure checked. 
Receive bevacizumab by vein in the day hospital. 
Every 
other 
cycle 
You will have CT scan or other imaging every other cycle (every 8 weeks) to determine 
how your tumor is being affected by the therapy.  This result will be used to guide 
continuation of therapy. 
Fill out Quality of Life questionnaire 
 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study team if you are thinking about stopping 
or decide to stop.  They will help you to stop safely and determine if a final follow-up visit is 
needed.  
 
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 Bayer Health Care 
Corporation and Onyx 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. 
 
The study team may stop you from taking part in this study at any time if they believe it is in 
your best interest, if you do not follow the study rules, or if the study is stopped. 
 
What side effects or risks can I expect from being in the study? 
 
 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s 
office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
 
The bevacizumab and sorafenib used in this study may affect how different parts of your body 
work such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood 
and will let you know if changes occur that may affect your health. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 8 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
There is also a risk that you could have side effects from the study drugs/study approach. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
 
Risks and side effects related to sorafenib include those which are: 
 
Likely: 
• Belly pain 
• Diarrhea 
• Nausea or the urge to vomit 
• Fatigue or tiredness 
• Increased blood level of a liver enzyme (ALT/SGPT) 
• Increased blood level of a liver or bone enzyme (alkaline phosphatase) 
• Increased blood level of a liver enzyme (AST/SGOT) 
• Increased blood level of a liver pigment (bilirubin) often a sign of liver problems 
• Increased blood level of creatinine (a substance normally eliminated by the kidneys into 
the urine) 
• Increased INR (measure of the ability of the blood to clot properly) which increases the 
risk of bleeding 
• Increased blood level of fat-digesting enzyme (lipase) 
• Decreased number of a type of white blood cell (lymphocyte) 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 9 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
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NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Decreased number of a type of blood cell that helps to clot blood (platelet) 
• Increased blood level of a digestive enzyme (amylase) 
• Weight loss 
• Decrease in the total number of white blood cells (leukocytes) 
• Loss of appetite 
• Increased blood sugar level 
• Decreased levels of a blood protein called albumin 
• Decreased blood level of calcium 
• Decreased blood level of sodium 
• Decreased blood level of phosphate 
• Hair loss 
• Swelling and redness of the skin on the palms of the hands and soles of the feet 
• Skin rash with the presence of macules (flat discolored area) and papules (raised bump) 
 
Less Likely: 
• Lack of enough red blood cells (anemia) 
• Fever associated with dangerously low levels of a type of white blood cell (neutrophils) 
• Irritation or sores in the lining of the anus 
• Fluid collection in the abdomen 
• Constipation 
• Bleeding in some organ(s) of the digestive tract 
• Irritation or sores in the lining of the mouth 
• Irritation or sores in the lining of the rectum 
• Irritation or sores in the lining of the small bowel 
• Vomiting 
• Swelling of the arms and/or legs 
• Fever 
• Chest pain not heart-related 
• Infection 
• Test that shows a problem in blood clotting 
• Increased blood level of cholesterol 
• Increased blood level of a liver enzyme (GGT) 
• Decreased blood level of carbon dioxide 
• Decreased number of a type of white blood cell (neutrophil/granulocyte) 
• Increased blood level of calcium 
• Increased blood level of potassium 
• Increased blood level of sodium 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 10 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Increased blood level of uric acid, a waste material from food digestion 
• Decreased blood sugar level 
• Decreased blood level of potassium  
• Joint pain 
• Back pain 
• Bone pain 
• Muscle spasms 
• Muscle pain 
• Leg and/or arm pain 
• Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) 
• Headache or head pain 
• Inflammation (swelling and redness) or degeneration of the peripheral nerves (those 
nerves outside of brain and spinal cord) causing numbness, tingling, burning 
• Difficulty sleeping or falling asleep 
• Sudden decrease of kidney function  
• Blood in the urine 
• Bleeding in the kidney 
• Presence of blood in a fallopian tube (tube between ovary to uterus [womb]) 
• Bleeding in the ovary 
• Bleeding in the prostate 
• Bleeding in the spermatic cord (a structure resembling a cord that suspends the testis 
within the scrotum and contains the vas deferens [the tube that carries sperm] and other 
vessels and nerves) 
• Bleeding in the testis 
• Bleeding in the uterus (womb) 
• Bleeding in the vagina 
• Bleeding from the lungs  
• Cough 
• Shortness of breath 
• Nose bleed 
• Irritation or sores in the lining of the voice box 
• Irritation or sores in the lining of the throat 
• Irritation or sores in the lining of the windpipe 
• Voice change 
• Dry skin 
• Itching 
• High blood pressure  


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 11 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Formation of a blood clot that plugs the blood vessel; blood clots may break loose and 
travel to another place, such as the lung 
Rare but Serious: 
• Collection of signs and symptoms that indicate sudden heart disease in which the heart 
does not get enough oxygen. Sudden symptoms such as chest pain, shortness of breath, or 
fainting could indicate heart disease and should be reported right away.  Signs such as 
abnormal EKG and blood tests can confirm damage to the heart.  
• Decrease in heart's ability to pump blood during the "active" phase of the heartbeat 
(systole) 
• Heart attack caused by a blockage or decreased blood supply to the heart 
• Gastrointestinal perforation : A tear or hole in the stomach or gut that can lead to serious 
complications and may require surgery to repair 
• Serious, life-threatening allergic reaction requiring immediate medical treatment by your 
doctor.  The reaction may include extremely low blood pressure, swelling of the throat, 
difficulty breathing, and loss of consciousness.  
• Bleeding in the brain 
• Abnormal changes in the brain that can cause a collection of symptoms including 
headache, confusion, seizures, and vision loss associated with MRI imaging findings 
(RPLS) 
• Severe reaction of the skin and gut lining that may include rash and shedding or death of 
tissue 
• Potentially life-threatening condition affecting less than 10% of the skin in which cell 
death causes the epidermis (outer layer) to separate from the dermis (middle layer) 
 
Risks and side effects related to bevacizumab include those which are: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab, more than 20 and up to 100 may have: 
• High blood pressure which may cause headache or blurred vision  
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab, from 4 to 20 may have: 
• Anemia which may require blood transfusion 
• Low white cell count that may increase the risk of infection 
• Infection, including collection of pus in the belly or rectum 
• Abnormal heartbeat which may cause palpitations or fainting 
• Pain in the belly, rectum, chest, joints, muscles, or tumor 
• Low appetite, constipation, diarrhea, heartburn, nausea, vomiting, or dehydration 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 12 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving bevacizumab, from 4 to 20 may have: 
• Internal bleeding which may cause black tarry stool, blood in vomit, coughing up of 
blood, or blood in urine  
• Bleeding from other sites, including the vagina or nose 
• Blockage of internal organs which may cause vomiting or inability to pass stool 
• Sores in mouth 
• Allergic reaction during or after infusion of bevacizumab which may cause fever, 
chills, rash, itching, hives, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Delay in healing of wounds or spontaneous opening of wounds 
• Weight loss, tiredness, or dizziness 
• Damage to the jawbone which may cause loss of teeth 
• Headache 
• Numbness, tingling, or pain in the fingers or toes 
• Hoarseness, stuffy nose, or cough 
• Blood clot in limbs or lungs which may cause swelling, pain, or shortness of breath 
• Leakage of protein in the urine, which can rarely lead to damage to the kidney 
 
RARE, AND SERIOUS 
In 100 people receiving bevacizumab, 3 or fewer may have: 
• Clots in the arteries, causing stroke (which may cause paralysis or weakness) or heart 
attack (which may cause chest pain or shortness of breath). This risk is significantly 
increased in patients who are elderly or with history of diabetes 
• Heart failure which may cause shortness of breath, swelling of ankles, or tiredness 
• Bowel perforation (a tear in the bowel) that can cause pain or bleeding and require 
surgery to repair 
• A tear or hole (fistula) in internal organs such as the nose, throat, lungs, esophagus, 
rectum, or vagina.  These conditions may cause serious infections or bleeding and 
require surgery to repair 
• Flesh-eating bacteria syndrome, an infection in the deep layers of skin 
• Bleeding in the tumor, brain, belly, or lungs which may cause confusion, blood in 
stool or coughing up blood 
• Brain damage which may cause headache, seizure, blindness (also known as 
Reversible Posterior Leukoencephalopathy Syndrome) 
• Kidney damage which may require dialysis 
 
Additional Notes on Possible Side Effects for Bevacizumab: 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 13 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Risk in children or adolescents: abnormal bone changes which may interfere with growth. 
• Risk in pre-menopausal women: more likely to develop menopause when taking 
bevacizumab. 
 
 
Bevacizumab is the common name for the commercial drug Avastin.  The bevacizumab used in 
this trial, however, is for use in research studies only and may be made at locations 
different from those where Avastin is made.   Although some differences may exist, 
bevacizumab for research use and the commercial drug, Avastin, are manufactured by a similar 
process, meet similar standards for final product testing, and are expected to be very similar in 
safety and effectiveness. 
 
For more information about risks and side effects, ask your study team. 
 
Other risks associated with this study include risks related to radiation exposure associated with 
the tests you will receive.  This research study involves exposure to radiation from PET scans 
and potentially from CT scans used to guide biopsies for your safety.  Please note that this 
radiation exposure is not necessary for your medical care and is for research purposes only.   The 
total amount of radiation you will receive in this study is from 3 injections (scans or repetitions) 
of 15 mCi of F-18 FDG (a radioactively labeled form of sugar) in the PET scans and from CT 
directed biopsies (when needed).  The NIH Radiation Safety Committee has reviewed the use of 
radiation in this research study and has approved this use as involving slightly more than 
minimal risk and necessary to obtain the research information desired. 
 
Using the standard way of describing radiation dose, from participating in this study, you will 
receive a total of 14.6 rem to your bladder wall, 10.1 rem to your heart wall, and 7.4 rem to your 
spleen.  All other organs will receive smaller amounts of radiation. 
 
Although each organ will receive a different dose, the amount of radiation exposure you will 
receive from these procedures is equal to a uniform whole-body exposure of 3.7 rem.  This 
calculated value is known as the “effective dose” and is used to relate the dose received by each 
organ to a single value.  The amount of radiation received in this study is within the dose 
guideline established by the NIH Radiation Safety Committee for research subjects.  The 
guideline is an effective dose of 5 rem (or 5,000 mrem) received per year2.   
 
For comparison, the average person in the United States receives a radiation exposure of 0.3 rem 
(or 300 mrem) per year from natural background sources, such as from the sun, outer space, and 
from radioactive materials that are found naturally in the earth’s air and soil.  The dose that you 
will receive from this research study is about the same amount you would normally receive in 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 14 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
12.3 years from these natural sources.   If you would like more information about radiation and 
examples of exposure levels from other sources, please ask the investigator for a copy of the 
pamphlet called, An Introduction to Radiation for NIH Research Subjects. 
 
The effects of radiation exposure on humans have been studied for over 60 years.  In fact, these 
studies are the most extensive ever done of any potentially harmful agent that could affect 
humans.  In all these studies, no harmful effect to humans has been observed from the levels of 
radiation you will receive by taking part in this research study.   However, scientists disagree on 
whether radiation doses at these levels are harmful.  Even though no effects have been observed, 
some scientists believe that radiation can be harmful at any dose - even low doses such as those 
received during this research.    
 
One possible effect that could occur at these doses is a slight increase in the risk of cancer.   
Please be aware that the natural chance of a person getting a fatal cancer during his/her lifetime 
is about 1 out of 4 (or 25 percent).  The increase in the chance of getting a fatal cancer, as a result 
of the radiation exposure received from this research study, is 0.15%.  Therefore, the total risk of 
fatal cancer may be estimated to increase from 25 percent to 25.15%.  This change in risk is 
small and cannot be measured directly.  Compared with other everyday risks, such as flying in an 
airplane or driving a car, this increase is considered slight. 
Please tell your doctor if you have taken part in other research studies or received any medical 
care at the NIH or other places/hospitals that used radiation.  This way we can make sure that 
you will not receive too much radiation.  Consider x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
 
If you are pregnant or breast feeding, you may not participate in this research study.  It is best to 
avoid radiation exposure to unborn or nursing children since they are more sensitive to radiation 
than adults.  
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  Bevacizumab by itself has 
been shown to be useful in the treatment of certain cancers such as colorectal cancer.  Sorafenib 
by itself has been shown to be useful in the treatment of certain cancers such as kidney cancer.  
While doctors hope sorafenib and bevacizumab will be useful against your cancer, there is no 
proof of this yet.  We do know that the information from this study will help doctors learn more 
about sorafenib and bevacizumab as a treatment for cancer.  This information will help future 
cancer patients. 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 15 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
 
• Getting standard treatment or care for your cancer in the community 
• Taking part in another study 
• Both drugs are commercially available, although not approved for your condition, and 
you can obtain them if your doctor agrees to prescribe them 
• Getting no treatment 
• Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer. It does not treat the 
cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible.  
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people. 
 
• Qualified representatives from Bayer Health Care Corporation and Onyx Pharmaceuticals 
who produce sorafenib and are the pharmaceutical sponsors of this trial. Genentech 
Pharmaceuticals who produce bevacizumab. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. 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. 
 
What are the costs of taking part in this study? 
While you are on study at the National Cancer Institute, we will pay for the medications and 
treatments associated with the study.  We cannot, however, assume the cost of your overall 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 16 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
medical care.  Any studies done outside of the NCI may require you or your insurance company 
to cover the cost of the service. 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .    
You can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web 
site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study team Nicole Houston, RN (301) 443-6431, and/or 
Principal Investigator Dr. Christina Annunziata (301) 402-7189 if you feel that you have been 
injured because of taking part in this study.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution if you are eligible and choose to participate in another trial. 
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study team, Nicole Houston, RN (301) 443-6431, and/or Principal Investigator Dr. 
Christina Annunziata (301) 402-7189.  
 
For questions about your rights while taking part in this study, call the Clinical Center Patient 
Representative at (301) 496-2626. 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 17 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Please note:  This section of the informed consent form is about additional research studies that 
are being done with people who are taking part in the main study.   You may take part in these 
additional studies if you want to.  You can still be a part of the main study even if you say ‘no’ to 
taking part in any of these additional studies. 
 
You can say “yes” or “no” to each of the following studies.  Please mark your choice for each 
study.   
 
Optional Studies 
We would like to keep some of the specimens and data that are collected for future research.  
These specimens and data will be identified by a number and not your name.  The use of your 
specimens and data will be 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 decide now that your specimens and data can be kept for research, you can change your 
mind at any time.  Just contact us and let us know that you do not want us to use your specimens 
and/or data.  Then any specimens that remain will be destroyed and your data will not be used 
for future research. 
 
Benefits  
The benefits of research using tissue include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them.  
 
Risks  
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
 
Making Your Choice  
 
Please read each sentence below and think about your choice. After reading each sentence, circle 
and initial the answer that is right for you.  No matter what you decide to do, it will not affect 
your care. 
 
 
1. My specimens and data may be kept for use in research to learn about, prevent, or treat cancer.  
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page 18 of 21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Yes 
No 
Initials  __________ 
2. My specimens and data may be kept for use in research to learn about, prevent or treat other 
health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
3. Someone may contact me in the future to ask permission to use my specimen(s) and/or data in 
new research not included in this consent.  
 
Yes 
No 
Initials  __________  
4. I agree to have the two optional tumor biopsies for research test at week 6 and at the end of the 
study as specified in this study. I may decide at any time to change my mind about the biopsies 
even if I agree to them at this time. 
 
Yes 
No 
Initials  __________ 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
You will get a copy of this form.    If you want more information about this study, ask your study 
doctor. 
 
 
 
Yes 
No 
Initials  __________ 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
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: 
07-C-0058 
CONTINUATION:  page  19  of  21  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Conflict of Interest 
 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  The following link contains details on this process 
http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf.  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 
 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
07-C-0058 
CONTINUATION:  page  20  of  21 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 for 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 your study 
team, Nicole Houston, RN (301) 443-6431 and/or Principal Investigator, Dr. Christina 
Annunziata (301) 402-7189.  If you have any questions about the use of your specimens or data 
for future research studies, please contact the Office of the Clinical Director, Telephone:  (301) 
496-4251. 
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5.  Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 
 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
07-C-0058 
CONTINUATION:  page  21  of  21 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 FEBRUARY 10, 2014 THROUGH FEBRUARY 9, 2015.  
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name