Conditions: Pheochromocytoma Paraganglioma
Keywords: Mutation in SDHB gene Mutation in SDHV gene Mutation in VHL gene Pharmacogenomics analyses Germline DNA examination
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
Background:

* Most treatments for malignant pheochromocytomas/paragangliomas (PHEO/PGL) are palliative and multidisciplinary. Chemotherapy using the combination of cyclophosphamide, vincristine, and dacarbazine has been successfully utilized in the management of rapidly progressive metastatic PHEO, with more than 50% complete or partial tumor response and more than 70% complete or partial biochemical response.
* Vascular endothelial growth factor (VEGF) expression and evidence of angiogenesis has been found in many PHEO/PGL, so it is plausible that interfering with VEGF signaling may result in anti-tumor activity in patients with PHEO/PGL.
* Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the anti-tumor activity of axitinib may result from its anti-angiogenic activity and that this is reversible when treatment is discontinued.
* Given the known clinical safety and efficacy of axitinib, an assessment of its activity in PHEO/PGL and its impact on the VEGF pathway in PHEO/PGL could provide valuable information.

Objectives:

* Determine the response rate of metastatic PHEO/PGL to axitinib (AG-013736).
* Determine the progression-free survival of metastatic PHEO/PGL treated with axitinib (AG-013736).
* Explore the relationship of potential biological markers of axitinib activity with clinical outcomes.
* Perform pharmacogenomics analyses of drug metabolism and transport proteins through germline deoxyribonucleic acid (DNA) examination.

Eligibility:

* Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of Pathology, National Cancer Institute (NCI)
* Biochemical evidence of PHEO/PGL
* Imaging confirmation of metastatic, locally advanced or unresectable disease.
* Measurable disease at presentation
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor

Design:

* Phase II, open label, non-randomized trial
* Patients with metastatic pheochromocytoma/paraganglioma will receive axitinib (AG-013736 twice a day (BID)) in eight-week cycles
* Patients will be evaluated for response every eight weeks using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
* Tumor biopsies are not mandatory but every attempt will be made to obtain these from patients prior to starting axitinib and again 20 - 30 days after treatment has begun.
* Approximately 12 to 37 patients will be needed to achieve the objectives of the trial

Detailed description:
Background:

* Most treatments for malignant pheochromocytomas/paragangliomas (PHEO/PGL) are palliative and multidisciplinary. Chemotherapy using the combination of cyclophosphamide, vincristine, and dacarbazine has been successfully utilized in the management of rapidly progressive metastatic PHEO, with more than 50% complete or partial tumor response and more than 70% complete or partial biochemical response.
* Vascular endothelial growth factor (VEGF) expression and evidence of angiogenesis has been found in many PHEO/PGL, so it is plausible that interfering with VEGF signaling may result in anti-tumor activity in patients with PHEO/PGL.
* Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the anti-tumor activity of axitinib may result from its anti-angiogenic activity and that this is reversible when treatment is discontinued.
* Given the known clinical safety and efficacy of axitinib, an assessment of its activity in PHEO/PGL and its impact on the VEGF pathway in PHEO/PGL could provide valuable information.

Objectives:

* Determine the response rate of metastatic PHEO/PGL to axitinib (AG-013736).
* Determine the progression-free survival of metastatic PHEO/PGL treated with axitinib (AG-013736).
* Explore the relationship of potential biological markers of axitinib activity with clinical outcomes.
* Perform pharmacogenomics analyses of drug metabolism and transport proteins through germline deoxyribonucleic acid (DNA) examination.

Eligibility:

* Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of Pathology, National Cancer Institute (NCI)
* Biochemical evidence of PHEO/PGL
* Imaging confirmation of metastatic, locally advanced or unresectable disease.
* Measurable disease at presentation
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor

Design:

* Phase II, open label, non-randomized trial
* Patients with metastatic pheochromocytoma/paraganglioma will receive axitinib (AG-013736 twice a day (BID)) in eight-week cycles
* Patients will be evaluated for response every twelve weeks (+/- 1 week) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
* Approximately 12 to 37 patients will be needed to achieve the objectives of the trial

Arms:
arm 1: Axitinib 5 mg twice a day on a 28-day cycle

Interventions: intervention 1: Axitinib (AG-013736)
Intervention descriptions: intervention 1: 5 mg twice a day on a 28-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
1
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Abbreviated Title: Phase II Axitinib in PHEO/PGL
CC Protocol #: 14-C-0001 G
Version Date: March 26, 2018
NCT Number: NCT01967576
Title: Phase II Study of Axitinib (AG-013736) with Evaluation of the VEGF-pathway in 
Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
NCI Principal Investigator: 
Andrea Apolo, M.D., GMB, CCR, NCI
Bldg 10, Rm 13N240
Bethesda, MD 20892
Telephone: 301-480-0536
E-mail: apoloab@mail.nih.gov
Investigational Agents: 
Drug Name:
Axitinib (AG-013736)
IND Number:
109,131
Sponsor:
Tito Fojo, M.D., PhD.
Manufacturer:
Pfizer Pharmaceuticals, Inc.
Commercial Agents: none


2
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
PRÉCIS 
Background:
Most treatments for malignant pheochromocytomas/paragangliomas (PHEO/PGL) are 
palliative and multidisciplinary.  Chemotherapy using the combination of 
cyclophosphamide, vincristine, and dacarbazine has been successfully utilized in the 
management of rapidly progressive metastatic PHEO, with more than 50% complete or 
partial tumor response and more than 70% complete or partial biochemical response.  
VEGF expression and evidence of “angiogenesis” has been found in many PHEO/PGL, 
so it is plausible that interfering with VEGF signaling may result in anti-tumor activity in 
patients with PHEO/PGL.
Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial 
growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the anti-tumor 
activity of axitinib may result from its “anti-angiogenic activity” and that this is 
reversible when treatment is discontinued.
Given the known clinical safety and efficacy of axitinib, an assessment of its activity in 
PHEO/PGL and its impact on the VEGF pathway in PHEO/PGL could provide valuable 
information.
Objectives:
Determine the response rate of metastatic PHEO/PGL to axitinib (AG-013736).
Determine the progression-free survival of metastatic PHEO/PGL treated with axitinib 
(AG-013736).
Explore the relationship of potential biological markers of axitinib activity with clinical 
outcomes.
Perform pharmacogenomics analyses of drug metabolism and transport proteins through 
germline DNA examination.
Eligibility:
Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of 
Pathology, NCI
Biochemical evidence of PHEO/PGL
Imaging confirmation of metastatic, locally advanced or unresectable disease.
Measurable disease at presentation
Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor
Design:
Phase II, open label, non-randomized trial
Patients with metastatic pheochromocytoma/paraganglioma will receive axitinib (AG-
013736 BID) in eight-week cycles
Patients will be evaluated for response every twelve weeks (+/- 1 week) using RECIST 
criteria
Approximately 12 to 37 patients will be needed to achieve the objectives of the trial 


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
TABLE OF CONTENTS 
PRÉCIS........................................................................................................................................... 2
Table of Contents............................................................................................................................ 3
1
INTRODUCTION .................................................................................................................. 7
1.1 
Study Objectives .............................................................................................................. 7
1.1.1
Primary Objective..................................................................................................... 7
1.1.2
Secondary Objectives................................................................................................ 7
1.2 
Background and Rationale ............................................................................................... 7
1.2.1 
Pheochromocytoma/Paraganglioma ......................................................................... 7
1.2.2 
The Genetics of Pheochromocytoma/Paraganglioma............................................... 8
1.2.3 
HIF-1a and VEGF Expression in Pheochromocytoma/Paraganglioma.................... 9
1.2.4 
Axitinib (AG-013736) ............................................................................................ 10
1.3 
Rationale......................................................................................................................... 20
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT....................................................... 20
2.1 
Eligibility Criteria .......................................................................................................... 20
2.1.1 
Inclusion Criteria .................................................................................................... 20
2.1.2 
Exclusion Criteria ................................................................................................... 21
2.2 
Screening Evaluation...................................................................................................... 23
2.2.1 
History and Physical Evaluation............................................................................. 23
2.2.2 
Baseline Imaging Studies........................................................................................ 23
2.2.3 
Baseline EKG.......................................................................................................... 23
2.2.4
Baseline Laboratory Evaluation.............................................................................. 23
2.2.5 
Histologic confirmation of pheochromocytoma/paraganglioma when available OR 
review of outside pathology report and Nuclear Medicine imaging to confirm diagnosis... 24
2.3 
Registration Procedures.................................................................................................. 24
2.4 
Treatment Assignment Procedures................................................................................. 24
3
STUDY IMPLEMENTATION ............................................................................................ 24
3.1 
Study Design [Cycle length = 28 days].......................................................................... 24
3.2 
Drug Administration ...................................................................................................... 25
3.2.1 
Axitinib Administration.......................................................................................... 25
3.2.2 
Self-Administered Study Drugs.............................................................................. 25
3.3 
Intrapatient Dose Escalation and Dose Modification for Toxicities.............................. 26


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
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3.3.1
Intra-patient dose escalations.................................................................................. 26
3.3.2
Dose reductions....................................................................................................... 26
3.3.3 
Management of Hypertension:................................................................................ 27
3.3.4 
Management of Proteinuria: ................................................................................... 29
3.4 
Study Calendar............................................................................................................... 30
3.5
Surgical Guidelines ........................................................................................................ 31
3.6
Criteria for Removal from Protocol Therapy and Off Study Criteria............................ 31
3.6.1 
Criteria for removal from protocol therapy: ........................................................... 32
3.6.2 
Off-Treatment Assessment ..................................................................................... 32
3.6.3 
Off-Study Criteria................................................................................................... 32
3.6.4 
Off Protocol Therapy and Off-Study Procedure..................................................... 32
4
CONCOMITANT MEDICATIONS/MEASURES.............................................................. 32
4.1 
Concurrent Therapies..................................................................................................... 32
4.2 
Supportive Care.............................................................................................................. 33
4.2.1 
Hand-foot reaction .................................................................................................. 33
4.2.2 
Nausea/vomiting ..................................................................................................... 33
4.2.3 
Diarrhea................................................................................................................... 33
4.2.4 
Hypothyroidism ...................................................................................................... 34
5
BIOSPECIMEN COLLECTION.......................................................................................... 34
5.1 
Correlative Studies for Research/Pharmacokinetic Studies........................................... 34
5.1.1 
Tissue Analysis for Potential Targets/Pathways Affected by Axitinib .................. 34
5.1.2
Enumeration of Circulating Endothelial Cells (CEC) ............................................ 34
5.2 
Sample Storage, Tracking and Disposition.................................................................... 35
5.2.1 
Samples Managed by Dr. Fojo’s Laboratory.......................................................... 35
5.2.2 
Samples Managed by Dr. Figg’s Laboratory.......................................................... 35
5.2.3 
Protocol Completion/Sample Destruction: ............................................................. 36
6
DATA COLLECTION AND EVALUATION..................................................................... 36
6.1 
Data Collection............................................................................................................... 36
6.1.1 
Exceptions for Data Recording............................................................................... 37
6.2 
DATA SHARING PLANS ............................................................................................ 37
6.2.1 
Human Data Sharing Plan....................................................................................... 37
6.3 
Response Criteria ........................................................................................................... 38


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
6.3.1
Antitumor Effect – Solid Tumors ........................................................................... 38
6.3.2
Definitions............................................................................................................... 38
6.3.3 
Disease Parameters ................................................................................................. 38
6.3.4 
Methods for Evaluation of Measurable Disease..................................................... 39
6.3.5 
Evaluation of Target Lesions.................................................................................. 40
6.3.6
Evaluation of Non-Target Lesions.......................................................................... 41
6.3.7
Evaluation of Biochemical Response ..................................................................... 41
6.3.8 
Evaluation of Best Overall Response ..................................................................... 41
6.3.9 
Duration of Response.............................................................................................. 42
6.3.10
Progression-Free Survival....................................................................................... 43
6.3.11
Response Review.................................................................................................... 43
6.4 
Toxicity Criteria............................................................................................................. 43
7
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
43 
7.1 
Definitions...................................................................................................................... 43
7.1.1 
Adverse Event......................................................................................................... 43
7.1.2 
Suspected adverse reaction ..................................................................................... 43
7.1.3 
Unexpected adverse reaction .................................................................................. 43
7.1.4 
Serious..................................................................................................................... 44
7.1.5 
Serious Adverse Event............................................................................................ 44
7.1.6 
Disability................................................................................................................. 44
7.1.7
Life-threatening adverse drug experience............................................................... 44
7.1.8 
Protocol Deviation (NIH Definition)...................................................................... 44
7.1.9 
Non-compliance (NIH Definition).......................................................................... 44
7.1.10
Unanticipated Problem............................................................................................ 44
7.2 
NCI-IRB and Clinical Director Reporting ..................................................................... 45
7.2.1 
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
45
7.2.2 
NCI-IRB Requirements for PI Reporting at Continuing Review........................... 45
7.2.3 
NCI-IRB Reporting of IND Safety Reports............................................................ 45
7.3 
IND Sponsor Reporting Criteria .................................................................................... 45
7.4 
Data and Safety Monitoring Plan................................................................................... 46
7.4.1 
Principal Investigator/Research Team .................................................................... 46


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
7.4.2
Sponsor Monitoring Plan........................................................................................ 46
8
STATISTICAL CONSIDERATIONS.................................................................................. 47
8.1 
Selection Based on Gender, Ethnic Background, or Race............................................. 47
8.2 
Justification for Exclusions............................................................................................ 47
8.3 
Study Design/Endpoints................................................................................................. 47
8.4
Sample Size/Accrual Rate.............................................................................................. 48
8.5
Analysis of Secondary Endpoints .................................................................................. 48
9
COLLABORATIVE AGREEMENTS................................................................................. 48
9.1 
Agreement Type............................................................................................................. 48
10
HUMAN SUBJECTS PROTECTIONS ............................................................................... 49
10.1 Rationale For Subject Selection..................................................................................... 49
10.2 Participation of Children................................................................................................ 49
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT.......................... 49
10.4 Evaluation of Benefits and Risks/Discomforts .............................................................. 49
10.5 Risks/Benefits Analysis.................................................................................................. 50
10.6 Consent Process and Documentation............................................................................. 50
10.6.1
Reconsent via the telephone.................................................................................... 50
10.6.2
Informed consent of non-English speaking subjects .............................................. 50
11
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION.............. 51
11.1 Axitinib 109,131............................................................................................................. 51
11.1.1
Source ..................................................................................................................... 51
11.1.2
Toxicity................................................................................................................... 51
11.1.3
Formulation and preparation................................................................................... 54
11.1.4
Stability and Storage............................................................................................... 54
11.1.5
Administration procedures...................................................................................... 54
11.1.6
Incompatibilities ..................................................................................................... 55
12
REFERENCES ..................................................................................................................... 57
13
APPENDICES ...................................................................................................................... 62
13.1 Appendix A: List of drugs that may have potential CYP3A4 interactions.................... 62
13.2 Appendix B: Study Diary............................................................................................... 65
13.3 Appendix C: Pfizer Fax Cover Form ............................................................................. 66


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
1
INTRODUCTION 
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective
To determine the response rate (RR) of metastatic or locally advanced
pheochromocytoma/paraganglioma to axitinib administered daily 
1.1.2
Secondary Objectives
Determine the progression-free survival 
In an exploratory manner examine the extent of activation of the VEGFR pathway in 
pheochromocytoma/paraganglioma using a semi-quantitative immunohistochemistry 
assay and examine the relationship with response to therapy
Perform pharmacogenomics analyses of drug metabolism and transport proteins through 
germline DNA examination.
1.2
BACKGROUND AND RATIONALE
1.2.1
Pheochromocytoma/Paraganglioma
Pheochromocytomas (PHEO) and Paragangliomas (PGL) are chromaffin cell-derived tumors 
that secrete and/or metabolize catecholamines. They are infrequent tumors occurring with an 
annual incidence of 3 – 8 cases per million per year in the general population. Its prevalence 
among patients with hypertension has been estimated to be 0.1 – 0.6%. Most tumors are 
sporadic, however approximately 25% of cases are associated with germline mutations in one of 
five major susceptibility genes. 1,2
Clinical manifestations of PHEO/PGL are diverse, with similar symptoms occurring in other 
disease conditions. Most of the signs and symptoms are attributed to the direct actions of the 
catecholamines. These include hypertension, headache, palpitations, and anxiety. Hypertension 
can be paroxysmal or sustained. Some patients may present with orthostatic hypotension. 3
Biochemically silent tumors may be suspected from tumor mass effects or incidentally found on 
imaging studies.4
PHEOs are derived from the adrenal gland; PGL come from parasympathetic-associated tissues 
and from extra-adrenal sympathetic-associated chromaffin tissue. Both adrenal and extra-adrenal 
tumors show similar histopathological characteristics. The diagnosis of PHEO and PGL is based 
on the presence of symptoms, biochemical confirmation, and different imaging modalities. 
Biochemical testing is based on the continuous production of catecholamine metabolites and 
metanephrines.5,6 Imaging procedures include anatomical and functional techniques.3,7,8
Malignant disease may occur in as many as 35% of patients with extra-adrenal PHEO and even 
more frequently in those with specific mutations. 9 Biochemical, morphological, and molecular 
markers have been investigated for use in the distinction of benign from malignant PHEO/PGL, 
but none appear to reliably indicate malignancy. Clinical criterion for malignancy is the 
presence of metastases, or presence of tumors in areas that normally do not contain chromaffin 
cells. 10
PHEO metastasizes via hematogenous or lymphatic routes. Most common sites of involvement 
are lymph nodes, lung, bone, and liver. The frequency of malignant PHEO in certain genetic 


8
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
disorders ranges from 1 to 90%. Metastases may be present at presentation or may occur later. 11
Succinate dehydrogenase (SDH) mutations are found in approximately 30% of patients with 
malignant PHEO/PGL.12 Metastases to the liver and lungs are associated with a shorter survival. 
Overall, the estimated 5-year survival rates are between 34 and 74%.11
The clinical presentation of malignant PHEO/PGL is similar to benign tumors. Most common 
metastatic sites are local lymph nodes, bone (50%), liver (50%), and lung (30%). While 
histopathological characteristics of tumors may not show definite diagnosis of malignancy, 
clinical correlates, such as tumor weight > 80g, high tumor concentration of dopamine, tumor 
size > 5 cm, presence of confluent tumor necrosis, extra-adrenal tumor location, adrenal PHEO 
that do not take up metaiodobenzylguanidine (iobenguane, MIBG), persistent postoperative 
hypertension and a younger age have been associated with increased likelihood for malignancy. 
13
At present, most treatments for malignant PHEO/PGL are palliative and multidisciplinary. 
Pharmacologic management of functional component of the tumor is similar to that of benign 
disease. Surgical therapy can be used to potentially cure malignant disease; however, tumor 
dissemination limits the chance for a curative resection.14 Other treatment modalities include 
cytoreductive techniques, radiopharmaceuticals, chemotherapy, radiotherapy, and experimental 
therapies. Targeted radiotherapy using 123-I MIBG is an option in systemic treatment.15
Radiolabelled somatostatin analogues are being investigated.16 Chemotherapy using the 
combination of cyclophosphamide, vincristine, and dacarbazine has been successfully utilized in 
the management of rapidly progressive metastatic PHEO, with more than 50% complete or 
partial tumor response and more than 70% complete or partial biochemical response.17 External 
beam radiation, radiofrequency ablation, cryotherapy, microwave coagulation, and embolization 
have been used as well. 18,19
1.2.2
The Genetics of Pheochromocytoma/Paraganglioma
Approximately 10-50% of cases may be hereditary. Hereditary PHEO/PGL is associated with 
multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF-1), von Hippel-
Lindau syndrome (VHL), and familial paraganglioma-pheochromocytoma caused by mutations 
in the genes encoding the components of succinate dehydrogenase complex (SDH). 20,21
Multiple endocrine neoplasia type 2 is an autosomal dominant syndrome consisting of 
pheochromocytoma, medullary thyroid carcinoma and hyperparathyroidism.22 The syndrome is 
caused by a mutation in the RET proto-oncogene located on chromosome 10.23 The RET proto-
oncogene encodes a glial cell line-derived neurotrophic factor (GDNF) that is specifically 
expressed in neural crest-derived cells such as catecholamine-producing chromaffin cells in the 
adrenal gland. 24MEN2-associated PHEO are usually benign, localized to the adrenals, secrete 
epinephrine, and often present with paroxysmal hypertension. 
Von Hippel-Lindau syndrome is caused by mutations in chromosome 3 encoding the VHL tumor 
suppressor gene.25,26 VHL-associated PHEO typically develop according to Knudson’s two-hit 
model: with an inherited germline mutation of VHL and a loss of function of the wild type allele. 
Pheochromocytoma developing in VHL has noradrenergic phenotype, with tumors located intra-
adrenally, and is bilateral in about half of patients, with less than a 7% incidence of metastases. 27
Although the incidence of PHEO in VHL is low (about 1%), the presence of hypertension should 
prompt search for PHEO.28


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Neurofibromatosis 1 is an autosomal-dominant condition. About 1-2% of patients with NF have 
a PHEO and about 5% of PHEO patients have NF. PHEO in NF is caused by germ-line 
mutations in the NF-1 gene. 29
Familial PHEO/PGL syndrome is caused by mutations in the genes encoding the subunits of the 
succinate dehydrogenase (SDH) - SDHB, SDHC, and SDHD. The SDH enzyme is a complex 
consisting of four subunits and is located in the mitochondrial membrane without a cytosolic 
component. It plays an important role in phosphorylation and intracellular oxygen sensing and 
signaling.30 Mutations in SDHB, SDHC, and SDHD were shown to cause pheochromocytoma-
paraganglioma syndromes. 31 SDHD-associated PGLs have been observed in 4-7% of apparently 
sporadic PHEO with malignant disease occurring at a frequency < 3%. 32 SDHD mutations are 
associated with greater propensity to develop head and neck PGL and multiple tumors (mostly in 
the head and neck but also in the extra-adrenal abdominal, pelvic, and thoracic regions) with low 
risk for aggressive or malignant behavior. 33,34
1.2.3
HIF-1a and VEGF Expression in Pheochromocytoma/Paraganglioma
One of the hallmarks for cancer formation is unregulated angiogenesis. In a search for histologic 
markers for malignancy in PHEO/PGLs, several studies have shown that tumoral vascularity is 
increased in malignant compared to benign PHEOs. 35,36 Utilizing immunostaining for Factor 
VIII and density of tumoral blood vessels has been shown to be increased in malignant lesions. 
Mean intratumoral microvessel density (using immunostaining with anti-CD31) in malignant 
pheochromocytomas is increased approximately two-fold as compared with benign tumors.35
Angiogenesis is a critical step in tumor growth and metastatic invasion. In a study of 19 PHEOs, 
induction of the genes for HIF1a, VEGF and VEGFR were found to be increased significantly in 
the malignant PHEO/PGLs.37 Hypoxia-inducible factor 1 subunit alpha (HIF-1a) is a 
transcription factor involved in glycolysis and angiogenesis. In normoxemic conditions, HIF-1a 
is inactivated. In situations of hypoxia, HIF1a becomes stabilized, thereby initiating a cascade of 
events leading to induction of genes necessary for angiogenesis, such as VEGF.38
Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors 
involved in both tumor growth and metastasis. VEGF is a mitogen, a survival factor for vascular 
endothelial cells. Its receptor, VEGFR, is a tyrosine kinase and participates in the signaling 
mechanism for angiogenesis, vasculogenesis, vascular permeability, and endothelial cell motility 
among others. 39,40 In the study by Salmenkivi and others, VEGF expression was shown to be 
absent in normal adrenal medulla whereas it was found in all PHEOs studied, with moderate or 
strong immunoreactivity noted in the malignant tumors and only weakly positive to absent 
immunostaining in benign PHEOs. 41 In another study of surgical specimens of benign and 
metastatic human PHEO, VEGF expression was also shown to be significantly higher in 
metastatic human pheochromocytomas. 42 Xeno-transplanted PC12 showed marked VEGF 
expression and proliferation that were inhibited by anti-VEGF antibodies resulting in inhibited 
angiogenesis.43
Defects in the SDH gene causes hypoxia in the tumor cells leading to induction of hypoxia-
inducible factors leading to promotion of angiogenesis. Mutations in the succinate 
dehydrogenase gene lead to succinate accumulation in the mitochondria and results in inhibition 
of HIF-1a prolyl hydroxylase stabilizing the HIF-1a subunit even in normal oxygen availability 


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
leading to stimulation of angiogenesis that can promote malignant transformation and aggressive 
tumor behavior. 37
As of July 2013, there are 3 ongoing studies, evaluating antiangiogenic agents in malignant 
PHEO/PGL. These agents are all tyrosine kinase inhibitors (TKI): pazopanib (NCT01340794), 
sunitinib (NCT00843037) and dovitinib (NCT01635907).
1.2.4
Axitinib (AG-013736)
1.2.4.1
Molecular formula and chemical name
Axitinib is a small molecule with the molecular formula C22H18N4OS:  (Figure 1). The free base 
has a molecular weight of 386.47. The chemical name of the compound is N-Methyl-2-[3-((E)-2-
pyridin-2-yl-vinyl-)-1H-indazol-6-ylsulfanyl]-benzamide
Figure 1: Structural Formula of Axitinib
Axitinib is white to light yellow crystalline powder.
1.2.4.2
Non-clinical studies
1.2.4.2.1 Primary pharmacodynamics
Axitinib is a small molecule adenosine triphosphate (ATP)-competitive inhibitor that binds to the 
unphosphorylated (non-activated) “DFG-out” conformation of the catalytic domain of a receptor 
tyrosine kinase (RTK).44 This conformation is also known as the “deep pocket” or “back pocket” 
conformation and is occupied by the juxtamembrane (JM) domain of the receptor, when the 
latter is in the “DFG out” state.
Axitinib binds to this conformation while allowing the JM domain to simultaneously bind,
uniquely interacting with the JM domain when compared to other inhibitors of the same class. In 
the published enzymatic assays, axitinib was found to be highly potent (inhibition constant [Ki] 
= 28 picomolar) against the kinase activity of JM domain containing human VEGFR2
recombinant (Table 1). In additional kinase assays, axitinib also showed potent and ATP-
competitive inhibition of the RTK of VEGF receptors 1, 2, and 3, and platelet-derived growth 
factor receptor (PDGFR)- , but not closely-related family kinases including fibroblast growth 
factor receptor 1(FGFR1), FMS-like tyrosine kinase 3 (Flt-3), tyrosine kinase endothelial -2
(Tie-2) and colony stimulating factor 1 (CSFR-1) (Table 1). Kinase activity screening with 
several broad kinase panels showed that axitinib was inactive against most kinases of distant 
families in the kinome. Thus the unique binding mode of axitinib in the kinase domain afforded 
its high potency and selectivity for VEGFRs.


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Table 1: Enzyme Inhibitory Activities of Axitinib against Type III-V Family Kinases
Phospho-: phosphorylated; FLVK: FGF-like VEGFR-2 kinase domain protein; Kin: kinase insert domain protein; FLK-1:
mouse VEGFR-2 kinase domain protein; Flt1: Fms-like tyrosine kinase 1 (VEGFR-1) kinase domain protein; GST-PDGFR-
: GST 
fusion protein containing the amino acid residues between 558-1090 of PDGFR- ; CSF-1R: colony stimulating factor 1 receptor kinase 
domain protein; FGFR-1: fibroblast growth factor receptor-1 kinase domain protein.
In cell-based assays, axitinib inhibited VEGF-mediated auto-phosphorylation of VEGF receptors 
1, 2, and 3 with a 50% inhibitory concentration (IC50) of 0.09-0.12 nM, 0.2 ± 0.06 nM and 0.1-
0.29 nM, respectively. Axitinib had weaker inhibitory activity against PDGFR-
- and 
stem cell factor receptor (KIT) with IC50 values of 5.0 ± 1.0 nM, 1.6 ± 0.4 nM and 1.7 ± 0.6 nM, 
respectively (Table 2). Axitinib did not potently inhibit the cellular activities of other RTKs 
tested, including CSF1-R, Flt-3, FGFR-1, rearranged during transfection [a receptor tyrosine 
kinase] (RET), epidermal growth factor receptor (EGFR), and mesenchymal-epithelial transition 
(cMet). Axitinib inhibited the survival of human umbilical vein endothelial cells (HUVECs) with 
an IC50 of 0.24 ± 0.09 nM and demonstrated approximately 1000-fold selectivity for VEGFR 
versus FGFR-1. Overall, in receptor binding studies and cell-based assays, it was concluded that 
axitinib is a potent and selective inhibitor of VEGF receptors 1, 2, and 3.45 Axitinib dose-
dependently inhibited endothelial cell (EC) tube formation derived from spheroidal ECs 
embedded in the 3-D fibrin matrix. Axitinib also inhibited VEGF-mediated EC adhesion and 
migration on extracellular matrix proteins and induced EC apoptosis as early as 6 hours after 
treatment in cell culture. In HUVECs, axitinib produced rapid and potent inhibition of 
endothelial nitric oxide synthase (eNOS), serine/threonine kinase (Akt), and extracellular signal-
regulated kinases (ERK)1/2 phosphorylation at concentrations that correlated with its potency for 
VEGF receptors. In PDGFR- -positive U87MG cells, axitinib dose-dependently inhibited 
platelet-derived growth factor (PDGF) -BB-stimulated cell migration, but not proliferation. 
Axitinib had little anti-proliferative effect on tumor cells that do not express VEGF receptors, 
PDGFRs, and/or stem cell factor receptor (KIT) receptor tyrosine kinases.


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Table 2: Cellular Biological Properties of Axitinib
1.2.4.2.2 In Vitro Activity of Major Metabolites of Axitinib
The major human plasma metabolites of axitinib include a sulfoxide (AG-028458 [also known as 
PF-03482595]) and an N-glucuronide (PF-04621675). In cells, the sulfoxide metabolite (AG-
028458) had limited activity against VEGF receptors, PDGFR- and KIT. In kinase counter 
screening assays, the sulfoxide metabolite only inhibited 2 kinases, Aurora-A and 5' adenosine 
monophosphate-activated protein kinase (AMPK), out of more than 100 kinases tested, with a 
>50% inhibition at the concentration of 1 µM; these biochemical inhibitory activities were also 
observed with axitinib. The N-glucuronide metabolite exhibited approximately 8300-fold less 
activity against VEGFR-2 auto phosphorylation and is assumed to have little activity against 
PDGFR and KIT based on computer modeling of the co-crystal structure.
1.2.4.2.3. Antiangiogenic Activity
Dynamic contrast enhanced- magnetic resonance imaging (Dce-MRI) studies showed that
axitinib treatment decreased the overall tumor blood flow/permeability at as early as 2 days after 
initiation of treatment, with a maximum reduction in permeability surface area product (Ktrans)
observed on Day 7 after dosing. The change in vascular Ktrans correlated with decreased 
microvessel density, cellular viability, and tumor growth.46,47 Axitinib reduced tumor 


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microvessel density (MVD, measured by CD-31 staining) after either acute or prolonged 
treatment in multiple xenograft tumor models. In addition, reduction of MVD was associated 
with an increased tumor apoptosis and a reduction in tumor cell proliferation compared with the 
vehicle-treated tumors.45
In spontaneous pancreatic islet-cell tumors of RIP-TAG-2 transgenic mice and murine Lewis
lung carcinoma in syngeneic mice, axitinib treatment (25 mg/kg, intraperitoneal (IP) or oral
(PO), BID resulted in robust and rapid (within 24 hours after dosing) reduction in EC
fenestrations, vascular sprouting, patency, and blood flow as well as decreased expression of 
VEGFR-2 and -3 in the remaining vessels.48 Neo-angiogenesis occurred as early as 1 day after 
drug withdrawal and tumors were fully re-vascularized within 7 days, which responded to a 2nd
cycle of axitinib treatment, suggesting that continuous daily dosing of axitinib may be optimal 
for anti-angiogenesis.49 In the same model, the delivery of a targeting antibody that recognizes a 
tumor surface E-Cadherin to the ex-vascular space and the tumor cells were not affected by 
axitinib treatment.50,51
1.2.4.2.4. In Vivo Anti-Tumor Activity
Single Agent Activity
Axitinib was evaluated for its single agent anti-tumor activity in subcutaneously (SC) or
orthotopic tumor models of colon, lung, kidney and liver in mice (Table 3). Axitinib consistently 
demonstrated anti-tumor activity in these nonclinical tumor models regardless of RTK 
expression status, consistent with its anti-angiogenesis mechanism of action. Overall, short-
dosing breaks, following a loading dose treatment period, did not have significant negative effect 
on tumor growth inhibition (TGI). Additional studies showed that the anti-tumor efficacy of 
axitinib is not driven by Cmax, rather by adequate plasma exposure above the concentration for 
VEGFR target inhibition (Ctarget) over a prolonged period of time (Table 4).


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Table 3: Anti-tumor Efficacy of Axitinib as a Single Agent in Mice
The anti-tumor efficacy of axitinib was compared to that of sorafenib in two human HCC
xenograft models (MHCC97H and LIMSH050). Compared to the vehicle control group, axitinib 
(15 mg/kg, BID PO) significantly reduced primary tumor growth in both models; and in the 
MHCC97H model also suppressed lung metastasis and serum alpha-fetoprotein (AFP) (an 
indicator of liver tumor burden). In both models, axitinib showed similar anti-tumor activity and 
tolerability as sorafenib or the combination of sorafenib plus sirolimus. Finally, in a 28-day 


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dosing study with the MHCC97H model, axitinib appeared to be better tolerated than sunitinib 
(at their respective therapeutic doses), while statistically equivalent anti-tumor efficacy was 
observed between the two compounds.
1.2.4.2.5. Pharmacologically Active Concentrations for Target Inhibition and Duration of
Action
Based on a series of studies using various xenograft tumor models, the pharmacologically active 
axitinib concentration for Ctarget was estimated as 0.1-0.49 nM (or 0.04-0.19 ng/mL, unbound). 
This translates to a human Ctarget of 24-98 nM (or 9.3-38 ng/mL, total plasma concentration), 
assuming a 99.5% human plasma protein binding.
The pharmacologically active dose (ED50) in mouse, was estimated to be 8.7 ± 1.6 mg/kg, BID. 
The ED70 and ED80 were 30 mg/kg and 60 mg/kg (BID), respectively. The total efficacious 
concentration (Ceff) for humans was estimated to be 56-170 nM, or 22-66 ng/mL. (Table 4)
Table 4: Summary of IC50 and EC50 Values from Various Assays and Determination of target
and Ceff of Axitinib
1.2.4.3
Clinical Studies
1.2.4.3.1 Pharmacodynamics 
The analysis of C (plasma exposure) against T (length of exposure) for the 10 mg/kg BID dose 
level (~ ED50) of axitinib concluded that a 50% TGI can be achieved with the exposure period 
of 10 hours/day, 16 hours/day, or 24 hours if the unbound trough concentration of axitinib 
reaches
0.85 nM, 
0.65 nM or
0.28 nM, respectively (the corresponding total concentration 


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for human is 66 ng/mL, 50 ng/mL or 22 ng/mL, respectively). The analysis also showed that 
inhibition of PDGFR- by axitinib was transient at 10 and 30 mg/kg, and probably only played a 
minor role in anti-angiogenesis and anti-tumor activity of axitinib (Figure 1). This result is 
supported by the fact that only the high dose of axitinib (100 mg/kg) was able to produce a 
significant (90%) and sustained (>7 hours) inhibition of PDGFR- phosphorylation in the C6 rat 
glioma model known to secrete PDGF and express high levels of active PDGFR- , and that the 
10 or 30 mg/kg dose levels of axitinib only produced partial and transient inhibition of PDGFR .
The efficacious human dose of axitinib was predicted by pharmacokinetic-pharmacodynamics 
(PK-PD) modeling using data from a MV522 TGI study and human pharmacokinetic (PK)
parameters determined in Phase 1 clinical studies.52 The modeling and simulation results 
predicted that 5-10 mg BID axitinib would result in a 40-60% TGI inpatients, assuming the 
pharmacodynamics (PD) parameters in patients are similar to those in MV522 tumors in mice.
Figure 2: Concentration and Time of Exposure Correlative Analysis for the Determination of 
Duration of Action for Axitinib
The duration of action against VEGFRs and PDGFR- was assessed based on analysis of the plasma concentration/time of
exposure relationship. Axitinib preferentially inhibited VEGFRs at the ED50 and ED70 doses. The PK profile was created by 
plotting plasma concentrations (± SEM) against time points of treatment with axitinib at 10 and 30 mg/kg and analyzed against 
values of the highest predicted Ctarget (0.49 nM) and the range of Ceff (0.28 – 0.85 nM, shaded area) of the compound. The 
IC50 values for VEGFR-2 (0.2 nM) and PDGFR- (1.6 nM) are also shown. Axitinib was dosed PO, BID, 8 hours apart. The 12 
hour concentrations were calculated based on the WinNonlin analysis of the PK. Accordingly, PK values between the 12 hour 
and 24 hour time frame were corrected using the estimated 12 hour plasma concentrations.
1.1.1.1.2 Clinical Safety and Efficacy 
As of 1 June 2012, 43 studies evaluating the safety, efficacy, and PK of axitinib have been
“completed”(C) or are “ongoing” (O): “Completed” signifies that the analysis for the primary 
endpoint has been completed and a clinical study report (CSR) is available; however, subjects 
may still be receiving treatment under the same protocol and may be being followed up for 
efficacy and safety. “Ongoing” signifies that the analysis for the primary endpoint has not been 
completed and a CSR is not available.


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These studies include 15 Phase 1 studies in healthy subjects (including 1 study in patients with 
hepatic impairment) and 28 studies in 2543 subjects with cancer treated with axitinib including 1 
continued access and 1 compassionate use study.
In the first Phase 1 dose-finding study (Protocol A40600010), thirty-six subjects with advanced 
solid tumors were treated with starting doses of 2 to 30 mg BID of Axitinib in 6 cohorts of 4 to 8 
subjects each. The primary dose-limiting adverse event (DLT) was hypertension at starting doses 
> 5 mg BID. Other DLTs included diarrhea, stomatitis, and elevation of liver transaminases. A 
significant food effect was observed, with a higher rate and extent of absorption following 
overnight fasting. The recommended Phase 2 starting dose was determined to be 5 mg BID 
(without food or drink 2 hours before and after each axitinib dosing) [20]. Based on these 
finding from the first in human (FIH) Phase 1 study (Protocol A40600010), the initial Phase 2 
studies in cancer patients were initiated with the recommendation that axitinib be administered 
with fasting two hours before and two hours after dosing. Of fourteen subjects treated at the 
MTD, two experienced DLTs (Grade 2 stomatitis and Grade 3 diarrhea.
Hypertension seemed to be the main DLT. Grade 1-3 hypertension was observed in six subjects, 
which was not dose-limiting and was managed with standard antihypertensive medications. All 
other treatment-related AEs at the 5-mg BID dose level were of Grade 1 or 2 in severity, with the 
exception of one subject who experienced Grade 3 dysphagia. 
Among the first ten patients in the Phase 1 study who received doses up to six times the MTD of 
5 mg BID (starting dose), two subjects with non-small cell lung cancer (NSCLC) cavitated their 
lung lesions and died of haemoptysis. Both subjects had adenocarcinoma, one with a centrally-
located lesion and the other with a peripheral-located lesion. Both subjects received a starting 
dose of 20 mg BID. One patient’s haemoptysis was considered to be related to axitinib.
Hypertension was noted in all of the first ten subjects, and five were Grade 3 or 4 in severity. 
Two subjects (receiving 10 mg BID and 20 mg BID as the starting dose) had seizures associated 
with hypertension and both recovered without sequelae. No home monitoring of blood pressure 
was done at the time.
Pharmacokinetics
Axitinib plasma pharmacokinetics was moderately variable, but exposures were generally dose 
proportional up to 15 mg daily dose. Axitinib has good oral bioavailability; a study in healthy 
volunteers indicated that the mean absolute oral bioavailability of the drug was 58%. An 
interaction study in healthy volunteers indicated that ketoconazole produced 2-fold increase in 
axitinib plasma exposures and a 1.5-fold increase in peak plasma concentration.
A study in healthy volunteers (A4061007) indicated that the mean absolute oral bioavailability of 
the drug was 58%. Interaction studies in healthy volunteers with the CYP3A4/5 inhibitor 
ketoconazole (A4061004) and CYP3A4/5 inducer rifampin (A4061026) produced a 2-fold 
increase and 79% reduction in axitinib plasma exposures, respectively. Axitinib has two major 
(non-pharmacologically active) circulating plasma metabolites, a glucuronide product and a 
sulfoxide product (A4061003). In subjects with moderate hepatic impairment (Child Pugh B), 
there was a ~2-fold increase in axitinib area under curve from zero to infinity (AUC (0-
1.3-fold increase in axitinib maximum plasma concentration (Cmax) compared to subjects with 
normal hepatic function (A4061036). No difference in axitinib plasma pharmacokinetics was 
observed between Caucasian and first-generation Japanese volunteers (n=20 each) (A4061026).


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Phase 1 studies in combination with chemotherapeutic/anticancer agents in cancer patients have 
indicated plasma pharmacokinetics of docetaxel, paclitaxel, carboplatin, capecitabine, 
gemcitabine, cisplatin, pemetrexed, oxaliplatin, 5-fluorouracil (5-FU), bevacizumab, and 
irinotecan (including its SN-38 activated metabolite) were similar in the absence and presence of 
axitinib. Likewise, axitinib plasma profiles and pharmacokinetic parameters were similar in the 
presence and absence of these co-administered chemotherapeutic/anticancer agents
A pooled population pharmacokinetic analyses using data from 17 clinical studies that included 
healthy volunteers (n=338) as well as patients (n=207) with solid tumors (including patients with 
advanced RCC) indicated that there are no clinically relevant effects of age, gender, body 
weight, race, renal function, and UGT1A1 and CYP2C19 genotype on axitinib plasma exposure. 
In addition, no apparent difference in pharmacokinetics between patients with advanced RCC 
and healthy volunteers was noted.
Safety 
Overall, the adverse events reported in axitinib clinical studies are considered manageable, were 
generally reversible and expected for this class of agents. For single-agent axitinib, the most 
common adverse events reported from 699 cancer subjects regardless of causality included 
diarrhea (397 subjects, 56.8%), fatigue (368 subjects, 52.6%), hypertension (318 subjects, 
45.5%), decrease appetite (286 subjects, 40.9%), nausea (264 subjects, 37.8%), dysphonia (242 
subjects, 34.6%), palmar-plantar erythrodysesthesia syndrome (202 subjects, 28.9%), weight 
decreased (197 subjects, 28.2%), vomiting (166 subjects,23.7%), constipation (165 subjects, 
23.6%), headache (151 subjects, 21.6%), cough (149 subjects, 21.3%), arthralgia and dyspnea 
(140 subjects, 20%). Additionally, hypothyroidism and proteinuria were reported as adverse 
events in 122 subjects (17.5%) and 117 subjects (16.7 %), respectively. Grade 3+ events 
occurred most frequently for hypertension (134 subjects, 19.2%), fatigue (90 subjects, 12.9%), 
and diarrhea (65 subjects, 9.3%).
Efficacy 
Completed Single-Agent Axitinib Studies
Preliminary evidence of antitumor activity has been observed across multiple tumor types testing 
axitinib as a single agent. Response assessments for subjects with solid tumors were evaluated 
according to RECIST. Efficacy results for completed Phase 2 studies are summarized in Table 5.


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
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Table 5: Efficacy of Axitinib in Completed Single-agent Phase 2 Clinical Studies
[References 53-57]
Table 6: Efficacy results from the Phase 3 study in previously-treated patients with advanced 
RCC comparing axitinib vs. sorafenib 58


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1.3
RATIONALE
The long-term survival for malignant PHEO/PGL may be limited because of its hormonal effects 
as well as its aggressive behavior and dissemination, particularly in some hereditary PHEO/PGL. 
Although several therapeutic modalities have been used to palliate malignant PHEO/PGL, a 
continued search for new agents to address the malignancy is needed to improve outcomes. One 
approach is to utilize drugs that target signaling pathways leading to decreased proliferation and 
survival of cancer cells. Some data in the literature suggests that in malignant PHEO/PGL, 
VEGF seems to play a role in the biology of the cancer and thus, its inhibition could reduce 
tumor growth. Sunitinib and imatinib has been used in a limited number of malignant 
pheochromocytomas with varying responses. Axitinib was designed to inhibit VEGFR that 
participates in tumor angiogenesis. In order to determine the activity of axitinib in tumor and 
hormonal responses in malignant PHEO/PGL, it will be used as a single agent in this study. The 
combination of cyclophosphamide; vincristine and dacarbazine have been shown to produce 
partial responses in malignant PHEO/PGL.  The majority of the patients may have already 
received this combination or will receive this combination chemotherapy in the future. Our goal 
is to develop multiple lines of effective treatments for this disease.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by 
the Laboratory of Pathology, NCI when such tissue is available to confirm
or
In the event that outside tissue is not available:
-
an outside pathology report confirms the diagnosis of Pheo/PGL, AND 
-
the patient has nuclear medicine imaging studies that would only be positive in an 
adult patient with a diagnosis of Pheo/PGL (F-DOPA, Dotatate, F-Dopamine or 
MIBG)
2.1.1.1
Imaging confirmation of metastatic disease
2.1.1.2
Measurable disease at the time of enrollment per RECIST 1.1. See Section 6.3 for the 
evaluation of measurable disease.
2.1.1.3
2.1.1.4
. Because no dosing or adverse event data are currently available on the 
use of Axitinib in patients <18 years of age, children are excluded from this study, but 
will be eligible for future pediatric trials.
2.1.1.5
Information available or pending regarding possible genetic alterations that can explain 
the patient’s pheochromocytoma/paraganglioma (mutations in SDHB, SDHV or VHL 
genes)
2.1.1.6
Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the 
case of nitrosourea) prior to enrollment date; 2 weeks if the last therapy was received as 
part of a “phase 0” or “exploratory IND” trial. Last surgery more than 4 weeks prior to 


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enrollment, to allow for wound healing. Core biopsies or FNA will not require any 
waiting period
2.1.1.7
there must be sites of measurable disease that did not receive radiation
2.1.1.8
Prior therapeutic MIBG is allowed
2.1.1.9
Organ and marrow function as defined below:
2.1.1.10
for Gilbert’s Syndrome. The upper limit value for bilirubin for subjects with Gilbert’s 
Syndrome is less than 3 mg/dl.
Note: A diagnosis of Gilbert’s disease will be made in the presence of (1) unconjugated 
hyperbilirubinemia noted on several occasions; (2) normal results from CBC count, 
reticulocyte count, and blood smear; (3) normal liver function test results; and (4) an absence 
of other disease processes that can explain the unconjugated hyperbilirubinemia.
2.1.1.11
2.1.1.12 Amylase and lipase equal to, or less than, the institutional ULN.  
2.1.1.13
40 ml/min (estimated or measured creatinine clearance) or serum 
2.1.1.14 Random urine protein < 20 mg/dL. If 
-hour urine protein 
collection will be performed to accurately demonstrate that the 24-hour total is <1000 
mg, the level acceptable for enrollment on study
2.1.1.15
00/mm3
2.1.1.16
0,000/ mm3
2.1.1.17 Ability to understand and sign an informed consent document.
2.1.1.18 Ability and willingness to follow the guidelines of the clinical protocol including visits 
to NICHD and NCI, Bethesda, Maryland for treatment and follow up visits.
2.1.1.19 Because the effects of chemotherapy on the developing human fetus are potentially 
harmful, women of childbearing potential and men who participate in the study must 
agree to use adequate contraception (hormonal or barrier methods) before, during the 
study and for a period of 3 months after the last dose of chemotherapy.
2.1.2
Exclusion Criteria
2.1.2.1
Patients with pheochromocytoma/paraganglioma tumors potentially curable by surgical 
excision alone as determined by the Principal Investigator in discussions with the 
surgical consultants.
2.1.2.2
Patients who have large abdominal masses impinging on bowel or pulmonary masses 
with encroached vessels and a potential to bleed will be considered on case by case 
basis after careful consultation with multiple disciplines such as radiologists and 
surgeons with main intent being patient safety.


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2.1.2.3
Unstable hypertension defined as a systolic blood pressure >150 mm Hg or diastolic 
pressure > 90 mmHg despite optimal medical management.
2.1.2.4
Untreated brain metastases (or local treatment of brain metastases within the last 6 
months) due to the poor prognosis of these patients and difficulty ascertaining the cause 
of neurologic adverse events.
2.1.2.5
Pregnancy, due to the possible adverse effects on the developing fetus.
2.1.2.6
Lactating women who are breast-feeding due to the possibility of transmitting axitinib 
to the child.
2.1.2.7
The presence of a second malignancy, other than squamous cell carcinoma of the skin 
or in situ cervical cancer because it will complicate the primary objective of the study. 
Cancer survivors who have been free of disease for at least one year can be enrolled in 
this study.
2.1.2.8
Patients with evidence of a bleeding diathesis
2.1.2.9
Patients must not have received prior therapy with a TKI. Prior TKI usage in 
pheochromocytoma affects the same pathway as axitinib. 
2.1.2.10 Gastrointestinal abnormalities including:
Inability to take oral medications
Requirement for intravenous alimentation
Prior surgical procedure affecting absorption including total gastric resection
Treatment for active peptic ulcer disease in the past 6 months
Active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, 
hematochezia or melena in the past 3 months without evidence of resolution 
documented by endoscopy or colonoscopy
Malabsorption syndrome
2.1.2.11 Current use or anticipated need for treatment with drugs that are known potent CYP3A4 
inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, 
erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, 
lopinavir, atazanavir, amprenavir, fosamprenavir, and delavirdine).
2.1.2.12 Current use or anticipated need for treatment with drugs that are known CYP3A4 or 
CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, 
phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and 
St. John’s wort). 
2.1.2.13 Requirement of anticoagulant therapy with oral vitamin K antagonists.  Low-dose 
anticoagulants for maintenance of patency of central venous access devices or 
prevention of deep venous thrombosis is allowed.  Therapeutic use of low molecular 
weight heparin is allowed.
2.1.2.14 Active seizure disorder or evidence of brain metastases, spinal cord compression, or 
carcinomatous meningitis.
2.1.2.15 Any of the following within 12 months prior to study drug administration: myocardial 
infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic 


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congestive heart failure, cerebrovascular accident or transient ischemic attack and 
within 6 months before study drug administration for deep vein thrombosis or 
pulmonary embolism.
2.1.2.16 Other severe acute or chronic medical or psychiatric condition, or laboratory 
abnormality that may increase the risk associated with study participation or study drug 
administration, or may interfere with the interpretation of study results, and in the 
judgment of the investigator would make the patient inappropriate for entry into this 
study
2.2
SCREENING EVALUATION
2.2.1
History and Physical Evaluation
Focused history and physical examination (including height, weight, vital signs and ECOG 
performance score) with documentation of 1) measurable disease, 2) opioid use and pain 
assessment and 3) prior therapies (surgical, radiotherapeutic and cytotoxic) will be conducted 
prior to starting therapy.
2.2.2
Baseline Imaging Studies 
Every patient should have a baseline clinical evaluation with CT scan of neck, chest, abdomen 
and pelvis prior to receiving treatment. In some patients an MRI may be more appropriate. 
Attempts will be made to obtain an FDG-PET scan prior to treatment in all patients, but this may 
be obtained after treatment starts. These must be completed within 28 days of enrollment.
2.2.3
Baseline EKG
Should be obtained within 28 days prior to enrollment.
2.2.4
Baseline Laboratory Evaluation 
To be obtained within one week prior to enrollment
Hematological Profile: CBC with differential and platelet count, prothrombin time, 
activated partial thromboplastin time
Biochemical Profile: electrolytes, BUN, creatinine, glucose, AST, ALT, bilirubin, 
calcium, phosphorous, albumin, magnesium, alkaline phosphatase, amylase and lipase
-hCG for female patients of childbearing age who have not had prior gynecologic 
surgery that precludes the possibility to bear children
Urine protein: A random urine will be obtained for protein. If the random urine protein 
level is
-hour urine protein collection will be performed to 
accurately demonstrate that the 24-hour total is <1000 mg, the level acceptable for 
enrollment on study
Hormonal profile: 24-hour urinary catecholamines and metanephrines; plasma 
catecholamines and metanephrines
Thyroid Panel: TSH, Free T4, and T3
Chromogranin A will be obtained in patients who are not taking antacids or H-2 blockers 
such as Zantac, Prilosec, Tums, or Pepsid. They should be off antacids and H-2
blockers for at least 2 weeks prior to blood test for reliable results. In patients who take 
these medications on a routine basis, the test will not be done.


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2.2.5
Histologic confirmation of pheochromocytoma/paraganglioma when available OR
review of outside pathology report and Nuclear Medicine imaging to confirm diagnosis.
NOTE: Stained slides, a block of primary tissue, or 10 unstained sections on charged slides from 
the time of diagnosis will be sought for each patient. If needed for confirmation of diagnosis 
these will be submitted to the Laboratory of Pathology/CCR to be used in confirmation of the 
diagnosis. Otherwise they may be used for research purposes. Tissue blocks from a known 
recurrence are an acceptable substitute if original tumor samples are unavailable
2.3
REGISTRATION PROCEDURES
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 sent via 
encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.
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.
2.4
TREATMENT ASSIGNMENT PROCEDURES
Cohorts
Number
Name
Description
1
Cohort 1
Patients with pheochromocytoma/paraganglioma
Arms
Number
Name
Description
1
Arm 1
Axitinib 5 mg twice a day on a 28-day cycle
Randomization and Arm Assignment
Subjects in cohort 1 will be assigned to arm 1.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN [CYCLE LENGTH = 28 DAYS]
In the first 16 weeks of therapy, patients will be seen in clinic every 4 weeks to monitor 
therapy. Occasionally exceptions will be made to allow for shorter or longer intervals to 
accommodate weather and personal circumstances. We will allow a 7-day flexibility plan 
when needed, although every effort will be made to stay on schedule.
After the first 16 weeks patients will be seen every 12 weeks, with 7-days flexibility before 
or after the target date.
A history and physical examination will be performed at each outpatient visit (for medical 
record only, not for research record)
Every twelve weeks appropriate scans will be repeated as summarized in section 3.4.


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Intrapatient dose escalations will be allowed beginning at week 4 for all patients who meet 
criteria (section 3.3)
CBC with differential, electrolyte panel, hepatic panel, mineral panel, urine analysis, serum 
amylase, and serum lipase every 4 weeks in the first sixteen weeks, and then at every re-
assessment. A thyroid panel (TSH, free T4, and T3) will be obtained at baseline, every 4 
weeks x 2, and then every 12 weeks (+/- 1 week)
Conventional imaging studies deemed appropriate for monitoring the patient’s disease as 
done for on-study disease assessment will be obtained and reviewed every 12 weeks. 
Measurable disease will be monitored as described in section 6.3
Hypertension can occur with axitinib. In the Investigator’s Brochure, the frequency of 
hypertension adverse events was 42% including a 13% incidence of grade 3 hypertension. 
Therefore, all patients must have blood pressure measured and recorded twice daily during 
the first 4 weeks after starting therapy or after any dose escalation, then once daily or three 
times per week as needed and recorded in a patient diary. These diaries will be kept in a 
research record but the BID and/or daily or three times a week BP measurements will not be 
recorded in C3D. Patients and study team members will communicate by phone to discuss 
the blood pressure readings during the initial 4 weeks and at other times when daily 
monitoring is necessary. The guidelines for management of blood pressure elevation are in 
section 3.3.3
3.2
DRUG ADMINISTRATION
3.2.1
Axitinib Administration
3.2.1.1
Patients will receive axitinib twice daily on a continuous dosing regimen and this will 
generally be administered on an outpatient basis except when admission is required for 
clinical reasons or research purposes. Reported adverse events and potential risks are 
described in Section 11.1.2. Appropriate dose modifications for axitinib are described in 
Section 3.3
3.2.1.2
Axitinib is supplied as 1- and 5-mg tablets and is administered orally twice a day with 
or without food. Patients are to swallow the tablets whole with approximately 250 ml of 
water, each morning and evening (i.e., every 12 hours)
3.2.1.3
Axitinib will be given as self-administered oral doses at the initial level of 5 mg every 
12 hours continuously in a 28-day cycle. All patients will be evaluated for dose 
escalation beginning at week 4. In addition to the starting dose level of 5 mg every 
12 hours, two additional levels (7 and 10 mg on every-12-hour schedules) will be 
considered. An interval of at least 4 weeks must elapse between any dose escalations. 
(See Section 3.3)
3.2.2
Self-Administered Study Drugs 
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 Pfizer Pharmaceuticals, Inc.
Study drug acquisitions, inventory, and dispensing will be documented using the NIH Clinical 
Center Pharmacy Department’s Investigational Drug Monitoring System. Axitinib, an oral self-
administered investigational agent, will be accounted for, handled, and disposed of 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 


26
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
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 activities associated with drug accountability and compliance monitoring for 
orally self administered investigational agents. Study drug will be dispensed in light-resistant 
containers. Each patient will be instructed to document in a study diary (Appendix B) the daily 
intake of axitinib, including the time the dose is taken and whether or not any doses are missed, 
BP self monitoring and to date and sign the entry. They will bring the study diary and any unused 
drug to their next scheduled clinic appointment. 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 capsule count and record 
the results on the approved CCR Pill Count Case Report Form which is to be maintained in the 
research record; and (3) dispense the new partial and full bottle(s) of axitinib to the patient. 
Unused study drugs are to be returned to the research nurse who will dispose of them according 
to the SOP.
3.3
INTRAPATIENT DOSE ESCALATION AND DOSE MODIFICATION FOR TOXICITIES
Subjects will be monitored closely for adverse events. In addition to optimizing supportive care 
as described in Section 4.2, axitinib doses may be adjusted for individual subjects. The dose 
levels are found in Table 7.
Table 7: Axitinib dose levels
Starting dose level 1
5 mg every morning; 5 mg every evening
Dose level 2
7 mg every morning; 7 mg every evening
Dose level 3
10 mg every morning; 10 mg every evening
Dose level –1
3 mg every morning; 3 every evening
Dose level –2
2 mg every morning; 2 mg every evening
3.3.1
Intra-patient dose escalations
After four weeks of therapy, patients who tolerate axitinib for at least two consecutive weeks 
with no adverse reactions > Grade 2 (CTCAE V4), with the exception of hypertension, that will 
be limited to not > Grade 1, may have their dose increased. When a dose increase from 5 mg 
twice daily is recommended, the axitinib dose may be increased to 7 mg twice daily, and further 
to 10 mg twice daily using the same criteria. Dose escalations may not occur more frequently 
than every four weeks and should be in increments of one dose level. Patients are eligible for 
dose escalation whether or not they are receiving antihypertensive medication at the time of 
study entry.
3.3.2
Dose reductions
Dose reductions will be according to the guidelines in Table 8.
Table 8: Axitinib-related adverse events
Grade
Response
G1
Continue axitinib
All G2
except G2 PPES*
Maintain axitinib dose with symptomatic treatment
G2 PPES and all G3
Interrupt axitinib administration and re-evaluate at least weekly until 


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
the adverse event improves to Grade 1 or to the pre-treatment 
baseline. The axitinib dose will be reduced one dose level (DL –1) 
the first time a grade 3 adverse event is recorded, and after resuming 
axitinib treatment, reduced a second dose level (DL –2) if the 
adverse event recurs and a further dose reduction is required. Grade 
3 metabolic adverse events that can be corrected to Grade 1 or to 
pre-treatment baseline within 48 hours will not necessitate a dose 
reduction. Patients who experience an adver
Grade 3 that 
does not resolve to Grade 1 or baseline within 3 weeks will have 
treatment discontinued and be removed from study
G4
Discontinue therapy if a Grade 4 clinical adverse event is recorded. 
Grade 4 metabolic adverse events will be managed as Grade 3 
adverse events.
*Abbreviations used PPES: palmar-plantar erythrodysesthesia syndrome
3.3.3
Management of Hypertension: 
New or additional antihypertensive therapy should be started if 2 BP readings, preferably taken 
in the clinic and separated by at least 1 hour, show the following: 2 systolic BP readings greater 
than 150 mm Hg or 2 dBP readings greater than 100 mm Hg. Alternately, the dose of existing 
antihypertensive medication(s) may be increased. If the patient is already on maximal 
antihypertensive treatment, the axitinib dose should be reduced by 1 dose level Or the addition of 
Demser should be considered (see below).
Patients who have 2 systolic BP readings, separated by at least 1 hour, greater than 160 mm Hg, 
or 2 dBP readings, separated by at least 1 hour, greater than 105 mm Hg, should have treatment 
with axitinib held. (Note: if axitinib is held, patients receiving antihypertensive medications 
should monitor closely for hypotension and restart axitinib at one lower dose level as soon as BP 
is <150/100 mm Hg.  Plasma half-life of axitinib is 2 – 4 hours and BP usually decreases within 
1-2 days following dose interruption). Treatment with axitinib should be restarted at 1 lower 
dose level as soon as the systolic blood pressure reduces to less than 150 mm Hg and the dBP 
reduces to less than 100 mm Hg.
Patients who develop recurrent systolic hypertension (2 BP readings separated by at least 1 hour 
show systolic pressure >150 mm Hg) or recurrent diastolic BP >100 mm Hg following previous 
axitinib dose reduction should undergo another dose reduction by one dose level.  
Guidance on dose interruption and reduction for hypertension is summarized in the Table 9,
below.
Many patients with PHEO/PGL may have taken or may be taking Demser (metyrosine) to 
manage hypertension caused by malignant PHEO/PLG. This protocol allows the continued use 
of Demser while receiving axitinib if the patient has been Demser as part of their pre-study 
regimen.  
If a patient begins axitinib as part of this study, and develops hypertension or has worsening 
hypertension, Demser can be considered as a possible option to control blood pressure when the 
standard antihypertensive medications have not been effective. In this case a treatment break 


28
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
from axitinib may be needed in order to allow Demser dosing for 10-14 days prior to resuming 
axitinib.


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Table 9: Hypertension Management Plan for Axitnib
Degree of Blood Pressure Elevation
Management
Systolic Pressure
OR
Diastolic Pressure
If not on maximal 
antihypertensive treatment, 
institute new or additional 
antihypertensive medication and 
maintain dose of axitinib
If on maximal antihypertensive 
treatment, reduce axitinib to one 
lower dose level
Interrupt dosing and begin 
Demser treatment for 10-14 days 
and then resume axitinib at the 
same dose level.
2 BP readings separated 
by at least 1 hour show 
systolic pressure  >150 
mm Hg
2 BP readings 
separated by at least 1 
hour show diastolic 
pressure >100 mm Hg
2 BP readings separated 
by at least 1 hour show
systolic pressure  >160 
mm Hg
OR
2 BP readings 
separated by at least 1 
hour show diastolic 
pressure  >105 mm Hg
Interrupt dosingA; adjust 
antihypertensive medication; as 
soon as BP is less than 150/100 
mm Hg, restart axitinib at one 
lower dose level.  
Interrupt dosing and begin 
Demser treatment for 10-14 days 
and then resume axitinib at same 
dose level.
Recurrent hypertension 
following previous dose 
reduction (2 BP readings 
separated by at least 
1 hour show systolic 
pressure  >150 mm Hg)
OR
Recurrent dBP >100 
mm Hg (2 BP readings 
separated by at least 
1 hour) following 
previous dose reduction
Repeat axitinib dose reduction by 
one lower dose level. If a patient is 
on an axitinib dose of 2 mg every 
12 hours, discontinue axitinib
G4 Hypertension
Discontinue axitinib
AIf axitinib is held, patients receiving antihypertensive medications should monitor closely for 
hypotension. Plasma half-life of axitinib is 2 – 4 hours and BP usually decreases within 1-2
days following dose interruption
3.3.4
Management of Proteinuria: 
If a random urine protein level is
, perform a 24-hour urine collection. Dosing 
may continue while waiting for test results.
If < 2 g proteinuria/24 hour is reported, continue dosing at the same dose level.
24-hour urine collection 
for proteinuria and creatinine clearance (interval at investigator discretion) until 
proteinuria is < 2 g/24 hours. Restart axitinib at the same dose or one lower dose level at 
discretion of the investigator.  


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Note: The presence of hypertension and proteinuria favors the use of angiotensin-converting 
enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), because angiotensin 
inhibitors restore nephrin expression. Calcium channel blockers may interact with anti-VEGF 
drugs through a cytochrome P-450 pathway, thus exposing patients to a risk of under-dosage or 
over-dosage of the anti VEGF agent. Newly enrolled subjects on calcium-channel blockers will 
be changed to alternative antihypertensive medications, with ACE-inhibitors as the first choice 
and ARB as an alternative.  If calcium-channel blocker use is deemed necessary, it will be used 
only under approval of the PI.
Note: In case of hypertensive crisis (Grade 4 NCI CTCAE), axitinib will be discontinued. 
3.4
STUDY CALENDAR
Baseline evaluations including laboratory examinations, and history and physical exam 
conducted within one week prior to administration of protocol therapy. Scans must be done 
within four weeks prior to the start of therapy. In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy.
Week
Pre-
Study
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Q
12
wke
Off 
Studyk
Axitiniba
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed 
consent
X
Medical 
history,
physical exam
vital signs, PS
X
X
X
X
X
X
Concurrent 
medications
X
X -----------------------------------------------------------------------------------------------------
---
Diary review
X
X
X
X
X
CBCb, serum
chemistryb
X
X
X
X
X
X
X
Plasma 
Catecholamines 
/metanephrines
X
X
X
X
X
X
X
24-hour urine 
catecholamines 
+
metanephrines
X
X
X
X
X
X
X
Urinalysis (for 
protein, Protein 
Creatinine 
ratio)
X
X
X
X
X
X
PT/PTT
X
X
X
X
TSH, Free T4, 
T3
X
X
X
X
X
X
Chromogranin 
Af
X
X
X
X
EKG
X
Adverse event 
evaluation
X
X -----------------------------------------------------------------------------------------------------
---
X


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Week
Pre-
Study
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Q
12
wke
Off 
Studyk
Imagingc and
tumor 
measurements
X
X
X
Research blood 
sampled
X
X
X
Advanced 
Directive j
X
aAxitinib will be taken twice daily for 28 days as one cycle
b BUN, creatinine, glucose, AST (SGPT), ALT (SGPT), bilirubin, calcium, phosphorous, magnesium, sodium, 
potassium, total protein, albumin, alkaline phosphatase, amylase, lipase, within one week prior study entry. 
CBC with differential & Platelet should also be obtained within one week prior to study entry
c CT scan of chest, abdomen and/or pelvis and FDG-PET scan examining areas of known or suspected disease 
involvement prior to receiving treatment. In some patients an MRI may be more appreciate. This must be 
completed within 28 days prior to enrollment.  During therapy patients will undergo CT or MRI staging every 
12 weeks (+/- 1 week).
d Research labs will be obtained at baseline, then at 8, 16 and 24 weeks. See section 5.1 for tube type and 
volume.
e After 16 weeks on study
f Chromogranin A will be obtained in patients who are not taking antacids or H-2 blockers such as Zantac, 
Prilosec, Tums, Pepsid, They should be off for at least 2 weeks prior to blood test for reliable results. In 
patients who take these medications on a routine basis, the test will not be done.
j As indicated in section 10.3, all subjects will be offered the opportunity to complete an NIH advanced 
directives form.  This should be done preferably at baseline but can be done at any time during the study as 
long as the capacity to do so is retained.  The completion of the form is strongly recommended, but is not 
required.
k Off study visit: patients will be invited to clinical center approximately four weeks following the last dose of 
study drug. If patents are not able to come, they will be asked by phone for performance status, any adverse 
events and new cancer treatment.
3.5
SURGICAL GUIDELINES 
If a major surgery or an interventional procedure (*e.g., endoscopy) is required, treatment with 
axitinib must be interrupted at least 36 – 48 hours before the procedure and the patient blood 
pressure should be closely monitored for hypotension.  Patients may resume axitinib seven days 
after minor surgery and 2-3 weeks after major surgery, assuming their wound has completely 
healed and no wound healing complications (e.g., delayed healing, wound infection or fistula).
Axitinib should be held for a minimum of 4 weeks in any patient undergoing elective bowel 
surgery.
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 4 weeks following the last dose of study therapy.


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
3.6.1
Criteria for removal from protocol therapy:
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies:
Disease progression as defined in section 6.3.5
Intercurrent illness that prevents further safe administration of treatment
Unacceptable adverse event(s) as described in section 3.3
Non-compliance to therapy regimen
Patient decides to stop therapy
Investigator discretion
Positive pregnancy test
3.6.2
Off-Treatment Assessment
Patients will be assessed approximately 4 weeks following the last dose of study drug
with
o
Laboratory: Chemistries as defined in section 3.4, CBC
o
Medical history and physical exam
[These assessments can be performed by the patient’s local physician or at the NCI in Bethesda]
Patients will be removed from study 4 weeks following off treatment date if assessment 
indicates they have met the criteria for disease progression. If they have not met disease 
progression criteria, they will remain on study in order to determine their Progression Free 
Survival (PFS). Follow-up will be provided via either clinic visits or phone calls until such 
time as the patient either has disease progression, or begins an alternative treatment. Once 
progression has been determined, they will be removed from study.
3.6.3
Off-Study Criteria
Progression of disease and completion of off-study assessment
Death
Patient wishes to withdraw from the study
Patient receives an alternative treatment
The reason for removal from study will be documented.
3.6.4
Off Protocol Therapy and Off-Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Update Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
CONCURRENT THERAPIES
Incubation with recombinant CYP enzymes and human liver microsomes in the absence and 
presence of specific chemical inhibitors of human CYP suggest axitinib metabolism is 


33
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
primarily mediated by CYP3A4/5, and to a lesser extent by CYP1A2, CYP2C19 and 
UGT1A1. 
All potent CYP3A4/5 inhibitors (ketoconazole, itraconazole, clarithromycin, erythromycin, 
diltiazem, verapamil, delavirdine, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir) are 
not permitted within 7 days before dosing with axitinib.
The following CYP3A4/5 inducers (rifampin, rifabutin, carbamazepine, phenobarbital, 
phenytoin, St. John's wort, efavirenz, tipranavir) are not permitted within 12 days before 
dosing with axitinib.
During the study, potent CYP3A4/5 inhibitors and inducers are not recommended. 
Alternative therapies should be used when available. If usage of a potent CYP3A4 inhibitor 
or inducer is necessary, this must be in agreement with the Principal Investigator. See 
Appendix A for a complete list of CYP3A4/5 inhibitors, inducers and substrates.
The use of coumarin derivative anticoagulants such as warfarin (Coumadin
) is not 
recommended, though warfarin doses up to 2 mg daily are permitted for prophylaxis of 
thrombosis
Tobacco use will be strongly discouraged because smoking is a potent CYP1A2 inducer.  
Any subjects that are current smokers at the time of screening evaluation will be counseled 
regarding the interactions of smoking with the study medication and asked to cease smoking.
If they are willing to stop or limit smoking they will be considered for eligibility and allowed 
to enroll if they meet other eligibility requirements
The following antihypertensive medications commonly used in the treatment of 
pheochromocytoma are acceptable to use in conjunction with axitinib: phenoxybenzamine,
propranolol and metyrosine.
4.2
SUPPORTIVE CARE
Patients will be allowed to use erythropoietin or erythropoietin analogs prior to entry and during 
the course of the study.
4.2.1
Hand-foot reaction
Patients receiving axitinib who develop hand-foot reaction will be allowed to use topical 
emollients (e.g., Aquaphor® or Eucerin®), topical and/or oral steroids, antihistamine (H1-
receptor antagonist) agents, or vitamin B6 (pyridoxine: 50 to 150 mg orally each day). 
4.2.2
Nausea/vomiting 
Patients will not be given primary antiemetic prophylaxis. If a patient develops 
nausea/vomiting, antiemetics will be instituted for treatment of this side effect and may 
receive secondary antiemetic prophylaxis during continuing treatment with axitinib. Axitinib 
has been characterized as presenting minimal-low emetic risk; therefore, NK1 antagonists are 
not indicated and 5-HT3 antagonists should not be needed unless adverse effects preclude use 
of other antiemetic options.
4.2.3
Diarrhea
If diarrhea develops, and does not have an identifiable cause other than axitinib therapy, 
administer loperamide 4 mg p.o. after the first loose stool and 2 mg p.o. after each loose stool 


34
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
thereafter The occurrence of liquid stools after a 24 h diarrhea-free period will be considered 
a new episode.
If a patient develops blood or mucus in the stool, dehydration or hemodynamic instability, or 
if diarrhea persists > 48 h despite loperamide: discontinue loperamide and hospitalize the 
patient for treatment with IV fluids as needed.
For persistent diarrhea, other potentially helpful treatments may also be administered, such as 
somatostatin analogues, propantheline bromide, tincture of opium, diphenoxylate+atropine 
(Lomotil®) etc. Note: Propantheline bromide is not on the Clinical Center’s medication 
formulary and will not be readily available for dispensing from the Clinical Center pharmacy
4.2.4
Hypothyroidism
Axitinib is known to cause hypothyroidism.  Patients will receive replacement thyroid 
hormone according to standard medical practice if their thyroid function indicates 
hypothyroidism and is clinically indicated.
5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
As of amendment D all patients have completed the 24-week follow up and research samples are 
no longer being collected on this study.
5.1.1
Tissue Analysis for Potential Targets/Pathways Affected by Axitinib
Note on archival material: In order to accomplish these tests, a block of archival tumor material 
will be requested from each patient. A recent resection sample or blocks of tissue from the 
original resection will be requested. Where a block cannot be released by the governing 
Pathology Department, at least ten 10 x 8 mm re-cuts on charged slides will be requested.
5.1.1.1
Immunoblots/Immunohistochemistry:
The primary targets that may be evaluated based upon pre-clinical signaling data include but are 
not limited to the following: VEGFR-1, -2 and -3, AKT, p-AKT, ERK1/2, p-ERK1/2, MEK, p-
MEK, IGF1R, pIGF1R. These tests will be performed in the Department of Pathology, or in Dr. 
Sherry Yang’s laboratory BLDG 37, Rm 1048, phone 301-435-5409.
5.1.1.2
Studies of Microvessel Density 
Microvessel staining may be done in the Department of Pathology, or in Dr. Sherry Yang’s 
laboratory, but will not be required. Archival materials will be stained and analyzed for 
microvessel density (MVD) using standard immunohistochemical assays. Quantification of 
MVD will be performed using the method of Weidner et al. 59,60. Section will be stained for 
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.
5.1.2
Enumeration of Circulating Endothelial Cells (CEC)
Early increase of CEC following anti-angiogenic drug administration can be an interesting 
marker of treatment efficacy. Interpretation of CEC change must take into account multiple 
factors such as the mechanism of drug action, time of CEC measurement to drug administration, 


35
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
phenotype of CEC quantified [33,34]. Theoretically, various antigens can be used to characterize 
mature CEC. In general CD45 expression is used to exclude hematopoietic cells, CD133 to 
exclude immature cells. Commonly used endothelial markers include CD31, 146, 34, 144 or 105. 
However, there is a lack of consensus regarding combination to characterize CEC by flow 
cytometry analysis. In this study, we will evaluate pre- and post-treatment changes in mature 
circulating endothelial cells (CD 146+, CD133-), as determined by flow cytometry analysis. This 
evaluation will be conducted in Jane Trepel’s lab, NIH/NCI/GMB.
5.1.2.1
Specimen Collection
Blood samples should be drawn in 3 Blue/Black CPT tubes for a total volume of 24mLs at 
baseline and then weeks 8, 16 and 24.
5.2
SAMPLE STORAGE, TRACKING AND DISPOSITION 
5.2.1
Samples Managed by Dr. Fojo’s Laboratory
5.2.1.1
Storage/Tracking
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.
Samples will not be sent outside NIH without IRB notification and an executed MTA.
Research samples will be obtained from patients, as described in the protocol. Patient samples 
will either be processed and assayed fresh or will be coded in the laboratory of Dr. William Figg 
and then stored in a Liquid Nitrogen freezer in the laboratory of Dr. Tito Fojo. Records of 
sample acquisition will be held in the laboratory in a computerized database that is accessible by
password. A limited number of laboratory staff will have access to identifying patient 
information.
5.2.1.2
Protocol Completion/Sample Destruction:
Material remaining after completion of correlative studies will be transferred to the laboratory of 
Dr. William Figg. These samples will be managed in accordance with the laboratory’s policies 
and procedures. Any new use of the samples, specimens, or data will require prospective IRB 
review and approval.
5.2.2
Samples Managed by Dr. Figg’s Laboratory
5.2.2.1
Sample Data Collection
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user 
accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These 
computers all have a password restricted login screen. All Figg lab personnel with access to 
patient information annually complete the NIH online Protection of Human Subjects course. 
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 


36
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).
5.2.2.2
Sample Storage and Destruction
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80 C
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
5.2.3
Protocol Completion/Sample Destruction:
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. The PI will 
report any loss or destruction of samples to the NCI IRB as soon as he is made aware of such 
loss. If the patient withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not be 
able to be retrieved.
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (ex. 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.  Freezer problems, lost samples or other problems 
associated with samples will also be reported to the IRB, the NCI Clinical Director, and the 
office of the CCR, NCI.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant.


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End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Patients will be
followed for adverse events for 30 days after removal from study treatment or until off-study, 
whichever comes first.
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
Results in discontinuation from the study
Is associated with clinical signs or symptoms 
Requires treatment or any other therapeutic intervention
Is associated with death or another serious adverse event, including hospitalization. 
Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
Data will not be distributed outside NIH without IRB notification.
Dr. Fojo will continue to have access to the data for purposes of data analysis and publication 
when he is at Columbia University.  He will have access to the data via a secure flash drive.  It is 
also possible that data will be sent to him via encrypted email.
6.1.1
Exceptions for Data Recording
Data Recording during Long-term follow-up: When a subject has entered long-term follow-up
only a limited amount of information will be recorded in C3D: 
Progression-free survival and survival status, determined via phone calls, submission of 
imaging studies or actual clinic visits
Imaging Response per section 6.3.5
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share de-identified human data generated in this research for future research as follows:
De-identified data in a NIH-funded or approved public repository: clinicaltrials.gov
De-identified data in BTRIS 
De-identified in publication and/or public presentations
How and where will the data be shared? 
Data will be shared through:


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An NIH-funded or approved public repository: clinicaltrials.gov.
BTRIS (automatic for activities in the Clinical Center)
Approved outside collaborators under appropriate individual agreements.
Publication and/or public presentations.
When will the data be shared?
At the time of publication or shortly thereafter.
6.3
RESPONSE CRITERIA
6.3.1
Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 12 weeks (+/- 1
week). In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 
weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) 61.  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria.
6.3.2
Definitions
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with axitinib.
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable).
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.
6.3.3
Disease Parameters
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as:
By chest x-ray: >20 mm;
By CT scan: 
o
Scan slice thickness 5 mm or under as >10 mm with CT scan
o
Scan slice thickness >5 mm: double the slice thickness
With calipers on clinical exam: >10 mm.  


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All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions
under which such lesions should be considered must be defined in the protocol.
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph n
sidered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion that can be measured reproducibly should be selected. A
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.
6.3.4
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. The same method of assessment 
and the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical 


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
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examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules). 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: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible.
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances.
6.3.5
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions).


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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study
6.3.6
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis)
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 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. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).
6.3.7
Evaluation of Biochemical Response
Complete Biochemical Response (CR-B) – all major markers used for evaluation such as plasma 
or urinary catecholamines or metanephrines have normalized
Partial Biochemical Response (PR-B) – at least a 50% decrease, but not normalization, of the 
markers
Progressive Disease (PD-B) – at least a 25% increase of any major biochemical marker
Stable Disease (SD-B) – all other courses not described above.
6.3.8
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.
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Biochemical
Overall 
Response
Best Overall Response 
when Confirmation is 
RequiredA
CR
CR
No
CR-B
CR
4 wks. ConfirmationB
CR
Non-CR/
Non-PD
No
CR-B, PR-B, 
or SD-B
PR
4 wks. ConfirmationB
CR
Not 
evaluated
No
CR-B, PR-B, 
or SD-B
PR
PR
Non-CR/
No
CR-B, PR-B, 
PR


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Biochemical
Overall 
Response
Best Overall Response 
when Confirmation is 
RequiredA
Non-PD/
Not 
evaluated
or SD-B
PR
Non-CR/
Non-PD/
Not 
evaluated
No
CR-B, PR-B, 
or SD-B
PR
SD
Non-CR/
Non-PD/
Not 
evaluated
No
SD-B
SD
Documented at least 
once 4 weeks from 
baselineB
PD
Any
Yes or 
No
Any
PD
No prior SD, PR or CR
Any
PDC
Yes or 
No
Any
PD
Any
Any
Yes
Any
PD
Any
Any
Yes or 
No
PD-B
PD
ASee RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
BOnly for non-randomized trials with response as primary endpoint.
CIn exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression.
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after discontinuation of treatment
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDA
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
A‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease; to assign this category when no 
lesions can be measured is not advised
6.3.9
Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 


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recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.10 Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first.
6.3.11 Response Review
At the conclusion of the study, all responses will be reviewed by an expert(s) independent of the 
study. Simultaneous review of the patients’ files and radiological images is the planned 
approach.
6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).
7
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
7.1
DEFINITIONS
7.1.1
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.
7.1.2
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.
7.1.3
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, 


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
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if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected,” also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
7.1.4
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.
7.1.5
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:
Death
A life-threatening adverse drug experience
Inpatient hospitalization or prolongation of existing hospitalization
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
7.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
7.1.7
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.
7.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9
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.
7.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
Is unexpected in terms of nature, severity, or frequency in relation to 


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(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
Is related or possibly related to participation in the research; AND
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.
7.2
NCI-IRB AND CLINICAL DIRECTOR REPORTING
7.2.1
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 the NCI Clinical 
Director:
All deaths, except deaths due to progressive disease
All Protocol Deviations
All Unanticipated Problems
All non-compliance
Reports must be received within 7 days of PI awareness via iRIS.
7.2.2
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
3. A tabular summary of the following adverse events:
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research; 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
All Grade 5 events regardless of attribution; 
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. 
7.2.3
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.
7.3
IND SPONSOR REPORTING CRITERIA
An investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a, any serious adverse event, whether or not considered drug related, including those listed 
in the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event. For serious adverse events that occur more 


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
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than 30 days after the last administration of investigational agent/intervention, only report those 
that have an attribution of at least possibly related to the agent/intervention.
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor.
Tito Fojo, M.D., Ph.D., 
Columbia University
Division of Hematology/Oncology
177 Fort Washington Ave.
MHB 6GN -435
New York, NY 10032
Tel: 646-317-6299
Fax: 212-305-3035
E-mail: atf2116@cumc.columbia.edu
7.4
DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.
7.4.2
Sponsor Monitoring Plan
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on:
Informed consent process
Eligibility confirmation
Drug administration and accountability
Adverse events monitoring
Response assessment.


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The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct.
8
STATISTICAL CONSIDERATIONS
8.1
SELECTION BASED ON GENDER, ETHNIC BACKGROUND, OR RACE 
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  No information suggests that there are differences in drug metabolism or 
disease response in any patient subgroup based on gender, race, or ethnic background.  Efforts 
will be made to accrue a representative population and if differences in outcome are noted to 
correlate with gender, race, or ethnicity, accrual may be expanded or a follow-up study written to 
investigate these differences.
8.2
JUSTIFICATION FOR EXCLUSIONS
Due to lack of knowledge of the effects of axitinib on the fetus or on infants, as well as the 
possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial. 
Patients with HIV on protease inhibitors are excluded because information on drug interactions 
of anti-HIV agents with axitinib are lacking. Patients with unstable or serious medical conditions 
(ongoing or active infection, symptomatic congestive heart failure (AHA Class II or worse), 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements) are excluded due to the possibility that axitinib may 
worsen their condition and the likelihood that the underlying condition may obscure the 
attribution of adverse events with respect to axitinib. Patients under the age of 18 will be 
excluded from study. The effect of axitinib in children may be investigated in studies that 
exclusively enroll children.
8.3
STUDY DESIGN/ENDPOINTS
The primary objective of this study is to conduct a Phase II trial to determine if axitinib is able to 
be associated with sufficient clinical responses to merit further consideration for use in patients 
with metastatic pheochromocytoma/paraganglioma.
Secondary objectives are to determine the progression-free survival and to explore the 
relationship of potential biological markers of axitinib activity with clinical outcomes.  
Specifically, to examine the extent of activation of the VEGFR pathway in 
pheochromocytoma/paraganglioma in a qualitative manner by immunoblot and in a semi-
quantitative manner by immunohistochemistry staining; and also to assess the effect of axitinib 
on the VEGFR pathway for patients who have repeat biopsies taken while on treatment.
The study will be conducted using a phase II optimal design 62. The objective of the trial will be 
to determine if axitinib is able to be associated with a response rate (PR + CR), which can rule 
out 5% (that is, p 0 = 0.05) in favor of a more desirable 20% response rate (p1 = 0.20). Using 
alpha = 0.10 (probability of accepting a poor drug) and beta = 0.10 (probability of rejecting a 
good drug), initially 12 patients will be enrolled onto the trial. If zero of the 12 patients respond, 
then accrual will end, and we will conclude that the agent is unable to demonstrate a response 


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
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rate that is worthy of further consideration in this population. If 1 or more of 12 patients have a 
CR or PR, then accrual will continue until a total of 37 patients with measurable disease have 
been enrolled. If 1-3 of these 37 have a CR or PR, this will be considered inadequate for further 
investigation, while if 4 or more of 37 have a response, this will warrant further investigation in a 
subsequent trial. Under the null hypothesis (5% response rate), the probability of early 
termination is 54%. Primary clinical responses (PR + CR) will be assessed at 12 weeks (+/- 1
week). If zero of 11 patients responded, accrual will stop up to 4 months waiting to evaluate the 
last patient’s response before continuing accrual.
8.4
SAMPLE SIZE/ACCRUAL RATE
The accrual ceiling to the trial will be set at 37 patients. It is expected that 1 - 3 patients per 
month will enroll onto this protocol. Thus, accrual is expected to complete within 2-3 years. We 
receive approximately 2 referrals from Dr. Karel Pacak in NICHD each month. Many of these 
will be eligible for this study.  If we are unable to enroll 8 patients in the first year, accrual will 
be stopped.
8.5
ANALYSIS OF SECONDARY ENDPOINTS
Exploratory non-parametric analyses using trend tests will be performed to describe the 
relationship between the translational endpoints and the clinical outcome, primarily. Since all of 
these analyses will be performed with exploratory intent, the analysis results will be presented 
without any adjustment for multiple comparisons, but with careful discussion of the hypothesis-
generating nature of the analyses undertaken. Analysis for statistically significant correlations
will be planned for the following parameters defined as being of particular interest but are not 
limited to the following: VEGFR-1, -2 and -3, AKT, p-AKT, ERK1/2, p-ERK1/2, MEK, p-
MEK, IGF1R, pIGF1R. and Microvessel Density (CD31 staining)
In general, it is anticipated that non-parametric analyses will generally be used for these 
evaluations because of the limited number of subjects. In view of the exploratory nature of these 
analyses, any p-values reported will not be adjusted for multiple comparisons, and results of any 
such analyses will be stated carefully as being hypothesis generating, requiring additional 
confirmation.
For all evaluable patients (subjects who received at least 2 cycles), Kaplan-Meier analyses of 
progression free survival will also be performed. Appropriate confidence intervals at selected 
time points will also be provided. Since these will be considered secondary endpoints. The 
results will be reported as part of the descriptive report of the study.
Adverse events will be tabulated by type and grade, for all types of adverse events identified as 
being at least possibly attributable to the agent.
9
COLLABORATIVE AGREEMENTS
9.1
AGREEMENT TYPE
Axitinib is an investigational agent supplied to investigators by the Pfizer Pharmaceuticals, Inc. 
Axitinib is provided to NCI under a Clinical Trial Agreement (CTA).


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10
HUMAN SUBJECTS PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION
This study will be open to all individuals with pheochromocytoma/paraganglioma regardless of 
gender, ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are 
met. This study will be recruited through internal referral, our local physician referral base, and 
through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-
4Cancer). It should be noted that for the past several years we have seen on average over 80 new 
referrals per year. Subjects from both genders and all racial/ethnic groups are eligible for this 
study if they meet the eligibility criteria outlined in section 2. 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.
10.2 PARTICIPATION OF CHILDREN
Patients under the age of 18 will be excluded from study. The effect of axitinib in children may 
be investigated in studies that exclusively enroll children.
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.4 ), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in NIH MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects 
who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed.
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The potential benefit to a patient who enters study is a reduction in the bulk of his/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.


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10.5 RISKS/BENEFITS ANALYSIS
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 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.
10.6 CONSENT 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. The 
original of the signed informed consent will be placed in the patient's medical record and a copy 
in the research record. 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.
10.6.1 Reconsent via the telephone
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.  
A fully executed copy will be returned via mail for the subject’s records.
The informed consent process will be documented on a progress note by the consenting 
investigator.
10.6.2 Informed consent of non-English speaking subjects
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2).  The 
summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be 
given to the subject or their legally authorized representative and the signed original will be filed 
in the medical record.
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible). 


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We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form.
11
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION  
11.1 AXITINIB 109,131
11.1.1 Source
Axitinib is an investigational agent supplied to investigators by the Pfizer Pharmaceuticals, Inc. 
Axitinib is provided to the NCI under a CTA (see section 9.1).
11.1.2 Toxicity
The most commonly reported treatment-related adverse events of severity Grade 3 or higher 
were hypertension (39 subjects, 14%), fatigue (27 subjects, 10%), diarrhea (12 subjects, 4%), 
palmar plantar erythrodysaesthesia syndrome (8 subjects, 3%), hypertension aggravated (5 
subjects, 2%), and stomatitis (5 subjects, 2%), elevated triglycerides (1 subject, < 1%). 
Table 10: Treatment-Emergent, All-Causality Adverse Events in at Least 10% of Subjects with 
Solid Tumors Receiving Single Agent Axitinib


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Table 11: Laboratory Test Results Reported for Subjects with Solid Tumors Receiving Single-
Agent Axitinib.
Thirty-five (35) of 280 subjects (13%) treated with single agent axitinib discontinued therapy 
because of treatment-related adverse events (see Table 10).


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Table 12: Treatment-Related Averse Events Resulting in Treatment Discontinuation for 
Subjects Receiving Single Agent Axitinib at 5 mg twice daily
Note: Axitinib 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.
11.1.3 Formulation and preparation
Axitinib is supplied as an immediate-release film-coated tablets containing either 5 mg or 1 mg 
of the free base, axitinib, and common compendial excipients. The 5 mg tablets are red and 
triangular; the 1 mg tablet is red and oval. The film coating has no effect on the rate of release of 
the active axitinib.
11.1.4 Stability and Storage
Store at controlled room temperature storage within the temperature range 20° – 25°C (68° –
77°F) with excursions permitted to 15° - 30° C (59° – 86°F). Storage conditions should not 
exceed 25ºC. The current shelf life is 24 months when stored at controlled room temperature.
11.1.5 Administration procedures
Oral, axitinib should be taken with at least 250 mL of water and will be given with or without 
food.


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11.1.6 Incompatibilities
11.1.6.1 Product Description
Axitinib is white to light yellow crystalline powder.
Chemical Name: N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl-)-1H-indazol-6-ylsulfanyl]-benzamide 
Other Names: AG-013736
Classification: Kinase inhibitor (VEGF-R, and PDGF-R)
Mechanism of Action: Axitinib (AG-013736) is an oral, potent and selective inhibitor of VEGF 
receptors 1, 2, 3 (vascular endothelial growth factor receptors 1, 2, 3). Preclinical data suggest 
that axitinib has anti-tumour activity that appears to result from its anti-angiogenic activity, 
which is reversible when treatment is discontinued
Molecular Formula: C22H18N4OS
Molecular Weight: 386.47 Daltons
Structural formula:
11.1.6.2 Drug Interactions
Incubation with recombinant CYP enzymes and human liver microsomes in the absence and 
presence of specific chemical inhibitors of human CYP suggest axitinib metabolism is primarily 
mediated by CYP3A4/5, and to a lesser extent by CYP1A2, CYP2C19 and UGT1A1. A mean 
2-fold increase in exposure of axitinib was observed when axitinib was co-administered with 
ketoconazole, a potent inhibitor of CYP3A4/5. A mean 3.5-fold decrease in axitinib plasma 
exposure was observed when axitinib was co-administered with rifampin, a potent inducer of 
CYP3A4/5. Therefore, co-administration with potent inhibitors (ketoconazole, itraconazole, 
clarithromycin, erythromycin, diltiazem, verapamil, delavirdine, indinavir, saquinavir, ritonavir, 
atazanavir, nelfinavir) and inducers (rifampin, rifabutin, carbamazepine, phenobarbital, 
phenytoin, St. John's wort, efavirenz, tipranavir) of CYP3A4/5 may result in significant increases
and decreases in exposure of axitinib, respectively, and may alter the safety/efficacy of the drug. 
All potent CYP3A4/5 inhibitors and inducers are not permitted within 7 and 12 days, 
respectively, before commencing axitinib administration. During the study, potent CYP3A4/5 
inhibitors and inducers are not recommended in concurrent use with axitinib. Alternative 
therapies should be used when available. If usage of a potent CYP3A4/5 inhibitor or inducer is 
necessary, this must be in agreement with the Sponsor. The use of coumarin derivative 


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anticoagulants such as warfarin (Coumadin
) is not recommended, though warfarin doses up to 
2 mg daily are permitted for prophylaxis of thrombosis.


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12
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13
APPENDICES
13.1 APPENDIX A: LIST OF DRUGS THAT MAY HAVE POTENTIAL CYP3A4 INTERACTIONS
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy 
CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, 
OH; LexiComp Inc. 2007: 1899-1912. Only major substrates and effective inducers are listed.  
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/
CYP3A4 Substrates
Albuterol
Alfentanil
Alprazolam
Amiodarone
Amlodipine
Amprenavir
Aprepitant
Aripiprazole
Atazanavir
Atorvastatin
Benzphetamine
Bisoprolol
Bortezomib
Bosentan
Bromazepam
Bromocriptine
Budesonide
Buprenorphine
Buspirone
Busulfan
Carbamazepine
Cerivastatin
Chlordiazepoxide
Chloroquine
Chlorpheniramine
Cilostazol
Cisapride
Citalopram
Clarithromycin
Clobazam
Clonazepam
Clorazepate
Cocaine
Colchicine
Conivaptan
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel
Doxepin
Doxorubicin
Doxycycline
Efavirenz
Eletriptan
Enalapril
Eplerenone
Ergoloid mesylate
Ergonovine
Ergotamine
Erythromycin
Escitalopram
Estradiol
Estrogens, conj., synthetic
Estrogens, conj., equine
Estrogens, conj., esterified
Estrone
Estropipate
Ethinyl estradiol
Ethosuximide
Etoposide
Exemestane
Felbamate
Felodipine
Fentanyl
Flurazepam
Flutamide
Fluticasone
Fosamprenavir
Gefitinib
Haloperidol
Isradipine 
Itraconazole
Ketamine 
Ketoconazole
Lansoprazole
Letrozole
Levonorgestrel
Lidocaine
Losartan
Lovastatin
Medroxyprogesterone 
Mefloquine
Mestranol
Methadone
Methylergonovine
Methysergide
Miconazole
Midazolam
Miglustat
Mirtazapine
Modafinil
Montelukast
Moricizine
Nateglinide
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Norethindrone
Norgestrel
Ondansetron
Paclitaxel
Quinidine
Rabeprazole 
Ranolazine
Repaglinide
Rifabutin
Ritonavir
Salmeterol
Saquinavir
Sibutramine
Sildenafil
Simvastatin
Sirolimus
Spiramycin
Sufentanil
Sunitinib
Tacrolimus
Tamoxifen
Tamsulosin
Telithromycin
Teniposide
Tetracycline
Theophylline
Tiagabine
Ticlopidine
Tipranavir
Tolterodine
Toremifene
Trazodone
Triazolam
Trimethoprim
Trimipramine
Troleandomycin
Vardenafil
Venlafaxine
Verapamil


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Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Cyclophosphamide
Cyclosporine
Dantrolene
Dapsone
Dasatinib (1)
Delavirdine
Diazepam
Ifosfamide
Imatinib
Indinavir
Irinotecan
Isosorbide
Isosorbide dinitrate
Isosorbide mononitrate
Pergolide
Phencyclidine
Pimozide
Pipotiazine
Primaquine
Progesterone
Quetiapine
Vinblastine
Vincristine
Vinorelbine
Zolpidem
Zonisamide
Zopiclone
Note: When drugs classified as ‘substrates’ are co-administered with Axitinib, there is the 
potential for higher concentrations of the ‘substrate’.
CYP3A4 Inhibitors
Acetaminophen
Acetazolamide
Amiodarone
Amlodipine
Amprenavir
Anastrozole
Aprepitant
Atazanavir
Atorvastatin
Azelastine
Azithromycin
Betamethasone
Bortezomib
Bromocriptine
Caffeine
Cerivastatin
Chloramphenicol
Chlorzoxazone
Cimetidine
Ciprofloxacin
Cisapride
Clarithromycin
Clemastine
Clofazimine
Clotrimazole
Clozapine
Cocaine
Conivaptan
Cyclophosphamide
Cyclosporine
Danazol
Dasatinib (1)
Delavirdine
Desipramine
Diclofenac 
Dihydroergotamine 
Diltiazem
Disulfram
Docetaxel
Doxorubicin
Doxycycline
Drospirenone
Efavirenz
Enoxacin
Entacapone
Ergotamine
Erythromycin
Ethinyl estradiol
Etoposide
Felodipine
Fentanyl
Fluconazole
Fluoxetine
Fluvastatin
Fluvoxamine
Fosamprenavir
Glyburide
Grapefruit juice (2)
Haloperidol
Hydralazine
Ifosfamide
Imatinib
Indinavir
Irbesartan
Isoniazid
Isradipine
Itraconazole
Ketoconazole
Lomustine
Losartan 
Lovastatin
Mefloquine
Mestranol
Methadone
Methimazole
Methoxsalen
Methylprednisolone
Metronidazole
Miconazole
Midazolam
Mifepristone
Mirtazapine
Mitoxantrone
Modafinil
Nefazodone
Nelfinavir
Nevirapine
Nicardipine
Nifedipine
Nisoldipine
Nizatidine
Norfloxacin
Olanzapine
Omeprazole
Orphenadrine
Oxybutynin
Paroxetine
Pentamidine
Pergolide
Phencyclidine
Pilocarpine
Pimozide
Primaquine
Progesterone
Propofol 
Propoxyphene
Quinidine
Quinine
Quinupristin
Rabeprazole
Ranolazine
Risperidone
Ritonavir
Saquinavir
Selegiline
Sertraline
Sildenafil
Sirolimus
Sulconazole
Tacrolimus
Tamoxifen
Telithromycin
Teniposide
Testosterone
Tetracycline
Ticlopidine
Tranylcypromine
Trazodone
Troleandomycin
Valproic acid
Venlafaxine
Verapamil
Vinblastine
Vincristine
Vinorelbine
Voriconazole


64
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
Dexmedetomidine
Diazepam
Lansoprazole
Lidocaine
Pravastatin
Prednisolone
Zafirlukast
Ziprasidone
Note: When Axitinib is co-administered with compounds classified as ‘inhibitors’, increased 
plasma concentrations of Axitinib is the potential outcome.
CYP3A4 Inducers
Aminoglutethimide
Carbamazepine
Fosphenytoin
Nafcillin
Nevirapine
Oxcarbazepine
Pentobarbital
Phenobarbital 
Phenytoin
Primidone
Rifabutin
Rifampin 
Rifapentine
St. John’s wort (3)
Note: The co-administration of ‘inducers’ would potentially lower plasma Axitinib
concentrations.
Investigator’s Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006
Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23.
Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249
Frye et al. (2004). Clin Pharmacol Ther. 76:323-329.
Updated on May 1, 2007


65
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
13.2 APPENDIX B: STUDY DIARY
Day / Date
Axitinib taken
yes/no
Blood Pressure: record your BP prior to taking axitinib. If 
>150/>100, repeat in 5 minutes.  If still >150/>100, do not 
take axitinib and repeat in one hour.  If <150/<100 take the 
axitinib;  If still >150/>100 after one hour do not take the 
axitinib for that dose.
Symptoms, other 
medicines taken
Sunday
Date:
AM Y/N 
time ___
PM Y/N 
time ___
AM BP ________, time______
AM BP ________, time______ if needed
AM BP ________, time______ if needed
PM BP ________, time______
PM BP ________, time______ if needed
PM BP ________, time______ if needed
Monday
Date:
AM Y/N 
time ___
PM Y/N 
time ___
AM BP ________, time______
AM BP ________, time______ if needed
AM BP ________, time______ if needed
PM BP ________, time______
PM BP ________, time______ if needed
PM BP ________, time______ if needed
Tuesday
Date:
AM Y/N 
time ___
PM Y/N 
time ___
AM BP ________, time______
AM BP ________, time______ if needed
AM BP ________, time______ if needed
PM BP ________, time______
PM BP ________, time______ if needed
PM BP ________, time______ if needed
Wednesday
Date:
AM Y/N 
time ___
PM Y/N 
time ___
AM BP ________, time______
AM BP ________, time______ if needed
AM BP ________, time______ if needed
PM BP ________, time______
PM BP ________, time______ if needed
PM BP ________, time______ if needed
Thursday 
Date:
AM Y/N 
time ___
PM Y/N 
time ___
AM BP ________, time______
AM BP ________, time______ if needed
AM BP ________, time______ if needed
PM BP ________, time______
PM BP ________, time______ if needed
PM BP ________, time______ if needed
Friday
Date:
AM Y/N 
time ___
PM Y/N 
time ___
AM BP ________, time______
AM BP ________, time______ if needed
AM BP ________, time______ if needed
PM BP ________, time______
PM BP ________, time______ if needed
PM BP ________, time______ if needed
Saturday
Date
AM Y/N 
time ___
PM Y/N 
time ___
AM BP ________, time______
AM BP ________, time______ if needed
AM BP ________, time______ if needed
PM BP ________, time______
PM BP ________, time______ if needed
PM BP ________, time______ if needed


66
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018
13.3 APPENDIX C: PFIZER FAX COVER FORM   
On following page


67
Abbreviated Title: Phase II Axitinib in PHEO/PGL
Version Date: 3/26/2018

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
14-C-0001 
PRINCIPAL INVESTIGATOR: Andrea Apolo, M. D. 
STUDY TITLE:  
Phase II Study of Axitinib (AG-013736) with Evaluation of the VEGF-pathway in 
Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma 
Continuing Review Approved by the IRB on 03/25/19 
Amendment Approved by the IRB on 04/18/18 (G) 
Date posted to web: 04/06/19 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
INTRODUCTION
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.
Why is this study being done?
Axitinib (AG-013736) is an investigational (experimental) drug that is being studied in patients 
with metastatic pheochromocytoma/paraganglioma.  This drug was approved by the FDA in 
2012 for the treatment of kidney cancer. Although it is FDA-approved, it is still considered 
experimental in this study because it has never been studied in people with 
pheochromocytoma/paraganglioma. The main goal of this study is to find out if axitinib is able to 
stop tumors from growing, or shrink tumors in patients with this type of cancer.


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 2 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
Why are you being asked to take part in this study? 
You are being asked to be a part of this study because you have a diagnosis of metastatic 
pheochromocytoma/paraganglioma and have tried at least one treatment for the disease that 
either did not work or is no longer working. Taking part in this study may or may not make your 
health better.  While doctors hope axitinib 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 
axitinib as a treatment for cancer and could help future cancer patients.
How many people will take part in this study?  
Twelve patients will be enrolled at first.  If at least one of the first 12 patients has a good 
response (shrinkage or disappearance of their tumors) a total of 37 patients will be enrolled.
Description of Research Study 
You will receive the study drug, axitinib, orally twice a day, every day, in 28-day cycles. You 
will start at a dose of 5mg twice a day.  After 4 weeks, your dose may be increased to 7mg twice 
a day and later on to 10mg twice a day after you are carefully checked by your study team and 
are feeling good without any significant side effects. You may take axitinib with or without food. 
What will happen if you take part in this research study?   
Evaluation Tests before the Study Begins 
Prior to starting (or “enrolling”) on the study, an evaluation will be done at the NIH Oncology 
Clinic to determine if this study is appropriate for you. This is called “screening” and a different 
consent form explains the tests required for screening. 
All cancer diagnoses must be confirmed by a pathologist at the NIH, who will look at the 
specimen slides from your prior biopsy or surgery. If a pathology specimen is not available from 
previous surgery, a pathology report from a prior biopsy or surgery confirming your diagnosis 
will be accepted. Results from an imaging study that would only be positive in an adult patient 
with your diagnosis may also be accepted.  
What does this study involve? 
During the study 
If you enroll in the study you will need the following tests and procedures as part of the study. 
Many of these are part of regular cancer care.   They are being done more often because you are 
in this study.
• Blood and urine tests will be done once every 4 weeks during the first 3 months, and then 
once every 12 weeks after the first 3 months
• Blood tests for research-only purposes will be done at the beginning of the first cycle and 
then at 8, 16 and 24 weeks.
• You will check your blood pressure twice a day during the first 4 weeks, then once a 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 3 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
week after the first 4 weeks.  You will have a diary to write down your blood pressure 
readings.
• You will have a CT and/or MRI scan every 12 weeks as part of this study. The scan 
compares the baseline scan (before you begin axitinib) to the scan after receiving axitinib, 
in order to figure out if the tumor(s) are the same size, smaller, or larger.  You will need to 
have the scans in order to participate in the study. 
When you are finished taking the drugs 
You will be invited to clinical center approximately 4 weeks following the last dose of study 
drug.  The following assessments will be performed at this visit: 
Medical history and physical exam 
Routine blood and urine tests 
24-hour urine test 
Review of your side effects 
If you are unable to travel to the NIH, we will contact you by telephone and ask you about any 
side effects you might have and any new treatments you may have started.   
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 3 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.
Effective forms of birth control include
•
abstinence  
intrauterine device (IUD) 
•
hormonal [birth control pills, injections, or implants] 
•
tubal ligation 
•
vasectomy 
Drug Interactions 
You should not drink grapefruit juice or smoke cigarettes while participating in this study.  
Grapefruit juice and cigarette smoking are both known to interfere with the body’s ability to 
process the study medication. You should contact the research team before taking any 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 4 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
medication or supplement. Other medications and supplements may interact with axitinib and 
might affect the activity and/or side effects of axitinib. 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  Side effects can be mild or serious. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after you stop 
taking the drug.  In some cases, side effects can be serious, long lasting, or may never go away, 
and can even result in death.
You should talk to your study doctor about any side effects that you have while taking part in the 
study.  Likely side effects are those seen in up to one third of patients who received single agent 
axitinib in earlier trials.   
Risks and side effects of axitinib may include:  
Likely 
Less Likely 
Rare but Serious 
• Fatigue 
• Diarrhea 
• Hypertension 
• Nausea 
• Anorexia 
• Hoarseness of voice  
• Shortness of breath 
• Weight loss 
• Constipation 
• Headache 
• Vomiting 
• Cough 
• Leg pain  
• Gastroesophageal reflux 
disease 
• Mouth soars 
• Abdominal pain 
• Back pain 
• Insomnia 
• Leg swelling 
• Rash 
• Dizziness  
• Decrease in the white blood 
cells 
(the 
cells 
that 
fight 
infection) and can result in 
infection that may or may not 
require 
treatment 
with 
antibiotics  
• Decrease in red blood cells 
(the cells that carry oxygen to 
your body), which can cause 
tiredness 
and 
shortness 
of 
breath and may required a 
transfusion of  red blood cells)
• Decrease in platelets (the cells 
that help with blood clotting) 
which can increase the risk of 
bleeding or bruising
• Loss of protein in urine 
• Intestinal perforations 
• Stroke 
• Thrombosis ( Blood clots) 
• Myocardial Infarction ( heart 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 5 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
• Muscle pains 
• Thyroid abnormalities 
• Increased blood glucose 
• Electrolyte abnormalities  
• Low blood pressures  
• Skin peeling from hands and 
feet also known as the hand 
and foot syndrome 
attacks) 
• Arrhythmias (Heart rate or 
rhythm abnormalities) 
• Abnormal kidney function or 
failure 
• Liver function abnormality or 
failure 
• Reversible posterior 
leukoencephalopathy, a disorder 
associated with findings on 
MRI. The symptoms include   
headache, high blood pressure, 
decreased alertness, change in 
mental functioning, seizures, 
and 
vision 
loss, 
including 
blindness.  These symptoms are 
usually reversible. 
• Elevated levels of 
triglycerides. 
Since the drug is still being studied there may be other side effects that have not been described 
before.
If you are pregnant you will not be permitted to participate in this research study. If you are 
breast feeding and the protocol involves injection of radioactive material you will not be 
permitted to participate.  It is best to avoid radiation exposure to unborn or nursing infants since 
they are more sensitive to radiation than adults. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental treatment will cause your tumors to shrink.  
We do not know if you will receive personal, medical benefit from taking part in this study.   
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  Because there is not much information about the 
drug’s effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 6 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options
Getting treatment or care for your cancer without being on a study 
Taking part in another study 
Getting no treatment at all 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Research Subject’s Rights 
What are the costs of taking part in this study?
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
National Cancer Institute Institutional Review Board 
The study Sponsor, Dr. Tito Fojo or his representatives 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 7 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
Qualified representatives from Pfizer, the pharmaceutical company who produces 
axitinib. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time. 
Stopping Therapy
Your doctor may decide to stop your therapy for the following reasons: 
if he/she believes that it is in your best interest 
if  the cancer grows or becomes worse during treatment 
if you have side effects from the treatment that your doctor thinks are too severe 
if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Pfizer 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. 
Certificate of Confidentiality 
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
will be used for auditing or program evaluation internally by the NIH; or  
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
is necessary for your medical treatment and you have consented to this disclosure;  
is for other research.


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 8 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others.
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.
Pfizer Pharmaceuticals, Inc. is providing Axitinib for this study to NIH without charge.  No NIH 
employee involved in this study receives any payment or other benefits from Pfizer 
Pharmaceuticals, Inc. 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.
It might help people who have cancer and other diseases in the future.
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 


MEDICAL RECORD 
CONTINUATION SHEET for either:
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 9 of 11 pages 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either:
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 10 of 11 pages 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations.
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government.  However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action. 
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Andrea Apolo, M.D., Building 10, Room 13N240, Telephone: 301-480-0536. You 
may also call the Clinical Center Patient Representative at 301-496-2626. If you have any 
questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone: 240-760-6070.
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 14-C-0001 
CONTINUATION: page 11 of 11 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 MARCH 25, 2019 THROUGH APRIL 22, 2020. 
Signature of Investigator 
Date 
Signature of Witness 
Date 
Print Name 
Print Name