Clinical trial NCT00828919
Conditions: Solid Tumors
Keywords: VEGFR inhibitor angi-angiogenic tyrosine kinase inhibitor
Sponsor: Pfizer
Start date: 2003-03-07; Completion date: 2023-08-14
Enrollment: 52 participants; Allocation: NA; Intervention model: 

Brief summary:
To allow continuation of axitinib (AG 013736) treatment to patients experiencing clinical benefit in a closing axitinib trial

Detailed description:
This is a roll over study aimed to provide continued access to axitinib (monotherapy or combination, according to treatment received in prior axitinib study) to patients who have documented stable, or responding disease, or received clinical benefit (as defined by protocol) at the time of the prior study closure.

Arms: arm 1: Patients continue the same treatment (axitinib monotherapy or in combination with crizotinib) as in prior axitinib study
Interventions: intervention 1: axitinib intervention 2: crizotinib
Intervention descriptions: intervention 1: BID oral tablets. dose of axitinib (AG 013736) will be the same as they were taking in the previous trial intervention 2: BID oral Capsules. Dose of crizotinib will be the same taken in previous axitinib trial.

Protocol documents:
Prot_SAP_000.pdf: 
Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
PFIZER CONFIDENTIAL
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CLINICAL PROTOCOL
CONTINUING ACCESS TO THE TYROSINE KINASE INHIBITOR OF VEGFR-2, 
AG-013736 (A406) FOR PATIENTS PREVIOUSLY RECEIVING AG-013736 IN 
CLINICAL TRIALS
Compound:
Axitinib (AG-013736)
Compound Name:
Inlyta®
US IND Number:
63,662
European Clinical Trial Database (EudraCT) 
Number:
2005-000051-15
Protocol Number:
A4061008
Phase:
N/A
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not to disclose it 
to others (except where required by applicable law) or to use it for unauthorized purposes.  In the event of any 
actual or suspected breach of this obligation, Pfizer should be promptly notified.


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Document History
Document
Version Date
Summary of Changes
Amendment 7
08 November 2018
Main changes include:*
1.
Update of protocol language to include 
reference/information on the combination 
options, as needed (the combination 
treatment is already allowed as per protocol, 
but relevant details are not specified). 
2.
Inclusion, as an Appendix, of A4061068 
Protocol (US IND#s 63,662 and 73,554) to 
be used as reference for patients in 
combination treatment with axitinib + 
crizotinib.
3.
Update of protocol wording, where possible, 
according to the new template to align with 
the current Pfizer SOP (Standard Operating 
procedures).
*Changes 1 and 2 are applicable only for patients 
coming from study A4061068 (ie, US sites).
Amendment 6
05 December 2012
Main changes include:

Update of safety information to align with 
most recent version of Investigator Brochure 
(IB).

Update AE and safety wording, including 
pregnancy and Hy’s law, to align with current 
Pfizer SOP (Standard Operating Procedures).

Review and simplification of wording and 
procedures where possible. 
Amendment 5
15 December 2008

See Amendment 5, Appendix D for details.
Amendment 4
06 February 2008

See Amendment 5, Appendix C for details.
Amendment 3
17 October 2006 

See Amendment 5, Appendix B for details.
Amendment 2
04 November 2004

See Amendment 5, Appendix A for details.


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Document
Version Date
Summary of Changes
Amendment 1
19 December 2002

See Amendment 1, for details.
Original 
Protocol
23 September 2002
N/A
This amendment incorporates all revisions to date, including amendments made at the
request of country Health Authorities, IRB/ERB, ECs etc.  


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SUMMARY
Indication:
Patients who have been treated in previous Pfizer sponsored oncology studies, with axitinib 
either as monotherapy or in combination with another anticancer drug.
Rationale:
Some patients in axitinib clinical trials may be experiencing clinical benefit from axitinib 
treatment either as monotherapy or in combination with another anticancer drug and may 
wish to continue treatment following completion of the trial. Such patients, after a written 
re consent, may continue to receive axitinib and the combination study drug (if applicable) at 
the same dose and schedule as specified in their prior axitinib protocol with the consensus of 
the principal investigator and the approval of the sponsor company until patients no longer 
experience clinical benefit, develop unacceptable toxicity or withdraw consent. Complete 
information for the study drug(s) may be found in the Single Reference Safety Documents, 
which for this study are the current Investigator Brochures (IBs).
Objectives:
The objective of the trial is to provide continued access to axitinib tablets and study drug(s) 
given in combination (if applicable) to patients who have completed their participation in a 
prior axitinib monotherapy or combination study and who have documented stable or 
responding disease at the time they discontinued in the trial. Continuing access will be 
provided to patients who have Progressive Disease (PD) but continue to experience clinical 
benefit from previous study treatment; in this case, clinical benefit is defined as the Sum of 
Longest Diameters (SLD) of measurable lesions remaining less than or equal to the baseline 
SLD in the previous axitinib trial (either monotherapy or combination).  These patients must 
not be eligible for treatment with other available approved therapy for the disease under 
study. 
Trial Design:
Axitinib trials (either monotherapy or combination) have been designed with a maximum 
number of treatment cycles or length of treatment time.  However, some patients may be 
deriving clinical benefit from the drug(s) and want to continue treatment with the 
investigational agent(s) but are unable to continue in their present trial.
This protocol will provide continued access to axitinib tablets and the combination study 
drug(s) if applicable for patients who were assigned to an axitinib-containing treatment arm 
in an axitinib clinical trial. For patients in combination treatment, if axitinib is interrupted 
due to toxicity, the continuation of the combination drug will be evaluated on a case by case 
analysis after discussion with the Sponsor (based on the benefit risk assessment and other 
available options).  


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To be eligible for this protocol, patients must have been receiving axitinib tablets (either 
monotherapy or combination) at the time their previous trial ended and have had Stable 
Disease (SD) or responding disease (PR or CR) according to the disease response criteria in 
the previous axitinib trial.  Patients who have Progressive Disease (PD) but continue to 
experience clinical benefit in previous axitinib study will be eligible for enrollment; in this 
case, clinical benefit is defined as the Sum of Longest Diameters (SLD) of measurable 
lesions remaining less than or equal to the baseline SLD in the previous axitinib trial.  These 
patients must not be eligible for treatment with other available approved therapy for the 
disease under study.  These patients will be allowed to continue receiving study treatment(s) 
until the SLD of measurable lesions becomes greater than the baseline SLD in the previous 
trial.
During treatment on this protocol, all patients will be evaluated for safety per local standard 
clinical practice. Axitinib dosing or combination therapy (if applicable) and concomitant 
treatments will be monitored. Follow up information on alive/death status will be collected 
every 2 months starting from last study visit. Efficacy parameters will not be evaluated as 
part of this protocol. Pending drug availability, patients may continue to receive axitinib 
tablets or the combination drug(s) (if applicable) until the axitinib development program is 
terminated or when they are no longer receiving benefit (defined as no longer having stable 
or responding disease according to institutional standards), or clinical benefit for eligible 
patients with PD as previously defined.  
Endpoints:
All patients will be assessed for safety by monitoring adverse events and laboratory values 
per local standard clinical practice.  Response to therapy will not be collected as part of this 
protocol.
Trial Treatments – Axitinib:
Axitinib will be supplied as 1-mg and 5-mg film-coated tablets for oral administration.
Trial Treatments – Combination Drug (if applicable):
The study drug(s) given in combination with axitinib will be supplied according to the 
indications reported in the parent study protocol included in the Appendix 1.
Statistical Methods:
Safety data will be summarized for all treated patients using appropriate tabulations and 
descriptive statistics (see Section 9.2).


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SCHEDULE OF ACTIVITIES: 
Assessments
Schedule
Written Informed Consent.
Before receiving axitinib tablets (either 
monotherapy or combination) in this
protocol.
Safety Assessments (eg, physical exams, 
blood pressure assessments, hematology, 
clinical chemistry, urinalysis).
According to local clinical practice. 
If not performed within the last 8 weeks as 
part of previous axitinib study serum or 
plasma thyroid function tests (Free T4 and 
TSH) should be performed at 
screening/baseline and repeated subsequently 
as clinically indicated, and according to local
clinical practice (but not less than every 
12 weeks (2 weeks). 
Pregnancy test and contraceptive check are to 
be performed at screening/baseline if 
clinically indicated, and repeated if indicated 
or required by EC/IRB or by local law.
The following assessments should be added 
only for patients previously enrolled in the 
parent protocol A4061068:

Liver function test (Alanine 
aminotransferase (ALT) and 
Aspartate aminotransferase (AST), 
Alkaline phosphatase, Bilirubin): to 
be performed every 4 weeks;

ECG: to be performed at the time of 
End of Treatment, and as clinically 
indicated;

Ophthalmologic examination: at the 
first occurrence of any vision changes 
and as clinically indicated.
Adverse Events.
According to local clinical practice.a
Concomitant Treatments.
According to local clinical practice. 
Axitinib (as monotherapy) Dosing.
As per the patient’s previous protocol.


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Assessments
Schedule
Axitinib and the other anticancer drug (as 
combination therapy) Dosing. 
As per the patient’s previous protocol.
28-day Safety Follow Up. 
aPatients should be followed for safety 
including thyroid testing at least 28 days after 
last dose and according to standard clinical 
practice. 
Follow up information on survival.
After follow up visit attempts should be 
made, where possible, to collect information 
every 2 months on alive/death status via 
phone call or routine visit.
a.
Adverse events should be collected throughout the trial, starting at the time written consent is given through 
to at least 28 days after the last dose of axitinib or combination drug(s) (if applicable).  Adverse events that 
are serious, suspected to be related to axitinib or study drug(s) given in combination (if applicable) or 
considered significant by the investigator or Pfizer medical monitor must be followed after therapy 
discontinuation until the event or its sequelae resolve or stabilize at a level acceptable to the investigator 
and the Pfizer medical monitor or his/her designated representative.  Following the active safety reporting 
period, other SAEs of which the investigator becomes aware should be reported to Pfizer, unless the SAE is 
attributed by the investigator to complications of either the underlying malignancy or any subsequent 
anti-cancer therapy or to the patient’s participation in a subsequent clinical study.  Refer to Section 8 for 
more details.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
APPENDICES .........................................................................................................................11
1. INTRODUCTION ...............................................................................................................12
1.1. Indication.................................................................................................................12
1.2. Background .............................................................................................................12
1.2.1. Molecular Formula and Molecular Activity...............................................12
1.2.2. Scope of Axitinib Clinical Program ...........................................................13
1.2.2.1. Overall Clinical Safety of Axitinib ...........................................13
1.2.2.2. Overall Clinical Safety of Combination Drug (if 
applicable) .........................................................................................14
1.3. Rationale..................................................................................................................14
2. TRIAL OBJECTIVES .........................................................................................................14
3. TRIAL DESIGN..................................................................................................................14
4. PATIENT SELECTION......................................................................................................15
4.1. Inclusion Criteria.....................................................................................................15
4.2. Exclusion Criteria....................................................................................................16
4.3. Life Style Guidelines...............................................................................................16
4.4. Sponsor Qualified Medical Personnel.....................................................................17
5. TRIAL TREATMENTS ......................................................................................................17
5.1. Allocation to Treatment (Axitinib and Combination Drug, if applicable)..............17
5.2. Drug Supplies (Axitinib and Combination Drug, if applicable) .............................18
5.2.1. Preparation and Dispensing (Axitinib and Combination Drug, if 
applicable)........................................................................................................18
5.2.2. Formulation and Packaging........................................................................18
5.2.2.1. Formulation and Packaging (Axitinib Monotherapy) ...............18
5.2.2.2. Formulation and Packaging (Combination Therapy, if 
applicable) .........................................................................................18
5.2.3. Administration............................................................................................18
5.2.3.1. Administration (Axitinib Monotherapy) ...................................18
5.2.3.2. Administration (Combination Therapy, if applicable)..............19
5.2.4. Dose Interruption and Reductions ..............................................................19
5.2.4.1. Dose interruption and reductions (Axitinib Monotherapy).......19


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5.2.4.2. Dose Interruption and Reductions (Combination Therapy, 
if applicable)......................................................................................22
5.3. Drug Storage and Drug Accountability (Axitinib and Combination Drug, if 
applicable) .................................................................................................................22
5.4. Concomitant Medication(s).....................................................................................23
5.4.1. Concomitant Medication(s) (Axitinib Monotherapy).................................23
5.4.2. Concomitant Medication(s) (Combination Therapy, if applicable) ...........25
5.5. Rescue Therapy.......................................................................................................25
6. TRIAL PROCEDURES.......................................................................................................25
6.1. Patient Enrollment...................................................................................................25
6.2. Trial Procedures ......................................................................................................25
6.3. Follow-up Visit .......................................................................................................26
6.4. Patient Withdrawal..................................................................................................26
7. SAFETY ASSESSMENTS..................................................................................................27
8. ADVERSE EVENT REPORTING......................................................................................27
8.1. Adverse Events........................................................................................................27
8.2. Reporting Period .....................................................................................................28
8.3. Definition of an Adverse Event...............................................................................28
8.4. Medication Errors....................................................................................................29
8.5. Abnormal Test Findings..........................................................................................30
8.6. Serious Adverse Events...........................................................................................30
8.6.1. Protocol-Specified Serious Adverse Events...............................................31
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................31
8.7. Hospitalization ........................................................................................................32
8.8. Severity Assessment................................................................................................33
8.9. Causality Assessment..............................................................................................34
8.10. Exposure During Pregnancy..................................................................................34
8.11. Occupational Exposure .........................................................................................35
8.12. Withdrawal Due to Adverse Events (See also Patient Withdrawal, 
Section 6.4)................................................................................................................36
8.13. Eliciting Adverse Event Information ....................................................................36
8.14. Reporting Requirements........................................................................................36
8.14.1. Serious Adverse Event Reporting Requirements .....................................36


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8.14.2. Non-Serious Adverse Event Reporting Requirements .............................37
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities ...................37
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................37
9.1. Sample Size Determination.....................................................................................37
9.2. Safety Analysis........................................................................................................37
9.3. Efficacy Analysis ....................................................................................................37
9.4. Data Monitoring Committee ...................................................................................37
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................38
11. DATA HANDLING AND RECORD KEEPING .............................................................38
11.1. Case Report Forms/Electronic Data Record .........................................................38
11.2. Record Retention...................................................................................................39
12. ETHICS..............................................................................................................................39
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............39
12.2. Ethical Conduct of the Trial..................................................................................39
12.3. Patient Information and Consent...........................................................................40
12.4. Reporting Of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................40
13. DEFINITION OF END OF TRIAL...................................................................................40
13.1. End of Trial in all Participating Countries ............................................................40
14. SPONSOR DISCONTINUATION CRITERIA ................................................................41
15. PUBLICATION OF TRIAL RESULTS............................................................................41
15.1. Communication of Results by Pfizer ....................................................................41
15.2. Publications by Investigators ................................................................................42
16. APPENDICES ...................................................................................................................44
LIST OF TABLES
Table 1.
Available Axitinib as Monotherapy Dose Levels.................................................18
Table 2.
Criteria for Dose Modification for Axitinib Monotherapy Related Adverse 
Events other than Hypertension, Hemoptysis or Proteinuria................................19
Table 3.
Hypertension Management Plan for Axitinib Monotherapy ................................21


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APPENDICES
Appendix 1. Study Protocol A4061068...................................................................................44


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1. INTRODUCTION
1.1. Indication
Patients who have been treated in previous Pfizer sponsored oncology studies, with axitinib 
either as monotherapy or in combination with another anticancer drug.
1.2. Background
Axitinib is a substituted indazole derivative that has a direct antiangiogenic effect mediated 
by the potent inhibition of vascular endothelial growth factor receptor 2 (VEGF-2; KDR) 
kinase activity.  Axitinib is also a potent inhibitor of VEGFR-1 (flt-1) and VEGFR-3.  
Axitinib is currently being investigated as an anticancer agent in a series of clinical trials.  
Axitinib studies have been designed with a maximum number of cycles or time that a patient 
can be on the trial.  Some patients may be deriving benefit from the drug and want to have 
continued access to this investigational agent.  This protocol will provide continued access to 
axitinib tablets to patients who were assigned to an axitinib-containing treatment arm in an 
axitinib clinical trial.
The background relevant to the study drug(s) given in combination with axitinib, if 
applicable, is described in the parent protocol(s) attached in the Appendix 1.  
1.2.1. Molecular Formula and Molecular Activity
Axitinib is a substituted indazole derivative that was discovered using structure-based drug 
design.  The molecular formula is C22H18N4OS with molecular weight of 386.47.  The 
chemical name is 
N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide: 
H
N
N
S
C O N H Me
N
The mechanism of action of axitinib is a direct anti-angiogenic effect mediated by the potent 
inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2; KDR) kinase activity.  
Axitinib is also a potent inhibitor of VEGFR-1 (flt-1) and VEGFR-3.


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1.2.2. Scope of Axitinib Clinical Program
Clinical trials with axitinib in cancer patients were initiated in April 2002.  The ongoing 
clinical program is designed to test the safety and efficacy of axitinib, either as a single-agent 
or in combination with other anti-tumor agents, in a variety of advanced solid tumors.
Tumor types under study include, but are not limited to, advanced RCC, advanced NSCLC, 
HCC, advanced gastric cancer, and other solid tumors.  Refer to the most recent version of IB 
for complete list of closed and ongoing studies, and the most updated information on the 
clinical program.
1.2.2.1. Overall Clinical Safety of Axitinib
As of 01 June 2012, a total of 4372 patients were enrolled into clinical studies in the axitinib 
clinical program and included in the safety (serious adverse event) database.  Of these, 
3075 patients received axitinib.  In total, 2543 patients with cancer received either 
single-agent axitinib or axitinib in combination with chemotherapy.  In addition, 516 healthy 
volunteers and 16 patients with hepatic impairment received single agent axitinib.
A complete overview of safety and additional information on axitinib can be found in the 
most current version of the Investigator’s Brochure (IB).
Overall, the adverse events reported in axitinib clinical studies are considered manageable 
and were generally reversible and expected for this class of agents.  For single-agent axitinib, 
the most common adverse events reported from 699 cancer patients regardless of causality 
included diarrhea (397 patients, 56.8%), fatigue (368 patients, 52.6%), hypertension 
(318 patients, 45.5%), decrease appetite (286 patients, 40.9%), nausea (264 patients, 37.8%), 
dysphonia (242 patients, 34.6%), palmar-plantar erythrodysaesthesia syndrome (202 patients, 
28.9%), weight decreased (197 patients, 28.2%), vomiting (166 patients, 23.7%), 
constipation (165 patients, 23.6%), headache (151 patients, 21.6%), cough (149 patients, 
21.3%), arthralgia and dyspnea (140 patients, 20%).  Additionally, hypothyroidism and 
proteinuria were reported as adverse events in 122 patients (17.5%) and 117 patients 
(16.7 %), respectively.  Grade 3+ events occurred most frequently for hypertension 
(134 patients, 19.2%), fatigue (90 patients, 12.9%), and diarrhea (65 patients, 9.3%).
In patients with solid tumors who received single-agent axitinib from completed studies, the 
majority of the hematological test abnormalities were Grade 1 and 2, however 53 patients 
(7.9%) reported Grade 3 lymphocytopenia, and the following Grade 3 or 4 events were 
reported: 9 patients (1.3%) hemoglobin decreased, 9 patients (1.3%) neutrophils decreased,
3 patients (0.4%) white blood cells decreased, 2 patients (0.3%) platelets decreased.  As per 
clinical chemistry, Grade 3 or 4 lipase abnormalities were reported in 26 patients (7%), 
hyponatremia in 34 patients (5%), hyperglycemia in 23 patients (3.3%), hyperkalemia in 
22 patients (3.2%), elevations in serum glutamic oxaloacetic transaminase (SGOT), aspartate 
aminotransferase (AST) and alkaline phosphatase in 13 patients (1.9%), total bilirubin 
increase in 5 patients (0.7%), and creatinine increased in 4 patients (0.6%).  For urinalysis, 
Grade 3 proteinuria was reported in 24 patients (3.4%).


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In Phase 3 study A4061032, hypothyroidism was reported in 69/359 patients (19%) receiving 
axitinib.  Hyperthyroidism was reported in 4/359 patients (1%).  In patients who had thyroid 
stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL 
occurred in 79/245 patients (32%) receiving axitinib.  Monitoring thyroid function before 
initiation of, and periodically throughout, treatment with axitinib is recommended.  
Hypothyroidism and hyperthyroidism should be treated according to standard medical 
practice to maintain euthyroid state.
1.2.2.2. Overall Clinical Safety of Combination Drug (if applicable)
An overview of safety and information on study drug(s) given in combination with the 
Axitinib is available in the parent protocol(s) in the Appendix 1. 
Additional information for the study drug(s) may be found in the Single Reference Safety 
Document, which for this study are the current Investigator Brochure (IBs).
1.3. Rationale
Some patients in axitinib clinical trials may be experiencing clinical benefit from axitinib
either as monotherapy or in combination with another anticancer drug and may wish to 
continue treatment following completion of the trial.  Such patients, after a written 
re-consent, may continue to receive axitinib and the combination study drug (if applicable) at 
the same dose and schedule as specified in their prior axitinib protocol, with the consensus of 
the principal investigator and the approval of the sponsor company until patients no longer 
experience clinical benefit, develop unacceptable toxicity or withdraw consent.
Complete information for the study drug(s) may be found in the Single Reference Safety 
Documents, which for this study are the current Investigator Brochures.
2. TRIAL OBJECTIVES
The objective of the trial is to provide continued access to axitinib tablets and to the study 
drug(s) given in combination (if applicable) to patients who have completed their 
participation in a prioraxitinib monotherapy or combination study and who have documented 
stable disease, responding disease or clinical benefit as described below at the time they 
discontinued from the previous trial.
3. TRIAL DESIGN
Axitinib trials (either monotherapy or combination) have been designed with a maximum 
number of treatment cycles.  However, some patients may be deriving clinical benefit from 
the drug(s) and want to continue treatment with the investigational agent(s) but are unable to 
continue in their present trial.
This protocol will provide continued access to axitinib tablets and the combination study 
drug(s) if applicable for patients who were assigned to an axitinib-containing treatment arm 
in an axitinib clinical trial.  For patients in combination treatment, if axitinib is interrupted 
due to toxicity, the continuation of the combination drug will be evaluated on a case by case 
analysis after discussion with the Sponsor (based on the benefit risk assessment and other 
available options).  


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To be eligible for this trial, patients must have been receiving axitinib tablets (as either 
monotherapy or combination as applicable) at the time their previous trial ended and have 
had Stable Disease (SD) or responding disease (PR or CR) according to the disease response 
criteria in the previous axitinib trial.  Patients who have Progressive Disease (PD) but 
continue to  experience clinical benefit in previous axitinib study will be eligible for 
enrollment; in this case, clinical benefit is defined as the Sum of Longest Diameters (SLD) of 
measurable lesions remaining less than or equal to the baseline SLD in the previous axitinib 
trial.  These patients must not be eligible for treatment with other available approved therapy 
for the disease under study.  These patients will be allowed to continue receiving study 
treatment(s) until the SLD of measurable lesions becomes greater than the baseline SLD in 
the previous trial.
During treatment on this protocol, all patients will be evaluated for safety and monitored per 
local standard clinical practice.  Axitinib dosing or combination therapy, if applicable) and 
concomitant treatments will be monitored.  Follow up information on alive/death status will 
be collected every two months starting from last study visit.  Efficacy parameters will not be 
evaluated as part of this protocol.  Pending drug availability, patients may continue to receive 
axitinib tablets or combination therapy (if applicable) until the axitinib development program 
is terminated or when they are no longer receiving benefit (defined as no longer having stable 
or responding disease according to institutional standards), or clinical benefit for eligible 
patients with PD as previously defined.  
4. PATIENT SELECTION
This clinical trial can fulfill its objectives only if appropriate patients are enrolled.  The 
following eligibility criteria are designed to select patients for whom protocol treatment is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular patient.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
trial:

Patients who were assigned to an axitinib-containing treatment arm in a previous 
clinical trial.

Patients who were receiving axitinib tablets at the time their previous trial ended.

Patients who have stable (SD) or responding disease (PR or CR) documented by the 
appropriate radiological, clinical, or laboratory assessments within 12 weeks before 
enrollment (Note: response criteria from the previous axitinib protocol should be used 
to determine stable or responding disease).


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
Patients who have Progressive Disease (PD) but have experienced clinical benefit 
from previous axitinib treatment will be eligible for enrollment; in this case, clinical 
benefit is defined as the Sum of Longest Diameters (SLD) of measurable lesions 
remaining less than or equal to the baseline SLD in the previous axitinib trial.  These 
patients must not be eligible for treatment with other available approved therapy for 
the disease under study.  The Pfizer clinician must approve the enrollment prior to 
treatment start. 

Patients who are informed of, and willing and able to comply with the investigational 
nature of the trial, and have signed a written informed consent in accordance with 
institutional and ICH GCP guidelines.
4.2. Exclusion Criteria
Patients presenting with any of the following will not be included in the trial:

Patients may not participate in this trial if the conditions for continuing treatment in 
the previous axitinib protocol are not met. 
4.3. Life Style Guidelines
All male and female patients who, in the opinion of the investigator, are biologically capable 
of having children and are sexually active, must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for 90 days  after the last dose of investigational product.  The investigator, in consultation 
with the patient, will select the most appropriate method of contraception for the individual 
patient from the permitted list of contraception methods, and instruct the patient in its 
consistent and correct use.  The investigator, at each study visit, will confirm and document 
consistent and correct use.  In addition, the investigator will instruct the patient to call 
immediately if the selected birth control method is discontinued or if pregnancy is known or 
suspected. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, injected or implanted hormonal methods of contraception.
2. Correctly placed intrauterine device (IUD) or intrauterine system (IUS).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).
4. Male sterilization with appropriately confirmed absence of sperm in the 
post-vasectomy ejaculate.


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5. Bilateral tubal ligation or bilateral salpingectomy.
Only for patients previously enrolled in the parent protocol A4061068 and under 
treatment with axitinib and crizotinib the following additional guideline is to be 
followed:
Sunlight Exposure
Patients will be advised to report any reaction to sun exposed skin. In addition, special 
precaution will be taken to limit any potential photo irritation effect, by minimizing the 
patients’ exposure to light including high intensity ultraviolet B light (UVB) sources such as 
tanning beds, tanning booths and sunlumps. Patients should be encouraged to apply 
sunscreen/sunblock daily.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the “Study Team on Demand”
(SToD).
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.
5. TRIAL TREATMENTS
5.1. Allocation to Treatment (Axitinib and Combination Drug, if applicable)
This trial is open label.  All patients will receive axitinib either as monotherapy or in 
combination with other study drug(s) according to the indications reported in the parent
protocol (Appendix 1). The dose and the schedule of axitinib and of the study drug(s) given 
in combination (if applicable) will be the same as they were taking in the previous trial.


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5.2. Drug Supplies (Axitinib and Combination Drug, if applicable)
The Global Supply Chain, Pfizer Global Research and Development will supply axitinib and 
the combination drug(s) (if applicable) for the trial.  Clinical Trial Material (CTM) will be 
shipped to the study sites with an Investigational Drug Receipt Confirmation form.  This 
form should be completed and returned as directed on the form.
5.2.1. Preparation and Dispensing (Axitinib and Combination Drug, if applicable)
The investigator, or an approved representative (eg, pharmacist), will ensure that all study 
drug is stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements. 
5.2.2. Formulation and Packaging
5.2.2.1. Formulation and Packaging (Axitinib Monotherapy)
Axitinib will be supplied as 1-mg and 5-mg film coated tablets for oral administration in 
HDPE (High density polyethylene) bottles with desiccant.
5.2.2.2. Formulation and Packaging (Combination Therapy, if applicable)
The combination therapy will be supplied according to the indications reported in the parent 
protocol (Appendix 1).
5.2.3. Administration 
5.2.3.1. Administration (Axitinib Monotherapy)
Axitinib will be administered orally.  Tablets should be taken with food, at approximately the 
same time each day.  Patients should be instructed that if they vomit any time after taking a 
dose, that they must not “make it up” with an extra dose, but instead resume subsequent 
doses as prescribed.  Missed doses may be taken late, up to 3 hours before the next scheduled 
dose, otherwise should be skipped. Patient must be instructed to record all doses (and missed 
or vomited doses) in a dosing diary supplied by the site.  If doses are missed or vomited, this 
must be indicated in the source documents and CRFs.
Patients experiencing drug reaction greater than Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 2 should undergo dose modification as recommended in
Section 5.2.4.
Table 1.
Available Axitinib as Monotherapy Dose Levels
Dose
Dispensed As
10 mg BID
2 X 5 mg Tablets BID
7 mg BID
1 X 5 mg Tablet +2 X 1mg Tablets BID
5 mg BID*
1 X 5 mg Tablet BID
3 mg BID
3 X 1 mg Tablets BID
2 mg BID
2 X 1 mg Tablets BID
* Dosing regimen other than twice a day dosing (BID) is allowed ONLY with discussion and concurrence of 
Sponsor.


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Once a patient has a dose reduction for study drug related toxicity, the dose normally will not 
be re-escalated.  However, patients who tolerate the lower dose without toxicities above 
Grade 1 for at least 8 weeks may be considered for re-escalation.  The investigator and 
sponsor’s medical monitor will discuss the case and decide if re-escalation is appropriate.
5.2.3.2. Administration (Combination Therapy, if applicable)
Patients receiving axitinib in combination with other study drug(s) should be treated 
according to administration rules showed in the relevant parent protocol (Appendix 1). 
5.2.4. Dose Interruption and Reductions
5.2.4.1. Dose interruption and reductions (Axitinib Monotherapy)
Adverse events and other symptoms will be graded according to the current Common 
Terminology for Adverse Events version 4.03 (CTCAE) (See URL: 
http://ctep.cancer.gov/reporting/ctc.html).  
This section contains management of adverse events except hypertension, hemoptysis and 
proteinuria which are discussed in subsequent sections. 
Patients developing a treatment-related CTCAE Grade 1 or 2 adverse event will have their 
dose continued at the same dose level.
If any patient requires doses lower than 2 mg BID, contact the sponsor for discussion. 
The criteria for dose modification for study drug related adverse events are summarized in 
Table 2 below.
Table 2.
Criteria for Dose Modification for Axitinib Monotherapy Related Adverse 
Events other than Hypertension, Hemoptysis or Proteinuria
Related Adverse Events
Intervention
Grade 1.
Continue at same dose level.
Grade 2.
Continue at same dose level.
Grade 3 nonhematologic treatment-related 
toxicity.
Decrease dose to one lower dose level.  
Grade 4 nonhematologic treatment-related 
toxicity or Grade 4 hematologic toxicity.* 
Interrupt dosing; re-start at one lower dose 
level as soon as improvement to CTCAE 
Grade 2.  If patient requires dose reduction 
below 2 mg BID, contact sponsor for 
discussion.
* Patients who develop grade 4 lymphopenia may continue study treatment without interruption.
Guidelines for dose reductions for specific adverse events are provided in the following 
sections.


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5.2.4.1.1. Dose Reduction for Hypertension (Axitinib Monotherapy)
Patients treated with axitinib will be issued blood pressure cuffs (provided by Pfizer) for 
home monitoring and instructed to measure their blood pressure (BP) twice daily, prior to 
taking each dose.  All blood pressure measurements will be recorded in a diary and brought 
to the nurse or study coordinator at each clinic visit for review.  Patients should be instructed 
by the study staff to contact their physician immediately for guidance if their systolic blood 
pressure rises above 150 mm Hg, diastolic blood pressure rises above 100 mm Hg, or if they 
develop symptoms perceived to be related to elevated BP (eg, headache, visual disturbance).  
See below for dose modifications for hypertension.
New or additional antihypertensive therapy (See Section 5.4, Concomitant Medication(s) for 
guidance) should be started if 2 blood pressure readings, taken in the clinic and separated by 
at least 1 hour, show the following: 2 systolic blood pressure readings greater than 150 or 
2 diastolic blood pressure readings greater than 100 mm Hg.  Alternately, the dose of existing 
antihypertensive medication(s) may be increased.  Note: the early introduction of 
antihypertensive agents for Grade 1 and Grade 2 hypertension in order to minimize the 
occurrence of more severe or persistent hypertension while undergoing treatment with 
axitinib will not constitute a Grade 3 toxicity.
If the patient is already on maximal antihypertensive treatment, the study drug should be 
reduced by 1 dose level.
Patients on maximal antihypertensive treatment (to be defined on an individual patient basis 
according to the judgment of the investigator, but may include up to 4 anti-hypertensive 
medications given for 2 weeks) who have 2 systolic blood pressure readings, separated by at 
least 1 hour, greater than 160 mm Hg, or 2 diastolic blood pressure readings, separated by at 
least 1 hour, greater than 105 mm Hg, will have treatment with axitinib held.  (Note: if study 
drug is held, patients receiving antihypertensive medications should monitor closely for 
hypotension). 
Blood pressure may decrease within 24 hours of stopping therapy.  Blood pressure 
measurements used to decide to discontinue or interrupt axitinib dosing or to adjust 
antihypertensive medications should be done in the clinic.  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, rounded down to 
accommodate dosage form availability, after the systolic blood pressure reduces to less than 
150 mm Hg and the diastolic blood pressure 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 study drug dose reduction should undergo another dose reduction by one 
dose level.  If a patient requires dose reduction below 2 mg BID, contact Sponsor for 
discussion.  Blood pressure measurements used for axitinib-discontinuation decision-making 
should be done in the clinic. 


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Guidance on dose interruption and reduction for hypertension is summarized in 
Table 3 below.
Table 3.
Hypertension Management Plan for Axitinib Monotherapy
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 study drug. 
If on maximal antihypertensive 
treatment, reduce study drug to 
one lower 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 dosing;* adjust 
antihypertensive medication; as 
soon as BP is less than 
150/100 mm Hg, restart study 
drug at one lower 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 diastolic BP 
>100 mm Hg (2 BP readings 
separated by at least 1 hour) 
following previous dose 
reduction
Repeat study drug dose reduction 
by one lower dose level.  If a 
patient requires dose reduction 
below 2 mg BID, contact Sponsor 
for discussion 
* If study drug 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.
5.2.4.1.2. Dose Reduction for Hemoptysis (Axitinib Monotherapy)
Bleeding from the lungs as evidenced by hemoptysis will be graded according to the 
Hemorrhage category of CTCAE.
Treatment with axitinib will be discontinued for hemoptysis of >½ tsp of bright red blood per 
day.  In addition, a radiologic assessment (eg, chest x-ray) should be considered for patients 
who have hemoptysis >½ tsp of bright red blood per day.  If the hemoptysis resolves to 
baseline within 1 week and there is no evidence of disease cavitation, treatment with axitinib 
may continue at the current dose level.  Patients who experience hemoptysis without 
resolution to baseline within 1 week, or with evidence of disease cavitation should 
discontinue from treatment with axitinib.
5.2.4.1.3. Dose Reduction for Proteinuria (Axitinib Monotherapy)
Monitoring for proteinuria before initiation of and periodically throughout treatment with 
axitinib is recommended, as per clinical judgment.  For patients who develop moderate to 
severe proteinuria, monitoring, and dose reduction or temporary interruption of axitinib given 
in monotherapy should be considered.


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General guidelines are reported below.  Medical judgment, and the patient’s clinical 
conditions, should always be considered to determine the most appropriate monitoring of 
proteinuria.  Safeguard of the patient’s safety and a positive risk-benefit assessment should 
always be evaluated when less restrictive monitoring is adopted.
Perform dipstick proteinuria (or equivalent semi-quantitative test) at regular frequency.  At 
documentation of >2+ or equivalent proteinuria by dipstick, patients should have a 24-hour 
urine collection for total protein.  Axitinib dosing may continue while waiting for test results.
If <2 g proteinuria/24-hour is reported, treatment with axitinib may continue without dose 
reduction.
If 2 g proteinuria/24-hour is reported, treatment with axitinib should be interrupted.  A 
24-hour urine collection for total protein and creatinine clearance should be performed 
weekly until results show <2 g proteinuria/24-hour, at which time treatment with axitinib 
may be restarted at one lower dose level.  Patients, once restarted on axitinib, will have 
weekly monitoring for proteinuria by semiquantitative testing (eg, dipstick) as long as the 
proteinuria reading is 2+ or higher, or, alternatively, by quantitative methods as long as 
proteinuria is 1 g/24-hour.  The 24-hour urine collection to monitor the degree of 
proteinuria should be repeated every 4 weeks until it has decreased to <500 mg/24-hour.
If recurrent 2 g proteinuria/24-hour is reported, treatment with axitinib should be 
interrupted again.  24-hour urine collection for total protein and creatinine clearance should 
be performed weekly until results show <2 g proteinuria/24-hour, at which time treatment 
with axitinib may be restarted at one lower dose level.  If a patient requires dose reduction 
below 2 mg BID, contact the Sponsor for discussion.
5.2.4.2. Dose Interruption and Reductions (Combination Therapy, if applicable)
The recommended dose modifications of the combination therapy with axitinib and other 
anticancer study drug(s) are detailed in the relevant parent protocol (Appendix 1). 
In case the patient withdraws the drug given in combination with axitinib, and continue 
on axitinib alone, the dose interruptions and modifications will follow the study 
A4061008 axitinib monotherapy dose modification rules. 
5.3. Drug Storage and Drug Accountability (Axitinib and Combination Drug, if 
applicable)
The investigator or an approved representative (eg, pharmacist) will ensure that all trial drugs 
are stored in a secure area, under recommended storage conditions and in accordance with 
applicable regulatory requirements.  
Axitinib and the other anticancer drug(s) given in combination should be stored at controlled 
room temperature (15-30C), in provided packaging.


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Investigators and site staff are reminded to check temperatures daily and ensure that 
thermometers are working correctly as required for proper storage of investigational 
products.  These include thermometers for both the room storage and refrigerator storage.  
Any temperature excursions should be reported immediately. 
To ensure adequate records, all study drug will be accounted for in the drug accountability 
inventory forms as instructed by Pfizer.  Unless otherwise authorized by Pfizer, at the end of 
the clinical trial all drug supplies unallocated or unused by the patients must be destroyed by 
procedures approved by Pfizer or returned to Pfizer or its appointed agent (eg, a contract 
research organization).
Axitinib is a hazardous drug (due to possible reproductive toxicity), and should be handled 
according to the recommended procedures described in the current edition of the American 
Society of Hospital Pharmacists (ASHP), Technical Assistance Bulletin on Handling 
Cytotoxic and Hazardous Drugs, American Hospital Formulary Service (AHFS) Drug 
Information (1999) and its references.  Procedures described in each institution’s pharmacy 
or hospital standard operating procedure manual should be followed when handling 
hazardous drugs.  Only qualified personnel who are familiar with procedures should 
undertake the handling, and safe disposal of study drug.
5.4. Concomitant Medication(s) 
5.4.1. Concomitant Medication(s) (Axitinib Monotherapy)
Palliative and supportive care for disease-related symptoms will be offered to all patients on 
this trial.  Low-dose oral steroids (defined as 5 mg per day prednisone or equivalent) or 
topical or inhaled steroids at any dose may be taken during the study.  The therapeutic use of 
colony-stimulating factors is a matter of clinical judgment.  Prophylactic use is permitted in 
patients who have experienced infection or grade 4 neutropenia during the previous cycle.  If 
colony stimulating factors are given, use should be consistent with product labeling and 
should be documented in the patient's medical record. 
In vitro studies with human liver microenzymes and recombinant CYP450 enzymes indicated 
that axitinib metabolism was primarily mediated by the drug-metabolizing enzyme CYP3A, 
and to a lesser extent by CYP1A2, CYP2C19 and UGT1A1.  Clinically, there is likelihood 
that axitinib plasma concentrations may be increased in the presence of co-administered 
strong inhibitors of CYP3A.  The potential exists for drug-drug interactions with CYP3A 
inhibitors such as grapefruit juice, ketoconazole, miconazole, itraconazole, erythromycin, 
clarithromycin, verapamil, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and 
delavirdine.  Caution should be exercised in patients receiving axitinib in combination with 
these and other strong CYP3A inhibitors Axitinib metabolism may be induced in patients 
taking CYP3A4 inducers (carbamazepine, dexamethasone, felbamate, omeprazole, 
phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St John’s wort) and this may 
reduce axitinib plasma concentrations.  Patients who require concomitant treatment with 
strong CYP3A inducers are not eligible for the trial.  Since CYP1A2 is also known to be 
induced in chronic smokers, there is likelihood that axitinib plasma concentrations may be 
reduced in these individuals. 


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The ability of axitinib to increase concentrations of co-administered drugs was also 
investigated in studies with human liver microsomes.  At expected therapeutic plasma 
concentrations (0.01 to 1.0 µg/mL), axitinib appears most likely to inhibit the drug 
metabolizing enzymes CYP1A2 and CYP2C8, 2 enzymes not frequently observed as 
predominant drug metabolizing enzymes.  However co-administration of axitinib with 
paclitaxel, a CYP2C8 substrate did not increase plasma concentrations of paclitaxel in 
patients, indicating lack of clinical CYP2C8 inhibition.  Axitinib is highly bound to proteins 
in human plasma (99.5% bound at concentrations of 0.2 to 20 µg/mL).  Therefore, drug 
interactions with other agents that are also highly bound to plasma proteins are a possibility.
Patients who need to be on chronic antacid therapy with histamine H2 antagonists (eg, 
cimetidine [Tagamet®], famotidine [Pepcid®], nizatidine [Axid®], ranitidine [Zantac]) or 
proton-pump inhibitors (eg, lansoprazole [Prevacid®], rabeprazole [Aciphex® ], pantoprazole 
[Protonix®], and esomeprazole [Nexium®]) or locally acting antacids (eg, Maalox®, Milk of 
Magnesia®, Amphojel®) should stagger the timing of their axitinib and antacid dosing.  
Patients should avoid use of antacids for 2 hours before through 2 hours after taking axitinib 
tablets. 
Axitinib is not likely to have drug-drug interactions with commonly used antihypertensive 
agents belonging to the class of ACE inhibitors including angiotensin II receptor antagonists 
(enalapril, captopril, losartan, vasartan), beta-blockers (atenolol, metoprolol, labetalol), or 
diuretics (hydrochlorothiazide, furosemide).  Within the class of calcium channel blockers, 
verapamil, and to a lesser extent nifedipine, nicardipine, and diltiazem have a potential for 
increasing axitinib plasma concentrations, due to CYP3A inhibition and should not be used 
as first choice in antihypertensive treatment.  Other calcium channel blockers (amlodipine, 
bepridil, felodipine) are less likely to raise axitinib plasma levels.  The above information is 
based on preclinical data from studies using human and animal metabolizing enzyme 
systems.
Patients who need to be on anticoagulant therapy during treatment with axitinib should be 
treated with low molecular weight heparin as the preferred therapy. 
All concomitant medications and blood products, as well as interventions (eg, analgesic use 
or paracentesis) received by patients from the first dose of study drug until the end of study 
visit will be recorded on the case report form (eCRF).
Regarding the concomitant surgery, no formal studies of the effect of axitinib on wound 
healing have been conducted, however caution is advise based on the mechanism of action. 
If a major surgery or an interventional procedure (eg, endoscopy) is required, treatment with 
axitinib must be interrupted at least 24 hours before the procedure. 
Patients may resume the treatment with axitinib according to the opinion of the investigator, 
when wound has completely healed and there are no wound healing complications (eg,
delayed healing, wound infection or fistula).


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5.4.2. Concomitant Medication(s) (Combination Therapy, if applicable)
Details regarding allowed concomitant medications, surgery and/or radiotherapy with the 
combination therapy are described in the parent protocol (Appendix 1). 
5.5. Rescue Therapy 
No mechanistically specific antagonists for axitinib are available and standard supportive 
measures should be used in the case of excessive pharmacological effects or adverse reaction.
6. TRIAL PROCEDURES
6.1. Patient Enrollment
To enroll patients the investigator must send a completed registration form to the appropriate 
Clinical representative.  The investigator should be prepared to answer questions concerning 
the patient’s eligibility.  Once eligibility is verified the clinical representative will confirm by 
facsimile that the patient has been accepted into the trial.  If the patient fails to start treatment 
within 14 days of registration the clinical representative should be contacted before the start 
of treatment.
6.2. Trial Procedures
During treatment on this protocol, all patients will be followed and monitored according to 
local clinical practice. 
Safety monitoring and laboratory analyses are to be performed as clinically indicated.
TSH, T3 (or free T3) and/or free T4 should be performed as clinically indicated.  If thyroid 
function tests were not performed during the 8 weeks before enrollment in this study, serum 
or plasma thyroid function tests (Free T4 and TSH) should be performed at 
screening/baseline visit, and subsequently as clinically indicated, and not less than every 
12 weeks (2 weeks). 
Pregnancy tests and contraceptive check should be performed at screening/baseline visit 
(when clinically indicated), and repeated if clinically indicated, and/or required by IRB/IECs, 
or local regulations.
Tumor assessments should be performed per standard clinical practice and results should be 
recorded in the patient’s clinic chart (but will not be collected in the study eCRF).
Only for patients previously enrolled in the parent protocol A4061068 and treated with 
axitinib and crizotinib the following assessments should be added:

Liver function test ((alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST), alkaline phosphatase, bilirubin): to be performed every 4 weeks. The tests 
should be perforrmed preferably at the clinical site’s local laboratory and, when not 
possible, patients will provide the results copy (from the nonclinical site laboratory), 
eg, by telephone, and bring a copy of the laboratory test results at the visit.


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
Electrocardiogram (ECG): to be performed at the time of End of Treatment, and as 
clinically indicated;

Ophthalmologic examination: at the first occurrence of any vision changes and as 
clinically indicated.
6.3. Follow-up Visit
If the patient discontinues the treatment (as monotherapy or combination therapy), a final 
safety evaluation including thyroid testing will be performed at least 28 days after the last 
dose of study drug(s) and documented in the source documents. 
Only for patients previously enrolled in the parent protocol A4061068 and treated with 
axitinib and crizotinib, the following assessments should be added in the final evaluation:

Liver function test (ALT and AST, Alkaline phosphatase, Bilirubin);

ECG;

Ophthalmologic examination (as clinically indicated).
Reported adverse events that are ongoing at the time of study discontinuation and serious, or 
≥ grade 3 or suspected to be related to the study drug(s), or clinically significant by the 
investigator or Pfizer medical monitor must be followed after the time of therapy 
discontinuation until the event or its sequelae resolve/stabilize at a level acceptable to the 
investigator and the Pfizer medical monitor or his/her designated representative.  Following 
the active safety reporting period, other serious adverse events (SAEs) of which the 
investigator becomes aware should be reported to Pfizer, unless the SAE is attributed by the 
investigator to complications of either the underlying malignancy or any subsequent 
anti-cancer therapy or to the patient’s participation in a subsequent clinical study.
Concomitant medications/treatments, AE and thyroid lab CRF shall be updated accordingly.
After the follow up visit, attempts should be made, where possible, to collect information 
every 2 months on patient alive/death status via phone call or routine visit.
6.4. Patient Withdrawal
A patient may withdraw from the trial at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol required schedule of study 
visits or procedures at a given study site.  If a patient does not return for a scheduled visit, 
every effort should be made to contact the patient.  In any circumstance, every effort should 
be made to document patient outcome, if possible.  The investigator should inquire about the 
reason for withdrawal, request the patient to return all unused investigational product(s), 
request the patient to return for a final visit, if applicable, and follow-up with the patient 
regarding any unresolved adverse events (AEs).


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If the patient withdraws consent, no further evaluations should be performed and no attempts 
should be made to collect additional data.  The sponsor may retain and continue to use any 
data collected before such withdrawal of consent.
7. SAFETY ASSESSMENTS
The safety of axitinib and the study drug(s) given in combination should be evaluated using 
the local standard clinical practice. 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well being of the patient.  When a protocol required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely manner.
Patients receiving axitinib (either as monotherapy or in combination therapy) should be 
monitored for signs and symptoms of hypothyroidism, such as fatigue, deepening of voice, 
cold intolerance, constipation, anorexia, periorbital edema, myxedema, or changes in skin or 
hair.  Hypothyroidism should be treated per standard medical practice to maintain euthyroid 
state.
In case of combination therapy, additional texts or examination might be required in
accordance with the parent protocol(s) (see Section 6.2 and 6.3 above and, for more details, 
see relevant sections in parent protocol Appendix 1).
Pregnancy Test
For female patients of child bearing potential (ie, who in the opinion of the investigator are 
biologically capable of having children and sexually active), a serum or urine pregnancy test 
will be performed at screening/baseline visit.  Pregnancy tests will also be done whenever 
one menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected).  Tests may also be repeated as per request of IRB/IECs or 
if required by local regulations.
8. ADVERSE EVENT REPORTING 
8.1. Adverse Events
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all adverse events the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event (See Section 8.6) requiring immediate notification to 


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Pfizer or its designated representative.  For all adverse events sufficient information should 
be obtained by the investigator to determine the causality of the adverse event.  The 
investigator is required to assess causality.  Follow-up by the investigator may be required 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For serious adverse events, the active reporting period to Pfizer or its designated 
representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving investigational product, through and including 
28 calendar days (longer follow up period might need to be adopted based on the 
combination drug characteristics) after the last administration of the investigational product.  
SAEs occurring to a subject after the active reporting period has ended should be reported to 
the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product are to be reported to the Sponsor.Adverse events (serious and non-serious) should be 
recorded on the CRF from the time the patient has taken at least one dose of investigational 
product through last patient’s last visit.
If a patient begins a new anticancer therapy, the adverse event reporting period for 
non-serious adverse events ends at the time the new treatment is started. 
Death must be reported if it occurs during the serious adverse event reporting period after the 
last dose of investigational product, irrespective of any intervening treatment.
8.3. Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a clinical investigation patient 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;


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
Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under trial should be reported as 
adverse events in the appropriate section of the CRF.  Disease progression assessed 
by measurement of malignant lesions on radiographs or other methods should not be 
reported as adverse events.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the Adverse Event (AE) page, and on the SAE form 
when appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.


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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.  
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in trial dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the trial, significant additional concomitant drug 
treatment, or other therapy; and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity; (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the safety reporting 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
safety reporting period, then the event leading to death must be recorded as an AE and as an 
SAE with CTCAE Grade 5 (see the Section 8.8 Severity Assessment).


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Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately life 
threatening and/or result in death or hospitalization.  However, if it is determined that the 
event may jeopardize the patient or may require intervention to prevent one of the other AE 
outcomes, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements). 
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in AST and/or ALT concurrent with abnormal elevations in total bilirubin 
that meet the criteria outlined below in the absence of other causes of liver injury are 
considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and should 
always be considered important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available.

For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).

Concurrent with:

For patients with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by one time the upper limit of normal or ≥3 times the 
upper limit of normal (whichever is smaller).


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The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be also considered.  In addition to repeating AST 
and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct and 
indirect bilirubin, gamma-glutamyl transferase, prothrombin time (PT)/INR, and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced patient, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a 
tuberculosis unit).
An emergency room visit does not necessarily constitute a hospitalization; however, the 
event leading to the emergency room visit should be assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pre-treatment lab abnormality);


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
Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a clinical trial (eg, for a procedure required by 
the trial protocol);

Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures. These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported and it meets the definition of an adverse event.  For example, 
an acute appendicitis that begins during the adverse event reporting period should be reported 
as the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
8.8. Severity Assessment
If required on the adverse event case report forms, the investigator will use the following 
definitions of severity in accordance with National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03 to describe the maximum intensity of the 
adverse event.  If the event is serious, the CTCAE grade reported in the adverse event CRF 
must be consistent with the description of CTCAE grade included in the narrative section of 
the serious adverse event report. 
GRADE
Clinical Description of Severity 
0
No Change from Normal or Reference Range (This grade is not included in 
the Version 4.03 document but may be used in certain circumstances.)
1
MILD Adverse Event
2
MODERATE Adverse Event
3
SEVERE Adverse Event
4
LIFE-THREATENING OR DISABLING Adverse Event
5
DEATH RELATED TO Adverse Event


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Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with patient's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious), the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an adverse event; generally, the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (See the Section 
on Reporting Requirements).  If the investigator's causality assessment is “unknown but not 
related to investigational product,” this should be clearly documented on trial records. 
In addition, if the investigator determines a serious adverse event is associated with trial
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational
product, or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products);

A male has been exposed, (eg, because of treatment or environmental exposure), to 
the investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If any study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to Pfizer drug safety unit on an SAE Report Form and an EDP supplemental 
form, regardless whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 


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subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
adverse event has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome 
forall EDP reports with an unknown outcome.  The investigator will follow the pregnancy 
until completion (or until pregnancy termination) and notify Pfizer of the outcome as a 
follow up to the initial EDP supplemental form. 
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly 
and the findings are reported).
If the outcome of the pregnancy meets the criteria for a serious adverse event (ie, ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise neonatal death, or congenital 
anomaly [in a live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal 
death], the investigator should follow the procedures for reporting serious adverse events.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the investigator assesses the neonatal death as related or 
possibly related to exposure to the investigational product. 
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The Investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See also Patient Withdrawal, Section 6.4)
Withdrawal due to adverse events should be distinguished from withdrawal due to other 
causes, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page. 
When a patient withdraws because of a serious adverse event, the serious adverse event must 
be reported in accordance with the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study patient.  In addition, each study patient will be 
questioned about adverse events.
8.14. Reporting Requirements 
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
event.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator 
awareness of the event. 
In particular, if the serious adverse event is fatal or life-threatening, notification to Pfizer 
must be made immediately, irrespective of the extent of available adverse event information.  
This timeframe also applies to additional new information (follow-up) on previously 
forwarded serious adverse event reports as well as to the initial and follow-up reporting of 
EDP and exposure via breastfeeding cases. 
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study patient initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information collected for SAEs is more detailed than that 
captured on the adverse event case report form.  In general, this will include a description of 
the adverse event in sufficient detail to allow for a complete medical assessment of the case 


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and independent determination of possible causality.  Information on other possible causes of 
the event, such as concomitant medications, vaccines, and/or illnesses must be provided.  In 
the case of a patient death, a summary of available autopsy findings must be submitted as 
soon as possible to Pfizer or its designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All adverse events are to be reported on the adverse event page of the CRF.  It should be 
noted that the form for collection of SAE information is not the same as the AE CRF.  Where 
the same data are collected, the forms must be completed in a consistent manner.  For 
example, the same AE term should be used on both forms.  AEs should be reported using 
concise medical terminology on the CRFs as well as on the form for collection of SAE 
information.
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
9.1. Sample Size Determination
The sample size is not statistically driven and is dependent upon the number of patients 
included in the clinical trial program for axitinib (as monotherapy or in combination therapy) 
who are eligible for this extension study and wish to continue with the treatment.
9.2. Safety Analysis
All patients receiving at least 1 dose of axitinib (as monotherapy or combination therapy) 
under this protocol will be included in the safety analyses.  Adverse events will be coded and 
grouped by body system.  The incidence of each adverse event will be tabulated and 
displayed by starting dose level.  Tabulations by maximum severity and relationship to 
Axitinib and/or with another anticancer drug(s) given in combination with axitinib, if 
applicable will also be included.  Summary patient listings will be provided for SAEs, 
adverse events resulting in discontinuation of axitinib, and deaths within 28 days of drug 
discontinuation and possibly or probably related to axitinib or to the anticancer drug(s) given 
in combination with axitinib.
9.3. Efficacy Analysis
Efficacy will not be assessed in this protocol.
9.4. Data Monitoring Committee 
This study will not use an external Data Monitoring Committee/Pfizer Safety 
Committee/Internal Oncology Business Unit-Safety Data Monitoring Committee.


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For the purpose of this protocol, Pfizer procedures for periodic safety review will be applied 
by an internal safety review team with medical and statistical capabilities to review 
individual and summary data collected in the safety and clinical databases.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During trial conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure that 
the protocol and GCPs are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs is accurate.  The investigator and institution will 
allow Pfizer monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification.
The trial site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used in this trial.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  CRFs 
must be signed by the investigator or by an authorized staff member to attest that the data 
contained on the CRF is true.  Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents will be the hospital’s or the physician’s chart.  In cases 
where the source documents are the hospital or the physician’s chart, the information 
collected on the CRFs must match those charts. 


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In some cases, the CRF, or part of the CRF, may also serve as the source document.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, serious adverse event forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement, whichever is longer.
If the investigator relocates, retires, or for any reason withdraws from the trial, Pfizer should 
be prospectively notified.  The trial records must be transferred to a designee acceptable to 
Pfizer, such as another investigator, another institution, or to an independent third party 
arranged by Pfizer.  Investigator records must be kept for a minimum of 15 years after 
completion or discontinuation of the study or for longer if required by applicable local 
regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the trial protocol, 
protocol amendments, informed consent forms, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Trial
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008).  Where mandated by local law, compliance with 1996 version of 
the Declaration of Helsinki applies.


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In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
Patient names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Pfizer in order to de-identify the trial 
patient.  In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of patient personal data.
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Pfizer before use.
The investigator must ensure that each study patient, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient or the patient’s legal representative before any 
study-specific activity is performed.  The investigator will retain the original of each patient’s 
signed consent form.
12.4. Reporting Of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in all Participating Countries 
End of Trial in all participating countries is defined as the time at which all patients enrolled 
in the study have completed treatment on study.


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this clinical trial may occur because of a regulatory authority 
decision, change in opinion of the IRB/IEC, drug safety problems, or at the discretion of 
Pfizer.  In addition, Pfizer retains the right to discontinue development of axitinib given as 
monotherapy or in combination at any time.
If a trial is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within a 4-week time period.  As directed by Pfizer, all 
trial materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF TRIAL RESULTS
Publication of study results is discussed in the CSA.
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial United Stated (US) Basic Results on www.clinicaltrials.gov for 
Pfizer-sponsored interventional studies (conducted in patients) that evaluate the safety and/or 
efficacy of a Pfizer product, regardless of the geographical location in which the study is 
conducted.  US Basic Results are submitted for posting within 1 year of the primary 
completion date (PCD) for studies in adult populations or within 6 months of the PCD for 
studies in pediatric populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com


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Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the study results themselves) before disclosure.


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If the study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement. 


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16. APPENDICES
Appendix 1. Study Protocol A4061068
(reference document for patients under axitinib and crizotinib treatment)
THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION
Note that sections of this document have been cross-linked within protocol A4061008 to
facilitate retrieval of relevant information. 
Please check what applies and refer to protocol A4061008 for all other study processes 
and schedule.


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CRIZOTINIB TREATMENT COMBINATION


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CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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Final Protocol Amendment #7, 08 November 2018
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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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THIS APPENDIX ONLY APPLIES TO PATIENTS UNDER AXITINIB AND 
CRIZOTINIB TREATMENT COMBINATION


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CRIZOTINIB TREATMENT COMBINATION


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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
PFIZER CONFIDENTIAL
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CRIZOTINIB TREATMENT COMBINATION


Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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CRIZOTINIB TREATMENT COMBINATION


Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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CRIZOTINIB TREATMENT COMBINATION


Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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CRIZOTINIB TREATMENT COMBINATION


Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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CRIZOTINIB TREATMENT COMBINATION


Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
PFIZER CONFIDENTIAL
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CRIZOTINIB TREATMENT COMBINATION


Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
PFIZER CONFIDENTIAL
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CRIZOTINIB TREATMENT COMBINATION


Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Axitinib (AG-013736)
Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Protocol A4061008
Final Protocol Amendment #7, 08 November 2018
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Protocol A4061008
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