A Phase II Study of the Efficacy and Safety of Axitinib Given on an Individualized Schedule for Metastatic Renal Cell Cancer After Treatment With Pd-1 or Pd-L1 Inhibitors
Phase: PHASE2
Conditions: Metastatic Renal Cell Cancer
Sponsor: Case Comprehensive Cancer Center

 
 
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STUDY NUMBER:      CASE 7815 
ClinicalTrials.gov:        NCT02579811 
PROTOCOL DATE:      08Oct2018 
 
Version Number:  10  
 
STUDY TITLE:  A PHASE II STUDY OF THE EFFICACY AND SAFETY OF AXITINIB 
GIVEN ON AN INDIVIDUALIZED SCHEDULE FOR METASTATIC RENAL CELL CANCER 
AFTER TREATMENT WITH PD-1 OR PD-L1 INHIBITORS 
 
 
 
 
 
PRINCIPAL INVESTIGATOR:  
Moshe C. Ornstein MD MA 
      
Cleveland Clinic Taussig Cancer Center 
 
9500 Euclid Avenue, CA-60 
      
Cleveland, Ohio 44195 
      
 
      
 
      
 
 
 
CO- INVESTIGATORS: 
 
Brian I Rini MD 
 
      
 
       
 
Jorge Garcia, MD 
 
     
 
       
 
Tim Gilligan, MD 
 
 
           
 
 
 
 
           
Monty Pal, MD / City of Hope 
Amir Mortazavi, MD / OSU  
Kimryn Rathmell MD / Vanderbilt 
 
STATISTICIAN: 
 
 
 
 
  
 
 
 
   
 
 
 

 
 
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RESEARCH NURSE:  
      
 
                                                 
 
 
STUDY COORDINATOR: 
 
 
 
 
 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center 
 
 
 
 
 
 
 
SUPPORT/FUNDING:  
Pfizer 
 
SUPPLIED AGENT(S): 
 Axitinib, Pfizer 
 
 
SUMMARY OF CHANGES 
 
Protocol Date 
Section 
Change 
13JUL2015 
 
Initial Submission to PRMC 
16SEP15 
 
PRMC Approved Version 
23OCT2015 
13.1 
Initial IRB approval; added, minor formatting and editing 
24NOV2015 
2.1 
Reworded the primary objective to clarify that the objective is 
to determine whether this individualized dosing schema will 
lead to improved PFS. 
 
3.1 
The inclusion criteria have been modified as follows: 
1. To highlight that anti-PD-1/PD-LI therapy must be the 
most recent therapy prior to enrollment on this study. 
2. To highlight that only one prior VEGF directed 
therapy is permitted.  
3. To clarify that prior VEGF directed monotherapy (i.e. 
not in combination with anti-PD-1/PD-LI therapy) is 
also permitted. 
 
3.2 
1.  Added an exclusion criterion to emphasize that more than 
one VEGF-based therapy given either as monotherapy or in 
combination with anti-PD-1/PD-LI therapy is not permitted. 
2.  Clarified that patients with controlled atrial fibrillation would 
not be excluded. 
3.  Removed exclusion criteria that would exclude patients who 
used CYP3A4 inhibitors and inducers within 7 and 12 days of 
the study, respectively. This issue is clarified in section 6.4. 
 
4.0 
The study calendar had a variety of formatting issues when 
changes were tracked. Therefore a new calendar was inserted. 
The following changes were made in the calendar/footnotes: 
1. Added row to state that ECOG/KPS will be collected on 
days a physical exam occurs. 

 
 
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2. Removed clinic visit from C1D14 assessment of toxicity. 
This will be done by phone call instead.  
3. Clarified timing of imaging (footnote 5). 
4. LDH will be drawn at baseline only (footnote 7). 
5. Clarified need / criteria for pregnancy test (footnote 8). 
6. Highlighted that protocol treatment should begin with 
three days of registration and not seven days. 
 
6.4 
Clarified which classes of drugs will be collected as 
concomitant medications during screening period and 
throughout study. 
1. Cardiac medications 
2. CYP3A4 meds (including list) 
3. Steroids (including dose) 
4. Anti-diarrhea medications 
 
6.4.1 
Clarified that the use CYP3A4 inhibitors and inducers in period 
immediately preceding study would not lead to exclusion but is 
not recommended. Also highlighted that the use of these meds 
is permitted during the study though not recommended. 
 
7.2 
1. Clarified number of 5mg and 1mg pills that will be given to 
patients at beginning of each cycle.  
2.  Provided name and fax number for diary sheets to be sent 
at the end of each cycle. 
 
10 
The statistics section has been revised and condensed with 
the following main changes: 
1. Primary statistical analysis has been changed to highlight 
its direct relationship to the primary objective.  
2. Patient sample size has been further clarified  
3. More information has been included with regards to the 
rationale for expected study duration.  
4. Toxicity criteria for study discontinuation have been 
added.  
25JAN2016 
1 
Administrative changes to Co-Investigator section on page 1  
14DEC2016 
 
Administrative changes to Co-Investigator section on page 1 
Updated protocol date 
 
3.1 
Inclusion-adding 2 week wash out and updated the Serum 
Creatinine to be less than or equal to 2.0 x ULN This is to align 
with our labs normal ranges  page 7 was also updated to reflect 
this change 
 
3.2 
Exclusion-CNS-Mets updated to 1 month stable instead of 3-
this is to align the protocol with parameters used in clinical 
practice.  Page 7 has also been updated   
 
3.3 
Language has been updated 
 
7.2 
Updated 1mg supply to 14-Day (#28) 
 
9.2 
Language updated to be after first dose of study drug  

 
 
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9.4 
Relationship language has been for alternate etiology  for 
unrelated events need to be provided 
 
15.6 
Removed 
 
15.7 
Removed 
 
15.8 
Removed 
20FEB2017 
Page 2 
Administrative changes adding Research Nurse phone 
number 
 
Synopsis 
& 
3.1/3.2 
Eliminate the restriction of ‘only ONE prior VEGF-based 
therapy (Bevacizumab or VEGF TKI) is permitted. Both 
inclusion & exclusion criteria. 
Rationale:  Allowing 2 prior VEGF-based therapies won’t 
impact the study objectives, and is consistent with clinical 
practice for Axitinib. 
 
Synopsis 
& 
3.2 
 
Eliminate the QTc interval exclusion criteria. 
Rationale: No QTc restriction for Axitinib in clinical practice. 
 
05JAN2018 
Cover 
Page 
Change PI. Add version number. 
Removal of Co-I Petros Grivas 
 
Synopsis 
& 
3.1 
Remove inclusion criteria of neoadjuvant or adjuvant therapy 
 
4 
Changed bone scan frequency after cycle 7 day 1 to every 16 
weeks per MD discretion.  
 
4 
Changed CT scans to ”following Cycle 11 Day 1 assessment, 
CT scans to be done every 12 weeks.” 
 
5 
Changed “drug-related” to “axitinib-related” in calendar 
footnote “a”.  
 
7.2 
Diary sheets will now be faxed to Keralee Morey (Fax: 216-636-
5675)  instead of Laura Wood  
 
7.2 
Changed method of diary sheet submission from fax only to 
“electronic/email or fax” 
 
10 
Sample size was decreased to 38 patients based on new data 
regarding efficacy of axitinib in this setting. Although the 
statistical analysis remains the same, the number of needed 
patients has changed.  
 
18Jul2018 
3.3 
Updated study coordinator to Jackie Tomer 
 
7.2 
Updated contact information for diary cards 
 
9.4 
Updated SAE reporting to Jackie Tomer 
08Oct2018 
Cover 
page 
Changed statistician to Brian P. Hobbs PhD. Updated OSU PI 
 
4 
Calendar was updated to resolve a discrepancy in imaging 
frequency between the calendar of footnotes. Also added 

 
 
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information on scan frequency for patients continuing axitinib 
post-PD. 
 
6.3 
PI was changed to Moshe Ornstein MD 
 
6.5 
This section was added to provide information regarding 
duration of follow-up  
 
8.2 
Imaging text was changed to reflect the calendar clarification 
 
 
SYNOPSIS 
 
Study Title: 
A Phase II Study of the Efficacy and Safety of Axitinib 
Given on an Individualized Schedule for Metastatic 
Renal Cell Cancer after Treatment with PD-1 or PD-L1 
Inhibitors 
Primary Objectives: 
To determine whether axitinib given on an 
individualized dose/schedule for metastatic renal cell 
carcinoma following immunotherapy with PD-1 or PD-
L1 Inhibitors leads to improved PFS 
Secondary Objectives: 
To characterize the objective response rates in patients 
given axitinib on an individualized dose/schedule 
To evaluate the tolerability and safety of an alternative 
method of axitinib titration. 
To characterize the anti-tumor effect, as measured by 
change in tumor burden per RECIST 1.1, of axitinib 
titration performed after initial RECIST PD on axitinib  
Study Design: 
A Phase II study, single arm study, open-label, safety 
and efficacy study. 
Duration: 
Approximately 3 years, including 18-24 months of 
recruitment, minimum 4 months of treatment and a 
minimum of 1 year of follow-up 
Planned Total Sample Size: 
38 evaluable patients will be enrolled in this study. 

 
 
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Inclusion/Exclusion Criteria: 
Inclusions: 
Histologically confirmed, locally recurrent or metastatic 
clear cell renal cell carcinoma 
Has received one prior systemic therapy regimen for 
mRCC directed against PD-1 and/or PD-L1 which must 
have been the most recent regimen 
o Prior 
high-dose 
interleukin-2 
therapy 
is 
permitted in addition to anti-PD(L)1 therapy, but 
is not required 
o Prior bevacizumab or VEGF TKI is  permitted 
either in combination with anti-PD(L)1 therapy 
OR as monotherapy when given PRIOR to anti-
PD(L)1 therapy- 
o  
o Prior treatment with combined ipilimumab and 
nivolumab is permitted 
o Prior axitinib in any setting is not permitted 
A minimum of two weeks since last dose of most recent 
RCC therapy assuming resolution of clinically significant 
treatment-related toxicities to grade 1, baseline, or 
controlled with supportive medications 
Evidence of measurable disease per RECIST 1.1.  
Male or female, age ≥ 18 years 
Karnofsky performance status ≥ 70 %.  
Adequate organ function as defined by: 
o 
Absolute neutrophil count (ANC) ≥1,000/μL  
o 
Platelets ≥100,000/μL 
o 
Hemoglobin ≥9.0 g/dL  
o 
Serum calcium ≤12.0 mg/dL  
o 
Serum Creatinine ≤2.0 x ULN 
o 
Total serum bilirubin ≤1.5 x ULN 
o 
SGOT≤2.5 x ULN and SGPT ≤2.5x ULN  
 
Signed informed consent and willingness/ability to 
comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures. 

 
 
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Exclusion: 
Non-clear cell RCC 
Major surgery within 4 weeks of starting the study 
treatment. 
Radiation therapy within 2 weeks of starting the study 
treatment. Prior palliative radiotherapy to metastatic 
lesion(s) is permitted, provided there is at least one 
measurable lesion that has not been irradiated. 
NCI CTCAE Version 4.03 grade 3 hemorrhage within 4 
weeks of starting the study treatment. 
Any of the following within the 6 months prior to study 
drug administration: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident or transient ischemic attack. 
Ongoing cardiac dysrhythmias of NCI CTCAE Version 
4.03 grade ≥2. Controlled atrial fibrillation is permitted. 
Uncontrolled hypertension (>160/100 mm Hg despite 
optimal medical therapy) 
Concurrent treatment on another clinical trial. Supportive 
care, non-treatment trials, and imaging trials are allowed. 

 
 
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Exclusion criteria (cont.) 
Pregnancy or breastfeeding. Female subjects must 
be surgically sterile or be postmenopausal, or must 
agree to use effective contraception during the 
period of therapy. All female subjects with 
reproductive potential must have a negative 
pregnancy test (serum) prior to enrollment. Male 
subjects must be surgically sterile or must agree to 
use effective contraception during the period of 
therapy. The definition of effective contraception will 
be based on the judgment of the principal 
investigator or a designated associate 
Other severe acute or chronic medical or psychiatric 
condition or laboratory abnormality that may 
increase the risk associated with study participation 
or study drug administration, or may interfere with 
the interpretation of study results, and in the 
judgment of the investigator would make the subject 
inappropriate for entry into this study.    
Uncontrolled CNS metastases. Patients are 
considered to have controlled CNS metastases (and 
thus eligible) if they have completed local therapy 
(XRT and/or surgery) and are off steroids with 
clinical and radiographic stability 1month from the 
end of CNS-directed therapy. 
Test Drug Administration: 
 
The intent is to maximize dose intensity of axitinib 
based on individual tolerability using the dose 
modification criteria described in Section 5.  Dose 
changes are done if selected toxicity (oral mucositis, 
diarrhea, fatigue, hand-foot syndrome) is < grade-2. 
There will be no mandated dosing or schedule 
changes for hypertension, hypothyroidism, skin 
color changes, heartburn etc.  Patients will continue 
therapy until progression according to RECIST 
criteria version 1.1 or investigator discretion of 
clinical benefit.  Patients may undergo dose 
escalation following disease progression at the 
discretion of the provider. 
 

 
 
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Treatment and Post-
Treatment Assessments: 
 
One cycle is defined as 28 days. 
During the first cycle: 
 History and Physical exam at beginning of 
each cycle 
 CBC with differential 
 Complete Metabolic Panel (CMP) 
 Thyroid function tests 
 Telephone encounter during first week to 
assess toxicity  
  Phone call after two weeks to assess 
toxicity 
 
During Subsequent Cycles: 
 History and Physical exam at beginning of 
each cycle 
 CBC with differential at beginning of each 
cycle 
 CMP  at beginning of each cycle 
 Telephone call or clinic visit 7 & 14 days 
after each dose change 
 Clinic visits or  telephone calls as needed to 
assess toxicity 
 
Every two cycles:  
 
 Restaging of involved areas  
 Thyroid function tests 
.   
Response: 
Response will be assessed as per RECIST version 
1.1 
Safety Variables & Analysis: 
Adverse Events will be assessed as per CTCAE 
version 4.03 

 
 
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ABBREVIATIONS  
ADL 
Activities of Daily Living 
ADR 
Adverse Drug Reaction 
AE 
Adverse Events 
AHFS 
American Hospital Formulary Service  
ANC 
Absolute Neutrophil Count 
ASHP 
American Society of Hospital Pharmacists  
AUC 
Area Under the Curve 
BID 
Twice Daily 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CCCC 
Case Comprehensive Cancer Center 
CCF 
Cleveland Clinic Foundation 
CITI 
Collaborative Institutional Training Initiative 
Cmax 
Maximum Plasma Concentration 
CMP 
Comprehensive Metabolic Panel 
CNS 
Central Nervous System 
CR  
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCRU 
Dahm’s Clinical Research Unit 
DSTC 
Data Safety and Toxicity Committee 
EC 
Ethics Committee 
EKG 
Electocardiogram 
FDA 
Food and Drug Administration 
HR 
Hazard Ratio 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
LAR 
Legally Acceptable Representative 
MD 
Medical Doctor 
mRCC 
Metastatic Renal Cell Carcinoma 
MRI 
Magentic Resonance Imaging  
NCI 
National Cancer Institute 
OS 
Overall Survival 
PD 
Progressive Disease 
PD(L)-1 
Programmed Cell Death Ligand 1 
PD-1 
Programmed Cell Death Protein  
PFS 
Profession Free Survival 

 
 
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PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR  
Partical Response 
PRMC 
Protocol Review and Monitoring Committee 
QD 
Every Day 
QOL 
Quality of Life 
RCC 
Renal Cell Carcinoma 
RECIST Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Events 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SOC 
Standard of Care 
TKI 
Tyrosine Kinas Inhibitor 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
VEGFR 
Vascular Endothelial Growth Factor 
XRT 
Radiation Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
SYNOPSIS: .................................................................................................................................... 5 
1. INTRODUCTION ...................................................................................................................... 15 
1.1 Background ..........................................................................................................................15 
1.2 Pharmacokinetics of axitinib ............................................................................................... 155 
1.3 Axitinib Dose Escalation Data ...............................................................................................17 
1.4  Rationale for the study .........................................................................................................21 
2.   OBJECTIVES ......................................................................................................................... 24 
2.1   Primary objective ................................................................................................................24 
2.2   Secondary objectives..........................................................................................................24 
3.   SUBJECT SELECTION .......................................................................................................... 24 
3.1   Inclusion criteria ..................................................................................................................24 
3.2   Exclusion criteria ................................................................................................................25 
3.3   Patient Registration ............................................................................................................27 
4.   STUDY CALENDAR ............................................................................................................... 28 
5.   DOSE-TITRATION SCHEMA ................................................................................................. 29 
6.   TREATMENT PLAN ............................................................................................................... 30 
6.1   Treatment schedule ............................................................................................................31 
6.2   Subject compliance and dropout .........................................................................................31 
6.3   Premature withdrawal/ discontinuation criteria ....................................................................31 
6.4   Concomitant Medications ...................................................................................................32 
6.4.1   Inhibitors and Inducers of CYP3A4 ...............................................................................32 
6.4.2   Anticoagulants ..............................................................................................................33 
6.4.3   Other Anticancer or Experimental Therapy ...................................................................33 
6.4.4   Antiemetic and Antidiarrheal Therapy ...........................................................................33 
6.4.5   Hematopoietic Growth Factors .....................................................................................33 
6.4.6   Other Concomitant Medications ...................................................................................33 
6.4.7   Concomitant Radiotherapy or Surgery ..........................................................................34 
6.5   Duration of follow-up ...........................................................................................................32 
7.  INVESTIGATIONAL MEDICINAL PRODUCT .......................................................................... 34 
Study agent ................................................................................................................................34 
7.1 Drug supply ..........................................................................................................................34 
7.2 Characterization of the Investigational medicinal product .....................................................34 

 
 
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7.3 Packaging, labeling and dispatch of the Investigational medicinal product............................35 
7.4 Stability and Storage ............................................................................................................36 
7.5 Accountability and Destruction of Investigational medicinal product .....................................36 
7.6 Drug Administration ..............................................................................................................36 
8.  MEASUREMENT OF DRUG EFFECT ..................................................................................... 36 
8.1 Safety assessment ...............................................................................................................36 
8.2 Efficacy assessments ...........................................................................................................36 
9. SAFETY AND REPORTING REQUIREMENTS ........................................................................ 37 
9.1 Adverse Event ......................................................................................................................37 
9.2 Adverse Event Documentation .............................................................................................38 
9.3 Serious Adverse Event ....................................................................................................... 388 
9.4 Reporting Serious Adverse Events .......................................................................................40 
9.5 Procedure for Expedited Reporting .......................................................................................40 
9.6 Follow up of Adverse Events and Serious Adverse Events ...................................................41 
9.7 Relationship ..........................................................................................................................41 
10. STATISTICAL ANALYSIS ....................................................................................................... 42 
10.1 Study design and justification for sample size .....................................................................42 
10.2 Study population .................................................................................................................43 
10.3 Statistical Anylysis ..............................................................................................................43 
11. ETHICS .................................................................................................................................. 43 
11.1 Informed Consent ...............................................................................................................43 
11.2 Institutional Review Board Approval ...................................................................................44 
12. DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF STUDY RECORDS ....... 44 
12.1 Documentation of subject’s participation .............................................................................44 
12.2 Regulatory Requirements ...................................................................................................44 
12.3 Subject Confidentiality ........................................................................................................45 
12.4 Confidentiality of the study ..................................................................................................45 
12.5 Registration of Clinical Trial ................................................................................................45 
12.6 Data reporting .....................................................................................................................46 
12.7 Case Report Forms ............................................................................................................46 
12.8 Maintenance of study records .............................................................................................46 
13. QUALITY ASSURANCE AND QUALITY CONTROL .............................................................. 46 
13.1 On site Monitoring / Auditing ...............................................................................................46 

 
 
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13.1  
Audits and inspections ...................................................................................................46 
13.2 
Data Safety and Monitoring Plan ...................................................................................47 
14. ADMINISTRATIVE PROCEDURES ........................................................................................ 47 
14.1 Amendments to the protocol ...............................................................................................47 
14.2 Protocol deviations and Violations ......................................................................................47 
14.3 Premature discontinuation of the study ...............................................................................47 
15. APPENDICES ........................................................................................................................ 48 
15.1 RECIST 1.1 Criteria ............................................................................................................48 
15.2 ECOG PERFORMANCE STATUS SCALE .........................................................................51 
15.3 KARNOFSKY PERFORMANCE STATUS SCALE .............................................................52 
15.4 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
 ...................................................................................................................................................53 
15.5 BLOOD PRESSURE MEASUREMENT / STUDY DRUG DOSING .....................................54 
 16. REFERENCES ...................................................................................................................... 55 
 
 
 

 
 
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1. INTRODUCTION 
 
1.1 Background 
Axitinib is a tyrosine kinase inhibitor (TKI) of the vascular endothelial growth factor receptor 
(VEGFR) approved January 2012 for the treatment of metastatic renal cell carcinoma 
(mRCC). 1, 2 The phase III AXIS trial that led to its approval randomized 723 mRCC patients 
with progressive disease following treatment with sunitinib, temsirolimus, bevacizumab, or 
cytokines to receive sorafenib 400mg BID or axitinib at a starting dose of 5mg BID.  Dose 
titration of axitinib to 7mg BID and further to 10mg BID was allowed for patients without 
grade 2 or higher toxicities or hypertension (BP > 150/90). The primary endpoint was PFS. 
Median PFS in the axitinib arm was 6.7 months compared to 4.7 months in patients 
randomized to sorafenib (HR 0.665; 95% CI 0.544-0.812; p<0.0001). The secondary 
endpoint of objective response rate (ORR) was also significant at 19% for the axitinib arm 
and 9% for sorafenib (p=0.0001) with a higher median duration of response in patients 
receiving axitinib compared to sorafenib (11 months vs. 10.6 months). Diarrhea, 
hypertension, and fatigue were the most common adverse events occurring in greater than 
30% of patients. 2  
1.2 Pharmacokinetics of axitinib 
The pharmacokinetics of TKIs demonstrate significant inter-individual variability, which may 
be contribute to the variable clinical response in patients. 3 However, despite variable anti-
tumor effects, some general principles about TKI pharmacokinetics have been well-
established.  Early clinical trials with axitinib demonstrate linear pharmacokinetics in that 
higher doses of the drug results in proportional increases in plasma level.  In a dose-finding 
phase I trial of thirty-six patients with advanced solid tumors who received axitinib with doses 
ranging between 5mg BID and 20mg BID, there were dose-proportional increases in mean 
steady-state concentrations, maximum plasma concentration (Cmax) and area under the 
curve (AUC)  (Figures 1, 2). 4 These findings were similarly noted in a phase I open-label 
study of 14 healthy volunteers 5 and have been reproduced in many studies. 6-8 
 

 
 
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Figure 1. Mean steady-state AG-013736 plasma concentrations on day 15 of dosing. (A) Cmax, 
maximum concentration; (B) AUC, area under the curve. QD, every day. 4 
 
 
Figure 2. Area under the curve (AUC) and maximum plasma concentration (Cmax) versus dose: 
linearity in pharmacokinetics. QD, every day. 4  
 

 
 
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A pooled axitinib pharmacokinetic and pharmacodynamic analysis from 17 clinical trials 
included a total of 590 subjects; 383 were healthy volunteers, 181 mRCC patients, and 26 
patients had other solid tumors. 9 These data demonstrated a linear relationship between 
the dose of axitinib, plasma exposure, and area under the plasma concentration-time curve 
(AUC).  Moreover, the probability of a response to treatment increased with each 100h x 
ng/mL increase in AUC (p<.0001).  PFS (13.8 vs. 7.4 months; p=.003) and OS (37.4 vs. 15.8 
months; p<.001) were significantly longer in the high-AUC group (>300 h x ng/mL) than the 
low-AUC group (<300 h x ng/mL). 9 These data indicate that higher exposure in general is 
associated with improved clinical outcomes.   
 
1.3 Axitinib Dose Escalation Data 
Based on the considerations above, a prospective trial was conducted to determine if dose 
titration of axitinib led to improved clinical outcomes in patients with mRCC. A phase 2, 
double-blinded, randomized, international trial enrolled 213 previously untreated mRCC 
patients to determine if a higher objective response rate would be observed in patients with 
escalated axitinib doses compared to patients who remained at 5mg BID among all 
patients eligible for titration. 10 In a 4 week lead-in period prior to randomization, all patients 
received axitinib 5mg BID. 112 patients with who tolerated the 5mg BID dose for four 
weeks were subsequently randomized to placebo titration or to have their axitinib titrated to 
7mg BID and then, if tolerated, to 10mg BID.  Patients in the dose-titration group 
experienced an increase in the mean axitinib drug exposure from prior to dose titration to 
15 days after dose titration (Table 1) 10, demonstrating the linear dose-proportional 
pharmacokinetics of axitinib dosing.   
 
 
 
 

 
 
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Table 1. Axitinib pharmacokinetic parameters prior to and after dose titration 10 
 
  
Eligible for dose titration 
Axitinib titration 
Placebo titration 
Day 15 of lead-in period  
(prior to titration) 
 
 
          AUC24 ng*h/mL 
176 (125-247) 
187 (107-327) 
          Cmax ng/mL 
28.6 (20·5-39.9) 
22.5 (15.1-33.7) 
Cycle 2 day 15  
(after titration) 
 
 
          AUC24 ng*h/mL 
259 (150-445) 
161 (102-255) 
          Cmax ng/mL 
31.7 (21.6-46.6) 
23.1 (16.4-32.5) 
 
 
The group of patients randomized to dose titration also had a higher objective response 
rates (ORR) than the placebo titration group (54% vs. 34%; p = 0.019) (Table 2).  
 
 
 
 
 

 
 
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Table 2. Best Observed Response by RECIST 10 
  
Total (N=213) 
Axitinib 
titration 
(n=56) 
Placebo 
titration 
(n=56) 
Non-
randomised 
(n=91) 
Complete response 1 (<1%) 
1 (2%) 
0 
0 
Partial response 
102 (48%) 
29 (52%) 
19 (34%) 
54 (59%) 
Stable disease 
60 (28%) 
13 (23%) 
24 (43%) 
23 (25%) 
Progressive 
disease 
38 (18%) 
13 (23%) 
11 (20%) 
11 (12%) 
Not assessed 
9 (4%) 
0 
1 (2%) 
2 (2%) 
Indeterminate 
2 (1%) 
0 
0 
1 (1%) 
 
Although the above data demonstrate that axitinib titration will lead to higher axitinib 
exposure, and, in general, higher exposure will be associated with a higher objective 
response rate, a number of mitigating factors to applying this in routine clinical practice exist. 
Firstly, the use of PK measurements to determine dose-titration is imprecise.  In this study, 
there was a 34% response rate in patients eligible for dose titration who were randomized 
to placebo.  Many of these patients had what would be considered ‘sub-therapeutic’ levels 
of axitinib yet still demonstrated an objective response (Figure 3).  Likewise, many of the 
patients in the active titration cohort who had stable or progressive disease actually had 
supra-therapeutic PK levels (Figure 3). These data suggest that although PK levels may 
reflect objective response on average for an entire cohort of patients, it does not accurately 
guide dosing for individual patients.  Further, several patients who escalated to 7mg BID and 
higher had to quickly reduce to 5mg BID dosing or lower, suggesting that the current dose 
titration schema is not suitable for all patients (i.e. the amount of dose increase in the current 
titration schema represents too big of a dose increase for some patients).  

 
 
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Figure 3.  PK levels in three patient cohorts (active titration, placebo titration, and non-
randomized) and response of individual patients.  Blue dots denote individual patient PK 
levels.  Horizontal green dashed line represent 300h x ng/mL which is considered the 
therapeutic plasma level of axitinib. 
 
 
 
Indeed, although the hazard ratio for PFS favored the titration arm (HR=0.85), this was not 
statistically significant (Figure 4). Closer examination of the PFS curves reveals and early 
drop in the titrated arm, in part due to toxicity encountered with titration. This also reveals 
the tail of the curve favoring dose titration (Figure 4), supporting a hypothesis that a more 
refined titration schema to allow for sustained titration could lead to enhanced clinical 
outcome.   
 
 

 
 
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Figure 4.  Kaplan-Meier Estimates of PFS From First Dose in Randomized Arms – 
Favorable but non statistically significant PFS in the titration arm (HR = 0.85; p=0.24).  
Early drop in the titration arm likely related to toxicities in titration arm.  Tail of curve 
demonstrating favorable long-term outcome in the titration arm. 10 
 
 
 
1.4  Rationale for the study  
As with many oral targeted drugs, axitinib is characterized by a variable plasma exposure at 
a given dose among patients and a lack of correlation between plasma levels and efficacy 
in individual patients. As such, and given rapid absorption and elimination, the clinical 
development of axitinib incorporated dose titration to allow for higher doses in patients who 
did not suffer from dose-related toxicities. However, as reviewed above, the current axitinib 
dosing schema (starting dose of 5mg BID with titration to 7mg BID and then 10mg BID) has 
several limitations. The goal of this study is to identify an individualized dose-titration 
algorithm for axitinib that will provide clinicians with a useful tool to optimize clinical outcome 
in patients with mRCC following treatment with immunotherapy (specifically, checkpoint 
inhibitors).  
Rationale for Proposed Schema: The proposed titration schema contains a number of 
critical components that differ from the current titration standard. The current package insert 
titration schema is predicated on the hypothesis of an inherent value to continuous therapy 
with axitinib even at a lower dose to maintain steady plasma concentration of the drug. As 

 
 
CASE 7815                                                                     Page 22                      Version date: 08Oct2018 
 
such, in previous clinical trials, axitinib has been given on a continuous schedule with dose 
reduction for patients that developed toxicity on continuous therapy. However, rodent data 
show that intermittent higher dose TKI therapy may be associated with improved efficacy 
than continuous lower dose therapy. 11 Therefore, in this study patients are treated to toxicity 
on an individualized dose and schedule and instead of dose-reduction upon grade 2 or 
greater toxicity, they take an individualized break from the drug and then resume the same 
dose.  The intent, therefore, is not to sustain continuous therapy with a lower dose, but rather 
to maximize the dose on an intermittent schedule even if it means having a few days off 
therapy. 
It is also well established that because of limited pill sizes available for oral drugs, dose 
reductions and dose escalations on a fixed schedule cannot be fine-tuned to the same extent 
as for IV chemotherapy. 12 With the usual dose reductions for axitinib to 3 mg bid and then 2 
mg BID patients receive 60% and 40% respectively of the starting dose level and some pts 
may be under dosed. Conversely with the standard dose escalation to 7 mg BID and then 
10 mg BID patients receive 140% and 200% of the starting dose respectively and some 
patients may be overdosed and end up requiring dose reduction. In our proposed study, 
most dose escalations and reductions are by a rate of 1mg BID which allows for a more 
precise titration schema based on tolerance and will likely result in less dose-escalation 
toxicity given the slower rate of titration.  
Rationale for Patient Population: This study will enroll patients with mRCC previously 
treated with immune checkpoint inhibitors of programmed death 1 (PD-1) and programmed 
death ligand 1 (PD-L1).  Anti-PD-1 and anti-PD-L1 inhibitors have demonstrated efficacy in 
TKI-refractory and previously untreated mRCC patients 13-16 and clinical trials with these 
compounds are being offered to patients with mRCC as first line therapeutic options. 17, 18 
There are currently no prospective data on the efficacy of axitinib in the post-PD-1/PD-L1 
setting, and the available retrospective data are limited to relatively small populations and 
demonstrate a PFS of approximately 7 months. 19, 20 Recruitment of large number of patients 
to a first-line individualized axitinib dosing trial would be challenging in the era of checkpoint 
inhibitors clinical trials, but a trial limited to the post-PD-1/PD-L1 setting would be beneficial 

 
 
CASE 7815                                                                     Page 23                      Version date: 08Oct2018 
 
both to identify an improved method of axitinib administration in general and also to 
prospectively document efficacy after PD-1/PD-L1 inhibition.    
Rationale for Allowance of Dose-escalation at Progression: Upon RECIST 1.1 PD, this 
study recommends dose-escalation in patients without > grade 2 toxicities. This 
recommendation is based on recently-presented data that suggest a clinical benefit to dose 
escalation of TKIs upon PD in mRCC. 21 In a retrospective review of 21 patients with mRCC, 
89% of whom were treated with axitinib, patients who underwent TKI dose-escalation 
following PD were assessed for tumor response. 58% of patients had a reduction in tumor 
burden following dose-escalation and patients remained on dose-escalated therapy post-
PD for almost as long as prior to PD (median 6.3 vs 6.8 months, with 28% of patients still on 
treatment). 21 This suggests a potential clinical benefit to TKI dose-escalation post-PD. 
These data also suggest that perhaps the patients who developed PD on their initial dose 
had sub-therapeutic axitinib levels and further underscore the need for a more precise dose-
titration schema to maximize the clinical benefit of axitinib.  
In summary, the present trial proposes a dose-titration schema of axitinib for patients with 
mRCC following treatment with immune checkpoint inhibitors. The study aims to identify a 
fine-tuned titration schema that will maximize dosing while allowing for intermittent individual 
breaks in hopes of improving overall efficacy. Building on retrospective data, the study will 
also prospectively evaluate the clinical effect of dose escalation following PD.   
 
 

 
 
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2.   OBJECTIVES 
 
2.1   Primary objective 
 
 To determine whether axitinib given on an individualized dose/schedule for metastatic 
renal cell carcinoma following immunotherapy with PD-1 and PD-L1 Inhibitors leads to 
improved PFS.  
 
2.2   Secondary objectives     
 
 To characterize the objective response rates in patients given axitinib on an 
individualized dose/schedule 
 To evaluate the tolerability and safety of an alternative method of axitinib titration.  
 To characterize the anti-tumor effect, as measured by change in tumor burden per 
RECIST 1.1, of axitinib titration performed after initial RECIST PD on axitinib 
3.   SUBJECT SELECTION  
 
This trial will be conducted in compliance with this protocol and with oversight by our 
institution’s Institutional Review Board (IRB).  Any questions about eligibility criteria must be 
addressed prior to patient registration.  
3.1   Inclusion criteria  
 
Patients will be eligible if they meet all of the following criteria at the time of registration:  
 Histologically confirmed, locally recurrent or metastatic clear cell renal cell carcinoma 
 Has received one prior systemic therapy regimen for mRCC directed against PD-1 and/or 
PD-L1 which must have been the most recent regimen 
o Prior high-dose interleukin-2 therapy is permitted in addition to anti-PD(L)1 
therapy, but is not required 

 
 
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o Prior bevacizumab or VEGF TKI is  permitted either in combination with anti-
PD(L)1 therapy OR as monotherapy when given PRIOR to anti-PD(L)1 therapy- 
o Prior treatment with combined ipilimumab and nivolumab is permitted 
o Prior axitinib in any setting is not permitted 
 A minimum of two weeks since last dose of most recent RCC therapy assuming 
resolution of clinically significant treatment-related toxicities to grade 1, baseline, or 
controlled with supportive medications 
 Evidence of measurable disease per RECIST 1.1.  
 Male or female, age ≥ 18 years 
 Karnofsky performance status ≥ 70 %.  
 Adequate organ function as defined by: 
o Absolute neutrophil count (ANC) ≥1,000/μL  
o Platelets ≥100,000/μL 
o Hemoglobin ≥9.0 g/dL  
o Serum calcium ≤12.0 mg/dL  
o Serum Creatinine ≤2.0 x ULN 
o Total serum bilirubin ≤1.5 x ULN 
o SGOT≤2.5 x ULN and SGPT ≤2.5x ULN  
 
 Signed informed consent and willingness/ability to comply with scheduled visits, 
treatment plans, laboratory tests, and other study procedures 
3.2   Exclusion criteria  
Patients will be ineligible if they meet any of the following criteria at the time of registration:  
 Non clear cell RCC 
 Major surgery within 4 weeks of starting the study treatment. 
 Radiation therapy within 2 weeks of starting the study treatment. Prior palliative 
radiotherapy to metastatic lesion(s) is permitted, provided there is at least one 
measurable lesion that has not been irradiated. 
 NCI CTCAE Version 4.03 grade 3 hemorrhage within 4 weeks of starting the study 
treatment (Section 15.4). 

 
 
CASE 7815                                                                     Page 26                      Version date: 08Oct2018 
 
 Any of the following within the 6 months prior to study drug administration: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure, cerebrovascular accident or transient ischemic 
attack. 
 Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.03 grade ≥2. Controlled atrial 
fibrillation is permitted. 
 Uncontrolled hypertension (>160/100 mm Hg despite optimal medical therapy) 
 Concurrent treatment on another clinical trial. Supportive care trials or non-treatment 
trials, e.g. QOL, and imaging trials, are allowed. 
 Pregnancy or breastfeeding. Female subjects must be surgically sterile or be 
postmenopausal, or must agree to use effective contraception during the period of 
therapy. All female subjects with reproductive potential must have a negative 
pregnancy test (serum) prior to enrollment. Male subjects must be surgically sterile 
or must agree to use effective contraception during the period of therapy. The 
definition of effective contraception will be based on the judgment of the principal 
investigator or a designated associate 
 Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, and in 
the judgment of the investigator would make the subject inappropriate for entry into 
this study.    
 Uncontrolled CNS metastases. Patients are considered to have controlled CNS 
metastases (and thus eligible) if they have completed local therapy (XRT and/or 
surgery) and are off steroids with clinical and radiographic stability 1 month from the 
end of CNS-directed therapy. 
 
 
 
 

 
 
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3.3 Patient Registration 
 
All patients will be screened by one of the principal investigators or sub-investigators prior 
to entry into this study. An explanation of the study and discussion of expected side effects 
and full disclosure of the “informed consent” document will take place.  Eligible and 
consented patients will be registered into the study. No eligibility exceptions will be made. 
To enter eligible patients on study, investigators register patients by contacting the 
Cleveland Clinic Lead Study Coordinator.  In the event that the Lead Study Coordinator 
cannot be reached, the Database Manager may be contacted to register a patient.  Contact 
information for these individuals is listed below.  All patients will be registered in ONCORE. 
Overture will act as the data management system. Please refer to the calendar for collection 
details. 
Title 
Name 
Phone 
E-mail 
Lead Study 
Coordinator 
Jackie Tomer 
216-444-
9814 
tomerj2@ccf.org 
Database 
Mgr 
Matthew Rump (216) 
444-
9301 
rumpm@ccf.org 
 
 
 
 
 
 
 
 
 

 
 
CASE 7815                                                                     Page 28                      Version date: 08Oct2018 
 
4.   STUDY CALENDAR  
Required Investigations 
Baseline 
(within 4 
weeks prior to 
C1D1) 
First Cycle 
(28 days) 
Day 7 and 14 
after each 
dose change 
(+/- 2 working 
days)  
 
Each 
Cycle  
Day 13,5 
(28 days 
+/- 3 
working 
days) 
Safety 
assessment6 
(Within 30 days 
after off 
treatment +/- 3 
days) 
Day 71    
(+/- 2 
working 
days) 
Day 141 
(+/- 2 
working 
days) 
History and Physical 
Exam 
X 
 
 
 
X9 
 
KPS and ECOG 
performance status 
X 
 
 
 
X 
 
Informed consent 
X 
 
 
 
 
 
Assessment of Toxicity 
 
X (phone 
call) 
X (phone 
call) 
X (phone call 
and/or clinic 
visit) 
X 
Assess for 
resolution of 
treatment-related 
toxicities within 
30 days of last 
dose 
CBC w/ differential, 
CMP, and LDH7 
X 
 
 
 
X 
as clinically 
indicated 
TSH, T3, T4 
X 
 
 
 
X4 
as clinically 
indicated 
Pregnancy Test8 
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
Radiographic 
Assessment2 
X 
 
 
 
X5 
 
Patient diary 
(BP/dosing) 
X-----------------------------------------------------------X 
1 No dose escalation prior to day 14 of cycle 1 
2 CTs (head, chest, abdomen, pelvis; with oral and IV contrast if possible) and bone scan required at baseline and must be done 
within 28 days of registration. MRI is allowed instead of CT head at baseline.. CT head will be done after baseline as clinically 
indicated. Follow-up scans are based on C1D1 date regardless of the date of baseline scans. 
3 Beginning at C5D1 this column can be extended to every 2 cycles per provider discretion. Following C13D1 visit, this can be 
extended to every 12 weeks (i.e., 3 cycles) 
4 Tests to be done at imaging timepoints points 
5 After baseline, bone scan only if indicative of metastatic disease at baseline or if clinical signs/symptoms develop.  CT Chest-
Abdomen-Pelvis will be done every 8 weeks based on C1D1 date regardless of the date of baseline scans.  Following Cycle 13 
Day 1 assessment, CT scans to be done every 12 weeks. [Note: patients continuing axitinib post-PD will have CT c/a/p every 8 
weeks and bone scans as needed per MD discretion] 
Following Cycle 7 Day 1 disease assessment, bone scan  to be done every 16 weeks per MD discretion (and every 24 weeks 
after C13 per MD discretion) 
6 Treatment-related AE reporting ends at the time new treatment is started (see section9.6). After C13D1, all SAEs will be 
documented, AEs will be followed per SOC but not necessary to document for study-related purposes. 
7 LDH at baseline only 
8 Serum pregnancy test for women of childbearing potential. No childbearing potential defined as > 12 months of non-therapy-
induced amenorrhea or surgically sterile. 

 
 
CASE 7815                                                                     Page 29                      Version date: 08Oct2018 
 
9 Targeted physical exam per MD discretion when patient is in for a clinic visit 
Protocol treatment should begin within 3 working days of patient registration.  
5.   DOSE-TITRATION SCHEMA 
 
 a Dosing modifications based only on the following grade 2 toxicities: oral  mucositis, diarrhea, hand-foot 
syndrome, fatigue. Dose modifications for other axitinib-related AEs can be considered per study principal 
investigator.CTC v4 definitions of grade 2 toxicities: 
 
 
Oral mucositis: Moderate pain; not interfering with oral intake; modified diet indicated 
Dose 
Level 
Dose 
If grade 2 or greater 
toxicity during days 1-7a 
If grade 2 or greater 
toxicity during 
days 8-14 a 
If no grade 2 or greater 
toxicity after 14 days a 
Dose 
reduction 
level 3 
2 mg 
BID 
Discuss with study sponsor 
Hold axitinib if needed (e.g. 
3 days) then resume at  
2 mg BID with breaks as 
neededc 
Stay on 2mg BIDc 
Dose 
reduction 
level 2 
3 mg 
BID 
Dose reduce to 2mg BIDb 
(can hold axitinib prior to 
restarting per MD 
discretion) 
Hold axitinib if needed (e.g. 
3 days) then resume at  
3 mg BID with breaks as 
neededc 
Stay on 3mg BIDc 
Dose 
reduction 
level 1 
4 mg 
BID 
Dose reduce to 3mg BIDb 
(can hold axitinib prior to 
restarting per MD 
discretion) 
Hold axitinib if needed (e.g. 
3 days) then resume at  
4 mg BID with breaks as 
neededc 
Stay on 4mg BIDc 
Starting 
dose level 
5 mg 
BID 
Dose reduce to 4mg BIDb 
(can hold axitinib prior to 
restarting per MD 
discretion) 
Hold axitinib if needed 
(e.g. 3 days) then resume 
at 5 mg BID with breaks 
as neededc 
Dose escalate to 
6 mg BID 
Dose 
escalation 
level 1 
6 mg 
BID 
Dose reduce to 5mg BIDb 
(can hold axitinib prior to 
restarting per MD 
discretion) 
Hold axitinib if needed (e.g. 
3 days) then resume at  
6 mg BID with breaks as 
neededc 
Dose escalate to 
7 mg BID 
Dose 
escalation 
level 2 
7 mg 
BID 
Dose reduce to 6mg BIDb 
(can hold axitinib prior to 
restarting per MD 
discretion) 
Hold axitinib if needed (e.g. 
3 days) then resume at  
7 mg BID with breaks as 
neededc 
Dose escalate to 
8 mg BID 
Dose 
escalation 
level 3 
8 mg 
BID 
Dose reduce to 7mg BIDb 
(can hold axitinib prior to 
restarting per MD 
discretion) 
Hold axitinib if needed (e.g. 
3 days) then resume at  
8 mg BID with breaks as 
neededc 
Dose escalate to 
10 mg BIDd 
Dose 
escalation 
level 4 
10 mg 
BID 
Dose reduce to 8mg BIDb 
(can hold axitinib prior to 
restarting per MD 
discretion) 
Hold axitinib if needed (e.g. 
3 days) then resume at  
10 mg BID with breaks as 
neededc 
Discuss dose escalation 
with sponsor 

 
 
CASE 7815                                                                     Page 30                      Version date: 08Oct2018 
 
 
Diarrhea: Increase of 4 - 6 stools per day over baseline 
 
HFS: Skin changes (e.g., peeling, blisters, bleeding, edema, or hyperkeratosis) with pain; limiting 
instrumental ADL 
 
Fatigue: Fatigue not relieved by rest; limiting instrumental ADL 
b After dose reduction, re-escalation as tolerated may be considered per provider discretion 
 
c Give break if needed (e.g. 3 days) when grade 2 or greater mucositis, diarrhea, HFS or fatigue develops. If 
patient consistently develops grade 2 or greater toxicity within 7 days on therapy after a break, consider dose 
reducing by one level 
 
d Dose escalation to 9mg BID can be considered per provider discretion 
 
6.   TREATMENT PLAN 
This prospective single arm study will evaluate the efficacy and safety of axitinib given on 
an individualized dosing schedule in subjects with metastatic clear cell RCC who have been 
treated with PD-1 and PD-L1 inhibitors. All subjects will be followed for Progression Free 
Survival (PFS), including patients who discontinue axitinib for toxicity. 
6.1   Treatment schedule  
The intent is to maximize sustained dose intensity of axitinib based on individual tolerability 
using the dose modification criteria described in Section 5. Dose and schedule changes are 
done if specific toxicity (oral mucositis, diarrhea, hand-foot syndrome, fatigue) is ≥ grade 2.  
Patients will initially continue therapy until progression according to RECIST criteria version 
1.1 (Section 15.1).  At progressive disease dose escalation above current dose is allowed 
based on investigator discretion of clinical benefit.  However, axitinib should be discontinued 
if a second RECIST PD following dose escalation, patient intolerability, or at provider 
discretion. 
6.2   Subject compliance and dropout  
Patients must strictly follow the dosing schedule during each course as described by their 
treating investigator. Compliance to study medication and blood pressure records will be 
ascertained by use of patient diaries and pill count (Section 15.5). Patients will record the 
date, time and number of pills consumed in the diary on a daily basis. The patient diary 
should be reviewed with the patient for completion and to address any discrepancies or 
absent data. The principal investigator or the designee will account for the number of 
capsules dispensed against those returned by the subject. Any deviations and missed doses 
will be recorded in the CRF and drug accountability logs for verification with the reasons. 

 
 
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The investigator/designee will try to ensure complete compliance with the dosing schedule 
by providing timely instructions to the subjects. Patients withdrawn prior to completion of first 
course because of non-compliance not related to study drug related toxicity will be replaced. 
Completed diary sheets must be submitted to CCF. 
6.3   Premature withdrawal/ discontinuation criteria  
Patients may withdraw from the trial at any time, for any reason, at their own request. 
Patients may be withdrawn at any time at the discretion of the investigator or sponsor for 
concurrent illness, safety, behavioral, or other reasons.  
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 and 
reason for withdrawal, if possible. The investigator should request the patient return all 
unused investigational product(s), request the patient to return for a final visit, if applicable 
and follow-up with the subject regarding any unresolved adverse events.  
If the subject withdraws from the trial and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.  
Patients will be withdrawn from treatment in the case of:  
• Disease progression per RECIST v1.1. Patients with initial disease progression are 
permitted and encouraged to stay on therapy with further axitinib upward dose 
titration (following the dose titration schema in Section 5) at MD discretion of clinical 
benefit until a second RECIST v1.1 PD. Principal Investigator (Moshe Ornstein MD) & 
Cleveland Clinic Data Manager must be notified by email when a patient with disease 
progression will be continuing on study for clinical benefit. 
• Unacceptable toxicity  
• Need for anti-cancer therapy not specified in the protocol. Surgery to remove a metastasis 
or palliative radiotherapy is permitted after discussion with the Principal Investigator (Moshe 
Ornstein, MD). 

 
 
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• Patient noncompliance  
• Patient lost to follow-up  
• Patient choice to withdraw from treatment (follow-up permitted by patient)  
• Patient choice to withdrawal consent to study (cessation of follow-up)  
6.4   Concomitant Medications  
The following medications/classes taken during the 15 days prior to Cycle 1 Day 1 and 
through Cycle 13  Day 1 must be recorded on the CRF. 
a. All cardiac medications 
b. CYP3A4 meds (specifically omeprazole, pantoprazole, lansoprazole, 
rabeprazole, esomeprazole, dexamethasone, diltiazem, phenytoin, rifampin, 
St. Johns wort, carbamazepine, phenobarbatol, amobarbitol, primidone, 
rifabutin, felbamate, verapamil, grapefruit juice, ketoconazole, itraconazole, 
erthyromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, 
lopinavir, amprenavir, delavirdine and nefazodone) 
c. Steroids (include dose) 
d. Anti-diarrheals 
6.4.1   Inhibitors and Inducers of CYP3A4  
Axitinib is primarily metabolized in the liver by CYP3A4/5. 22 There was a 1.5- and 2-fold in 
C max and AUC∞, respectively when axitinib was co-administered with ketoconazole, a 
potent inhibitor of CYP3A4.  Similarly, the C max and AUC∞ decreased 71% and 79%, 
respectively when co-administration of rifampin, a strong CYP3A4/5 inducer. Therefore, co-
administration with potent inhibitors (ketoconazole, itraconazole, clarithromycin, diltiazem, 
delavirdine, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir) and strong inducers 
(rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John’s wort, efavirenz, 
tipranavir) of CYP3A4 may result in significant increases/decreases in exposure of axitinib 
and may alter the safety/efficacy of the drug.  

 
 
CASE 7815                                                                     Page 33                      Version date: 08Oct2018 
 
During the study, concurrent administration of potent CYP3A4 inhibitors and inducers  
(omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole, dexamethasone, 
diltiazem, phenytoin, rifampin, St. Johns wort, carbamazepine, phenobarbatol, 
amobarbitol, primidone, rifabutin, felbamate, verapamil, grapefruit juice, ketoconazole, 
itraconazole, erthyromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, 
lopinavir, amprenavir, delavirdine and nefazodone) are not recommended. 
   Alternative therapies should be used when available.  
6.4.2   Anticoagulants  
 
The use of Coumarin-derivative anticoagulants such as warfarin (Coumadin) is not 
recommended. 
6.4.3   Other Anticancer or Experimental Therapy   
No other approved or investigational anticancer treatment will be permitted during the study 
period, including chemotherapy, biological response modifiers, hormone therapy, or 
immunotherapy. No other investigational drug may be used during treatment on this 
protocol, and concurrent participation in another clinical trial is not allowed. Supportive care 
trials or non-treatment trials, eg. QOL, and imaging trials are allowed. 
6.4.4   Antiemetic and Antidiarrheal Therapy  
Supportive care may include premedication with antiemetics to limit treatment-related 
nausea and vomiting. Patients may receive prophylaxis of treatment-induced diarrhea. 
6.4.5   Hematopoietic Growth Factors  
Prophylactic use of hematopoietic growth factors to support neutrophil or platelet counts is 
not permitted during this study. Patients who enter the study on stable doses of 
erythropoietin or darbepoietin may continue this treatment, and patients may start either 
drug during the study at the discretion of the investigator. Patients with neutropenic fever or 
infection should be treated promptly and may receive therapeutic colony-stimulating factors 
if appropriate. 
6.4.6   Other Concomitant Medications  
Anti-inflammatory drugs should be avoided to preserve renal function but narcotic 
analgesics may be offered as needed. Packed red blood cell and platelet transfusions should 
be administered as clinically indicated.  

 
 
CASE 7815                                                                     Page 34                      Version date: 08Oct2018 
 
Patients on this trial may be supported with appropriate hormone replacement therapy in the 
event they develop adrenal insufficiency in the absence of disease progression or 
unacceptable treatment-associated toxicity. Patients may receive bisphosphonates or 
denosumab for treatment of their bone metastases or hypercalcemia. 
6.4.7   Concomitant Radiotherapy or Surgery  
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician. Patients requiring radiotherapy will be considered to 
have disease progression, but may continue on axitinib if felt to be of clinical benefit per MD 
discretion. Axitinib treatment can continue during simple local radiation to metastatic bone 
lesions or briefly held at MD discretion. Axitinib should be held during radiotherapy that 
involves brain and spinal cord. The intensities, number, and dates of doses received for 
allowed palliative radiotherapy should be recorded on the appropriate CRFs.    
6.5 Duration of follow-up 
 
Patients will be followed until they are removed from the clinical trial either due to 
progressive disease (PD) or other reasons as outlined in section 6.3. A subsequent safety 
assessment within 30 days (+/- 3 days) will be conducted as per study calendar in section 
4. Duration of follow up of AEs and SAEs is listed in section 9.6. 
Patients on therapy for more at least 12 months will only be followed for SAEs, imaging, 
tumor measurements, off-study date, and survival status.  
 
7 INVESTIGATIONAL MEDICINAL PRODUCT  
Study agent 
Axitinib (AG013736; Inlyta) is a small molecule with the molecular formula C22H18N4OS.   It 
has a molecular mass of 386.469 g/mol.  The chemical name of axitinib is N-Methyl-2-[[3-
[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide 
7.1 Drug supply  
Axitinib will be supplied as 5mg and 1mg tabs by Pfizer, Inc.  
7.2 Characterization of the Investigational medicinal product  

 
 
CASE 7815                                                                     Page 35                      Version date: 08Oct2018 
 
Axitinib is available in red film-coated tablet form in 1mg and 5mg formulations. Patients will 
initially be given a 28-day supply of 5mg tablets (#56) and a 14-day supply of 1mg tablets 
(#28) to allow for easy dose titration or reduction during the initial cycle. For subsequent 
cycles, a sufficient quantity of 5mg and 1 mg tablets will be dispensed to allow for dose 
titration based on section 5.  
Axitinib will be administered orally BID at approximately the same time in the morning and 
evening on a continuous dosing schedule, ie, without a break in dosing in the absence of 
drug-related toxicity.  Axitinib tablets are to be taken approximately 12 hours apart and may 
be administered without regard to meals.  Tablets must not be crushed, split, or dissolved, 
and patients should be instructed to swallow the study medication whole without 
manipulation or chewing of the medication prior to swallowing. A diary sheet will be provided 
to the patients to provide guidance for the correct use of axitinib (Section 15.5).   
Patients must be instructed that if they miss a dose or vomit any time after taking a dose, 
they must not “make it up” with an extra dose, but instead resume subsequent doses as 
prescribed.  Any missed dose may be taken late, up to 3 hours before the next scheduled 
dose of that day, otherwise, it should be skipped and dosing resumed with subsequent doses 
as prescribed.  Patient must be instructed to record all doses (missed or vomited doses or 
extra 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.  
**ALL drug diary sheets must be submitted electronically (email) or faxed to Jackie Tomer 
(email: tomerj2@ccf.org; FAX: 216-636-6577  at the completion of each cycle of treatment.  
 
7.3 Packaging, labeling and dispatch of the Investigational medicinal product  
Axitinib will be dispensed in opaque plastic bottles to protect the compounds from light.  
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 

 
 
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pharmacy or hospital standard operating procedure manual should be followed when 
handling hazardous drugs. 
7.4 Stability and Storage  
Axitinib must be stored at controlled room temperature of 20°C to 25°C (68°F to 77°F).  
7.5 Accountability and Destruction of Investigational medicinal product  
The Principal Investigator (or an authorized designee) at must maintain a careful record of 
the inventory of the Investigational medicinal product received using the Drug Accountability 
Form. The study drug will be destroyed as per site’s destruction policies and documentation 
of study drug destruction will be provided to Cleveland Clinic. 
7.6 Drug Administration  
Study drug accountability records will be maintained at the site pharmacy and will be 
available for review by the study monitor during each monitoring visit and at the close out 
visit. All medication must be stored in a secure area under the proper storage 
requirements with access restricted to the site staff pharmacist or designee(s).  
Patient returned medication should be retained on site for monitor verification prior to 
destruction as per the institution’s policy. 
 8.  MEASUREMENT OF DRUG EFFECT  
8.1 Safety assessment  
The adverse effects of the drug will be assessed starting at Cycle 1 Day 1 including 
adverse events, vital signs and by clinically significant changes in the laboratory 
evaluations and EKGs. Treatment-related AEs will be assess for 30 days following 
discontinuation of study drug therapy or until initiation of subsequent treatment, however 
documentation for study related purposes is only required through C13D1. 
Adverse events (AE) will use the descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE). This study will utilize the 
CTCAE Version 4.03 for adverse event reporting.  
8.2 Efficacy assessments  

 
 
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Patients must have measurable disease at screening and will be evaluated for response 
on the basis of RECIST criteria version 1.1 (Section 15.1). Tumor measurements using 
physical examination, spiral CT scan and/or MRI or other appropriate techniques deemed 
suitable by the investigator will be performed at screening within 28 days of patient 
registration and repeated every 8 weeks until disease progression. After baseline, bone 
scan only if indicative of metastatic disease at baseline or if clinical signs/symptoms 
develop.  CT Chest-Abdomen-Pelvis will be done every 8 weeks based on C1D1 date 
regardless of the date of baseline scans.  Following Cycle 13 Day 1 assessment, CT scans 
to be done every 12 weeks. Disease assessment with CT chest-abdomen-pelvis will 
continue every 8 weeks for patients continuing on treatment following disease progression 
(bone scans to be done per MD discretion). Scans can be done more frequently per MD 
discretion; these scans will be submitted on an unscheduled disease assessment CRF.  
 
.  
 
9. SAFETY AND REPORTING REQUIREMENTS  
9.1 Adverse Event  
An adverse event (AE) is any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product during the course of a study and which 
does not necessarily have to have a causal relationship with this treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not considered related to the medicinal product.  
Disease signs, symptoms, and/or laboratory abnormalities already existing prior to the use 
of the product are not considered AEs after administration of the study product unless they 
reoccur after the subject has recovered from the pre-existing condition or they represent 
an exacerbation in intensity or frequency.  

 
 
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A laboratory test abnormality considered clinically relevant (e.g. causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations) or 
judged relevant by the Investigator should be reported as an adverse event.  
9.2 Adverse Event Documentation  
Adverse events will use the descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE). This study will utilize the 
CTCAE Version 4.03 for adverse event reporting (Section 15.4).  
All treatment-related adverse events (AE) and serious adverse events (SAEs) will be followed 
from the time first dose of study drug is administered and documented until resolution. Following 
C13D1, documentation is not needed for study related purposes.  
Treatment-unrelated SAEs and all AEs will be followed from the time the first dose of study drug 
is administered and documented for 30 days, until resolution, or until a new therapy is started 
(whichever comes first). 
All AEs must be recorded on case report forms (CRFs) through C13D1. Documentation 
must be supported by an entry in the subject’s file. Each event should be described in 
detail along with start and stop dates, severity, relationship to investigational product as 
judged by the Investigator, action taken and outcome.  
9.3 Serious Adverse Event  
A Serious Adverse Event or Reaction is any AE occurring at any dose that:  
• Results in death  
• Is life-threatening  
• Requires inpatient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly / birth defect  
• Is an important medical event that may not be immediately life threatening or result in 
death or hospitalization, but may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above (example: intensive 
treatment in an emergency room or at home for bronchospasm, convulsions that do not 

 
 
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result in hospitalization). Medical and scientific judgment should be exercised in deciding 
whether some events should be considered as serious because their quick reporting to the 
sponsor may be of interest for the overall conduct of the study.  
Life-threatening: The term “life-threatening” in the definition of “serious” refers to an 
adverse event in which the subject was at risk of death at the time of the event. It does not 
refer to an adverse event that hypothetically might have caused death if it were more 
severe.  
Hospitalization: Any adverse event leading to hospitalization or prolongation of 
hospitalization will be considered as Serious, UNLESS at least one of the following 
exceptions are met:  
The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the start 
of the study or for prophylactic insertion of a gastric feeding tube).  
OR  
The admission is not associated with an adverse event (eg, social hospitalization for 
purposes of respite care).  
However it should be noted that invasive treatment during any hospitalization may fulfill the 
criteria of ‘medically important’ and as such may be reportable as a serious adverse event 
dependent on clinical judgment. In addition where local regulatory authorities specifically 
require a more stringent definition, the local regulation takes precedent.  
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions.  
Important medical event: Any adverse event may be considered serious because it may 
jeopardize the subject and may require intervention to prevent another serious condition.  
Any death (regardless of cause) that occurs from the time of administration of the first dose 
of study therapy until 28 days after the final administration of the study drug, and any death 
occurring after this time that is judged at least possibly related to prior treatment with the 
study drug, will be promptly reported. 

 
 
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Adverse events should be documented and recorded at each visit using NCI CTCAE 
version 4.03 (section 15.4).   
 
9.4 Reporting Serious Adverse Events  
 
All serious adverse events (SAE) and other adverse events must be recorded on case 
report forms.  
SAEs should be reported to Pfizer using the Pfizer SAE form and cover page.  SAE’s 
should also be reported internally to individual institutions IRB per local IRB reporting 
policies and reported to the lead study coordinator by -email to Jackie Tomer at 
tomerj2@ccf.org or fax to 216-636-5677.  
Serious adverse events should be documented and recorded at each visit using NCI 
CTCAE version 4.03 (section 15.4).   
Drug-related SAEs from the time the first dose of study drug is administered will be 
followed and reported until resolution. 
Drug-unrelated SAEs from the time the first dose of study drug is administered continue to 
be followed and documented for 30 days following discontinuation of study drug 
administration, initiation of subsequent treatment, or resolution (whichever comes first). 
 
9.5 Procedure for Expedited Reporting  
 
Responsibility for Reporting Serious Adverse Events to Pfizer  
Each participating site will be responsible for submitting SAE (Initial and/or Follow-up 
reports) to Pfizer using the Pfizer’s SAE cover form. The initial SAE form must be faxed to 
Pfizer and Cleveland Clinic within 24 hrs after the site is made aware of the SAE.  
Reporting Serious Adverse Events to Local Research Ethics Boards  

 
 
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Cleveland Clinic will notify all Investigators of all Serious Adverse Events that are 
reportable to regulatory authorities as reported to Pfizer. This includes all serious events 
that are unexpected and related to protocol treatment. Investigators must notify their 
institutional review boards (IRBs) and file the report with their Investigator Site File. 
Documentation that serious adverse events (SAEs) have been reported to IRBs must be 
kept on file at each participating site.  
Documentation can be any of the following:  
• letter from the IRB acknowledging receipt  
• stamp from the IRB, signed and dated by IRB chair, acknowledging receipt  
• letter demonstrating the SAE was sent to the board  
All expedited serious adverse events occurring within a center should also be reported to 
local IRBs.  
9.6 Follow up of Adverse Events and Serious Adverse Events  
 
Drug-related SAEs will be followed until resolution. 
Drug-unrelated SAEs will be followed for 30 days following discontinuation of study drug 
administration, initiation of subsequent treatment, or resolution (whichever comes first). 
 
9.7 Relationship  
 
For all AEs, relationship to study drug will be reported on the appropriate AE CRF page. 
The PI must judge whether the study drug caused or contributed to the AE in which case it 
is considered to be an ADR, and report it as either:  
Related (definitely, probably or possibly): there is a reasonable possibility that the study 
drug caused or contributed to the AE; this conclusion may be supported by the following 
observations, though these are not required for the determination of relatedness:  
 There is a plausible time sequence between onset of the AE and study drug 
administration;  

 
 
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 There is a plausible biological mechanism through which study drug may have 
caused or contributed to the AE;  
Not related: It is highly unlikely or impossible that the study drug caused or contributed to 
the AE; this conclusion may be supported by the following observations, though these are 
not required for a determination of not related: an alternate etiology needs to be provided 
for the adverse event. 
 another cause of the AE is evident and most plausible;  
 the temporal sequence is inconsistent between the onset of the AE and study drug 
administration; a causal relationship is considered biologically implausible. 
10. STATISTICAL ANALYSIS  
10.1 Study design and justification for sample size  
 
Study design: This is a single-arm, single-stage phase II study investigating the use of an 
individualized dosing regimen of axitinib in patients with metastatic renal cell carcinoma. 
The primary outcome for this study is progression-free survival (PFS), defined as the 
interval between the date a patient first receives axitinib and the date of death or confirmed 
progression according to RECIST criteria. Any patient alive and without known progression 
at the time of analysis will be censored as of the last date the patient can be confirmed to 
be progression-free. Secondary endpoints include overall survival, RECIST-based 
response, and adverse events defined and graded according to NCI CTCAE Version 4.03 
criteria. 
Sample size: 38 evaluable patients.   
Justification for sample size: Based on prior studies patients treated with axitinib 
following anti PD-1 therapy for mRCC have a PFS of approximately 6.5 months.19, 20 The 
hypothesis of this study is that with appropriate dose titration based on toxicities patients 
will reach a more optimal drug dose to increase benefit while minimizing risk.  As such, we 
anticipate an approximately 45% increase in median PFS from 6.5 months to 9.5 months, 
which is felt to represent a clinically-meaningful improvement. Assuming accrual is fairly 

 
 
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uniform and will take approximately 18-24 months, there will be a minimum of 12 additional 
months of follow-up once the last patient has entered, and that PFS follows an exponential 
distribution (which is reasonable based on what has been seen historically in advanced 
RCC), 38 eligible and evaluable patients will be needed to test the above hypothesis with 
>80% power (based on a 1-sided MLE test with 10% type I error). Allowing for 
ineligible/unevaluable a total of 40 patients will be accrued. 
A 20% rate of discontinuation due to toxicity will be considered unacceptable. If at any time 
>2/10, >4/20, or >6/30 patients need to be discontinued due to toxicity, consideration will 
be given to stopping the study.  With these guidelines the likelihood of a boundary being 
crossed in the first 10 patients is 7% if the underlying risk is 10%, 32% if it is 20%, and 
62% if the risk is 30%. The overall likelihoods of a boundary being crossed at some point 
are 10%, 53%, and 89%, respectively.   
10.2 Study population  
The study population will consist of all patients who are registered and receive at least one 
dose of axitinib. All efficacy and safety analyses will be conducted using the study 
population. Any patient who is registered on to this trial but never receives study treatment 
will be described, including the reason(s) for non-participation.  
10.3 Statistical Anylysis  
Data analysis will primarily be descriptive in nature, although as discussed above the 
underlying hypothesis that axitinib titration can improve PFS will be tested using a MLE 
test. Categorical data, such as adverse events and response rate, will be summarized 
using proportions and frequencies. Continuous endpoints, such as dose information will be 
summarized using medians and ranges, and PFS and overall survival will be summarized 
using the Kaplan-Meier method.  
11. ETHICS  
11.1 Informed Consent  
Subject / Legally acceptable representative (LAR) (as applicable) consent must be obtained 
according to institutional review board (IRB) and/or ethics committee (EC) requirements prior 
to any study-specific screening procedures. Sample English consent forms for the trial will 

 
 
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be provided. A copy of the initial IRB/EC full board approval and approved consent form 
must be sent to Cleveland Clinic. The subject/LAR must sign consent prior to registration.  
11.2 Institutional Review Board Approval 
Initial approval: Full approval of the protocol and consent form by the appropriate IRB/EC 
must be obtained prior to commencement of the clinical trial. 
Continuing approval: Annual (or as required by the IRB/EC re-approval may be required 
for as long as subjects are being followed on protocol. It will be investigator’s responsibility 
to apply for and obtain the re-approval.  
Amendment: All protocol amendments will be confirmed in writing and submitted, as 
appropriate, for review by the IRB/EC and health authorities. Amendments will be reviewed 
and approved by applicable regulatory authorities prior to central implementation of the 
amendment, and by IRB/ECs prior to local implementation, EXCEPT when the amendment 
eliminates an immediate hazard to clinical trial subjects or when the change(s) involves 
only logistical or administrative aspects of the trial.  
Serious Adverse Events, Safety Updates and Investigator Brochure Updates: During the 
course of the study serious adverse events, safety updates or investigator brochure updates 
may be sent to you for reporting to your IRB/EC. If/when this occurs documentation of 
IRB/EC submission of this information must be forwarded to Cleveland Clinic. 
12. DOCUMENTATION, RECORD ACCESS AND MAINTENANCE OF 
STUDY RECORDS  
12.1 Documentation of subject’s participation  
A statement acknowledging the participation of a subject in this clinical trial must be 
documented in the subject's medical records.  
12.2 Regulatory Requirements  
The following are required from all investigators:  
• Completion of CITI - Collaborative Institutional Training Initiative 
• Completion of necessary IRB/EC training.  

 
 
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12.3 Subject Confidentiality  
Any research information obtained about the subject in this study will be kept confidential. 
A subject will not be identified by name, only by his/her initials. The subject’s name or any 
identifying information will not appear in any reports published as a result of this study.  
However, information obtained from individual subject’s participation in the study may be 
disclosed with his/her consent to the health care providers for the purpose of obtaining 
appropriate medical care. The subject’s medical records/charts, tests will be made 
available to Pfizer, the Cleveland Clinic Taussig Cancer Institute, the IRB, and any other 
regulatory authorities. This is for the purpose of verifying information obtained for this 
study. Confidentiality will be maintained throughout the study within the limits of the law.  
A subject’s name will not be given to anyone except the researchers conducting the study, 
who have pledged an oath of confidentiality. All identifying information will be kept behind 
locked doors, under the supervision of the study Principal Investigator and will not be 
transferred outside of the hospital. A subject may take away his/her permission to collect, 
use and share information about him/her at any time. If this situation occurs, the subject 
will not be able to remain in the study. No new information that identifies the subject will be 
gathered after that date. However, the information about the subject that has already been 
gathered and transferred may still be used and given to others as described above in order 
to preserve the scientific integrity and quality of the study.  
12.4 Confidentiality of the study  
Data generated as a result of this study are to be available for inspection on request by 
local health authority auditors, the Sponsor’s Study Monitors and other personnel (as 
appropriate) and by the IRB. The Investigator shall permit sponsor, authorized agents of 
the sponsor, CRO and regulatory agency employees to enter and inspect any site where 
the drug or records pertaining to the drug are held, and to inspect all source documents. 
The protocol and other study documents contain confidential information and should not be 
shared or distributed without the prior written permission of sponsor.  
12.5 Registration of Clinical Trial  
Prior to the first subject being registered/enrolled into this study, the Sponsor will be 
responsible for ensuring that the clinical trial is registered appropriately to remain eligible 

 
 
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for publication in any major peer-reviewed journal, adhering to the guidelines put forth by 
the International Committee of Medical Journal Editors (ICMJE).  
12.6 Data reporting  
The data will be collected on eCRFs  in Overture and analyzed after entry into a study 
database.  
12.7 Case Report Forms  
The eCRFs for the study will be provided by Database Manager for Cleveland Clinic . 
12.8 Maintenance of study records  
To enable evaluations and/or audits from Regulatory Authorities, the Sponsor, and the 
Investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, source documents, and detailed records of 
treatment disposition. The Investigator should retain these records after study close-out as 
required by United States regulations or as specified in the Clinical Trial Agreement, 
whichever is longer.  
If the investigator relocates, retires, or for any reason withdraws from the study, then the 
Sponsor should be prospectively notified. The study records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to the Sponsor. 
The investigator must obtain the Sponsor’s written permission before disposing of any 
records. 
13. QUALITY ASSURANCE AND QUALITY CONTROL  
As per the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the sponsor will be 
responsible for implementing and maintaining quality assurance and quality control systems.  
13.1 On site Monitoring / Auditing  
13.1  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform 
audits or inspections, including source data verification. The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 

 
 
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analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements.  
13.2 Data Safety and Monitoring Plan 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data 
and Safety Monitoring Plan in accordance with NCI regulations.  
14. ADMINISTRATIVE PROCEDURES  
14.1 Amendments to the protocol  
Modifications of the signed protocol are only possible by approved protocol amendments 
authorized by the Sponsor. All protocol amendments will be approved by the IRB prior to 
implementation. The Investigator must not implement any deviation from, or change to the 
protocol, except where it is necessary to eliminate an immediate hazard to trial subject or 
when the change(s) involves only logistical or administrative aspects of the trial.  
14.2 Protocol deviations and Violations  
All violations or deviations are to be reported to the site’s IRB. All IRB correspondence is to 
be forwarded to Cleveland Clinic The site must notify Cleveland Clinic immediately of any 
protocol violations.  
14.3 Premature discontinuation of the study  
The Sponsor reserves the right to discontinue the trial for any reason but intends only to 
exercise this right for valid scientific or administrative reasons. After such a decision, the 
Investigators must contact all participating patients immediately after notification. Standard 
therapy and follow-up for subjects will be assured and, where required by the applicable 
regulatory requirement(s), the relevant regulatory authority(ies) will be informed.  
The IRB will be informed promptly and provided with a detailed written explanation for the 
termination or suspension.  
As directed by the Sponsor, all study materials must be collected and all CRFs completed 
to the greatest extent possible.  
 

 
 
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15. APPENDICES  
15.1 RECIST 1.1 Criteria 
The determination of antitumor efficacy during this study will be based on objective tumor 
assessments made according to the RECIST system of unidimensional evaluation.  
Measurability of Tumor Lesions 
At baseline, individual tumor lesions will be categorized by the investigator as either 
measurable or non-measurable by the RECIST criteria as described below. 
Measurable:  
Tumor lesion: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm); 
 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
Non-Measurable:  All other lesions, including small lesions (longest diameter <10 mm or 
pathological lymph nodes with 10 mm to <15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques.  
NOTE: If measurable disease is restricted to a solitary lesion, its neoplastic nature should 
be confirmed by cytology/histology. 
Recording Tumor Measurements 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and measured 
and recorded at baseline and at the stipulated intervals during treatment.  Target lesions 
should be selected on the basis of their size (lesion with the longest diameters) and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically).  
The longest diameter will be recorded for each target lesion.  The sum of the longest 
diameter for all target lesions will be calculated and recorded as the baseline sum longest 

 
 
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diameter to be used as reference to further characterize the objective tumor response of 
the measurable dimension of the disease during treatment.  All measurements should be 
performed using a caliper or ruler and should be recorded in metric notation in centimeters. 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements are not required and these lesions 
should be followed as “present” or “absent.” 
Techniques for Assessing Measurable Disease 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at screening and during follow-up.  Imaging-based 
evaluation is preferred to evaluation by clinical (physical) examination when both methods 
have been used to assess the antitumor effect of a treatment. 
Definitions of Tumor Response 
Target Lesions 
Complete response (CR) is defined as the disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction in short axis 
to <10 mm. 
Partial response (PR) is defined as a 30% decrease in the sum of the longest 
dimensions of the target lesions taking as a reference the baseline sum longest 
dimensions. 
Progressive disease (PD) is defined as a 20% increase in the sum of the longest 
dimensions of the target lesions taking as a reference the smallest sum of the longest 
dimensions recorded since the treatment started, or the appearance of one or more new 
lesions.  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as a reference the smallest sum of the longest 
dimensions since the treatment started.  
Non-Target Lesions 
Complete response (CR) is defined as the disappearance of all non-target lesions.  All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD is defined as a persistence of 1 non-target lesions. 
Progressive disease (PD) is defined as unequivocal progression of existing non-target 
lesions, or the appearance of 1 new lesion. 

 
 
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The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease and 
progressive disease. 
Confirmation of Tumor Response 
To be assigned a status of PR or CR, changes in tumor measurements in patients with 
responding tumors must be confirmed by repeat studies that should be performed 
4 weeks after the criteria for response are first met.  In the case of SD, follow-up 
measurements must have met the SD criteria at least once after study entry at a minimum 
interval of 8 weeks. 
Determination of Tumor Response by the RECIST Criteria  
When both target and non-target lesions are present, individual assessments will be 
recorded separately.  Determination of tumor response at each assessment is summarized 
in the following table. 
Response Evaluation Criteria in Solid Tumors 
Target Lesions1 
Non-Target Lesions2 
New Lesions3 
Tumor Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
PD 
Any response 
Yes or No 
PD 
Any response 
PD 
Yes or No 
PD 
Any response 
Any response 
Yes 
PD 
 
1 Measurable lesions only. 
2 May include measurable lesions not followed as target lesions or non-measurable 
lesions. 
3 Measurable or non-measurable lesions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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15.2 ECOG PERFORMANCE STATUS SCALE  
 
Performance 
Status 
Definition 
0 
Fully active; no performance restrictions; can carry out all pre-disease activities 
1 
Restricted in strenuous activity. Fully ambulatory and able to carry out light 
work (light house work, office work, etc.) 
2 
Ambulatory and capable of all self-care but unable to perform any work 
activities.  Up and ambulatory > 50% of the day. 
3 
Capable of only limited self-care; confined to bed/chair > 50% of the day 
4 
Completely disabled, cannot carry out self-care, totally confined to bed/chair 
5 
Dead 
 
 
 

 
 
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15.3 KARNOFSKY PERFORMANCE STATUS SCALE  
 
 
Definition 
Degree of Functional Capacity Criteria 
Score 
Able to carry on normal 
activity and to work; no 
special care needed 
Normal, no complaints, no evidence of disease 
100 
Able to carry on normal activity, minor signs or symptoms of disease 
90 
Normal activity with effort, some signs or symptoms of disease 
80 
Unable to work; able to 
live at home and care 
for most personal 
needs; various degrees 
of assistance needed 
Cares for self, unable to carry on normal activity or to do active work 
70 
Requires occasional assistance, but is able to care for most needs 
60 
Requires considerable assistance and frequent medical care 
50 
Unable to care for self; 
requires equivalent of 
institutional or hospital 
care; disease may be 
progressing rapidly 
Disabled, requires special care and assistance 
40 
Severely disabled, hospitalization is indicated although death is not 
imminent 
30 
Hospitalization is necessary, very sick, active supportive treatment 
necessary 
20 
Moribund, fatal processes progressing rapidly 
10 
Dead 
0 
 
 

 
 
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15.4 National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) 
 
 
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study 
Reference Binder for this protocol.  Alternatively, the NCI CTCAE may be reviewed online 
at the following NCI website: 
http://ctep.cancer.gov/reporting/ctc.html 

 
 
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15.5 BLOOD PRESSURE MEASUREMENT / STUDY DRUG DOSING 
 
Axitinib Dosing 
Date
Time
Systolic      
(top number)
Diastolic     
(bottom number)
Write each dose below  (3mg, 
4mg, 5mg, 6mg, 7mg, 8mg, 
10mg)
a.m.
 
AM dose:   ______ mg
p.m.
 
□Yes
□No
PM dose:   ______ mg
a.m.
 
AM dose:   ______ mg
p.m.
 
□Yes
□No
PM dose:   ______ mg
a.m.
 
AM dose:   ______ mg
p.m.
 
□Yes
□No
PM dose:   ______ mg
a.m.
 
AM dose:   ______ mg
p.m.
 
□Yes
□No
PM dose:   ______ mg
a.m.
 
AM dose:   ______ mg
p.m.
 
□Yes
□No
PM dose:   ______ mg
a.m.
 
AM dose:   ______ mg
p.m.
 
□Yes
□No
PM dose:   ______ mg
a.m.
 
AM dose:   ______ mg
p.m.
 
□Yes
□No
PM dose:   ______ mg
 
  If Axitinib is interrupted, please continue to measure and record your blood pressure once per day.   
  Please bring this completed diary with you to each clinic visit.  
*If your systolic blood pressure (the top number) is above 150  OR  if your diastolic blood pressure (the bottom number) is above 90,                         
call  ______________________________  at ______________________  for further instruction.
Side effects and medications you took           
to treat the side effects
       Name____________________________________________  Patient # ____________________________       Study ID # _____________       Cycle #   _______    Page #  _____
Phase II  Study of Axitinib Given on an Individualized Schedule for Metastatic RCC after Treatment with PD-1 or PD-L1 Inhibitors
  Instructions: While on Axitinib, measure and record your blood pressure once a day, before your evening dose of Axitinib.   
BLOOD PRESSURE MEASUREMENT / STUDY DRUG DOSING 
Was your systolic blood pressure 
above 150 or diastolic blood 
pressure above 90?  *If yes, see 
above.
Blood Pressure Measurements

 
 
CASE 7815                                                                     Page 55                      Version date: 08Oct2018 
 
16. REFERENCES 
 
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