Conditions: Kidney Cancer
Keywords: Locally advanced clear cell renal cell carcinoma AG-013736 Axitinib Radical nephrectomy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if axitinib can help to control kidney cancer. The safety of this drug will also be studied.

Detailed description:
The Study Drug:

Axitinib is designed to decrease blood supply to the tumor, which may slow tumor growth.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will take axitinib by mouth 2 times a day every day for 12 weeks. The dose may be changed based on any side effects you may have. You should take the drug about 12 hours apart. You should take the pills at about the same time each day. If you vomit anytime after taking a dose, you must not "make it up" with an extra dose, but instead take the next dose as previously scheduled. Any missed dose may be taken late up to 3 hours before the next scheduled dose, otherwise, it should be skipped.

A blood pressure monitor will be given to each participant for home use. You will be given instructions and shown how to monitor your blood pressure.

You will be provided with a calendar to record the date and time of each dose, and your blood pressure reading before taking the drug. Missed doses should also be recorded. You must also bring the study drug bottle to each study visit so the research nurse can count any remaining pills.

A drug list will be given to you to record drugs taken within 4 weeks before you enrolled on the study and while on study. A new list will be provided during each clinic visit. You should not start a new prescription or over-the-counter drug before talking with the study doctor, except in the case of a medical emergency.

Study Visits:

At Week 1:

* You will be asked about any drugs you may be taking.
* Your performance status will be recorded.
* You will complete the questionnaire about kidney cancer care. This questionnaire will take about 5 minutes to complete.
* Women who are able to become pregnant will have a blood (about 1 teaspoon) or urine pregnancy test.

At Week 3:

* Your medical history will be recorded.
* You will have a physical exam.
* Your performance status will be recorded.
* You will have an ECG.
* Blood (about 2 tablespoons) will be drawn for routine testing to check your thyroid function.
* Urine (about 2 tablespoons) will be collected for routine testing.
* You will complete the questionnaire about kidney cancer care.

At Weeks 5 and 9, you will be called and asked if you have had any side effects. This call should take about 10 minutes.

At Weeks 7 and 12:

* Your medical history will be recorded.
* You will have a physical exam.
* Your performance status will be recorded.
* Blood (about 2 tablespoons) will be drawn for routine testing and to check your thyroid function.
* Urine (about 2 tablespoons) will be collected for routine testing.
* You will complete the questionnaire about kidney cancer care.
* You will have a CT scan of chest and abdomen to check the status of the disease.
* At Week 12 only, you will have an ECG.

At Week 13, you will have surgery to remove the kidney tumor. You will receive a separate consent form for this surgery.

At Week 19:

* Your medical history will be recorded.
* You will have a physical exam.
* Your performance status will be recorded.
* Blood (about 2 tablespoons) will be drawn for routine testing and to check your thyroid function.
* You will complete the questionnaire about kidney cancer care.
* You will have a CT scan of chest and abdomen to check the status of the disease.
* If you have been treated for high blood pressure while taking the drug, your blood pressure will be monitored and your blood pressure medication will be reduced. Once your blood pressure reaches a certain level, this will be managed by your primary care doctor.

After Week 19, every 4 months (+/- 2 weeks) for the first 1 year, every 6 months (+/- 2 weeks) for the third and fourth year, then every year (+/- 1 month) for a total of 5 years post surgery:

* Your medical history will be recorded.
* You will have a physical exam.
* Your performance status will be recorded.
* You will have a CT scan of the chest and abdomen to check the status of the disease.
* Blood (about 2 tablespoons) will be drawn for routine testing and to check your thyroid function.
* You will complete the questionnaire about kidney cancer care (only during the first 2 years).

Length of Study:

You will take axitinib for up to 12 weeks. You will stop taking axitinib earlier than expected if the disease gets worse or if you have severe side effects. In both cases, you will move on to surgery after axitinib has been stopped.

After surgery, you will be contacted by the study staff every 4 months (+/- 2 weeks) for 1 year, every 6 months (+/- 2 weeks) for the next 2 years and every 12 months (+/- 1 month) for 2 more years (for a total of 5 years after surgery).

This is an investigational study. Axitinib is FDA approved and commercially available to treat advanced kidney cancer in adults when 1 previous drug treatment for this disease has not worked. In this study, it is being used for research purposes.

Up to 40 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Axitinib Starting dose: 5 mg by mouth twice each day for 12 weeks.

Interventions: intervention 1: Axitinib
Intervention descriptions: intervention 1: Starting dose: 5 mg by mouth twice each day for 12 weeks.

Protocol document:
Prot_SAP_000.pdf: 
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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
A Phase II Clinical Trial Examining The Impact Of Neoadjuvant Axitinib On Primary Tumor Response In 
Patients With Locally Advanced Clear Cell Renal Cell Carcinoma 
Principle Investigator:   
Christopher G. Wood, M. D., FACS 
 
 
 
 
Associate Professor and Deputy Chairman 
 
 
 
 
Department of Urology 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
Co-Principle Investigator:  
Jose A. Karam, M.D. 
Assistant Professor 
Department of Urology 
The University of Texas M. D. Anderson Cancer Center 
 
Collaborators: 
 
 
Surena Matin, M. D. 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Urology 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
 
 
 
 
Nizar Tannir, M. D. 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Genitourinary Medical Oncology 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
Eric Jonasch, M. D. 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Genitourinary Medical Oncology 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
 
 
 
 
 
 
 
 
Pheroze Tamboli, M. D. 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Pathology 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
Catherine Devine, M. D. 
 
 
 
 
Assistant Professor 
 
 
 
 
Department of Diagnostic Radiology 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
 
 
 
 
Kamran Ahrar, M.D. 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Diagnostic Radiology 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
 
 
 
 
Diana Urbauer, M.S. 
 
 
 
 
Senior Statistical Analyst 
 
 
 
 
Division of Quantitative Sciences 
 
 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
 
 
 
 
 
 
 
Maria Lozano, R.N. 
 
 
 
 
       
Research Nurse Supervisor 
 
 
 
       
Department of Urology 
 
 
 
 
       
The University of Texas M. D. Anderson Cancer Center 
  
 


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SYNOPSIS 
Primary Objective:   
Assess objective response rate following the administration of axitinib for 12 weeks in patients 
with locally advanced biopsy-proven clear cell renal cell carcinoma prior to undergoing radical 
nephrectomy. 
Secondary Objectives: 
 
Study the safety, tolerability, and feasibility of the administration of axitinib in patients 
with locally advanced biopsy-proven clear cell renal cell carcinoma prior to undergoing 
radical nephrectomy. 
 
Assess disease-free survival and overall survival in patients with locally advanced biopsy 
proven clear cell renal cell carcinoma treated with 12 weeks of neoadjuvant axitinib 
followed by radical nephrectomy. 
 
Collect renal tissue, blood (serum, plasma, DNA, and PBMC), and urine for future 
correlative biomarker studies. 
 


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Table of Contents 
1. Background and Rationale 
2. Protocol drug 
2.1. Axitinib 
2.1.1. Dosage 
2.1.2. Pharmacokinetics and Pharmacodynamics 
2.1.3. Side Effects Profile 
3. Inclusion and Exclusion Criteria 
3.1. Study Population   
3.2. Inclusion Criteria 
3.3. Exclusion Criteria 
4. Trial Objectives 
4.1. Primary Objective 
4.2. Secondary Objectives 
5. Assessment of Response 
6. Statistical Considerations 
6.1. Statistical Considerations for Primary Objective 
6.2. Statistical Considerations for Secondary Objectives 
7. Treatment Plan 
7.1. Pre-treatment screening 
7.2. Treatment Phase 
7.2.1. Eligible patients 
7.2.2. Surgery date 
7.2.3. Treatment Assignment 
7.2.4. Adverse events monitoring and reporting 
7.2.4.1. Adverse events 
7.2.4.2. Serious Adverse events (SAE)  
7.2.4.2.1. SAE definition 
7.2.4.2.2. SAE reporting to Pfizer 
7.2.4.2.3. SAE reporting per M.D. Anderson guidelines 
7.2.5. Axitinib Starting Dose 
7.2.6. Axitinib dose modifications 
7.2.6.1. Axitinib dose increase 
7.2.6.2. Axitinib dose reduction for adverse events 
7.2.6.3. Axitinib dose-reduction for hypertension 
7.2.6.4. Axitinib dose-reduction for proteinuria 
7.2.7. Concomitant therapy 
7.2.8. Treatment intake monitoring 
7.2.9. Treatment Start 
7.2.10. Laboratory studies 
7.2.11. Imaging 
7.2.12. Surgery 
7.3. Post-treatment follow-up 
8. Tissue, Blood, and Urine Banking 
9. Good Clinical Practice 


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1. Background and Rationale 
The American Cancer Society estimated an incidence of ~54,000 cases of renal cancer in 2009, 
with ~13,000 dying of their disease 1. Seventy-five percent of renal tumors are of the clear-cell renal cell 
carcinomas (ccRCC). Angiogenesis plays an important role in the pathogenesis of ccRCC with production 
of VEGF 2. The recent FDA approval of receptor tyrosine kinase inhibitors such as Sunitinib, Sorafenib, 
Everolimus, and Temsirolimus has dramatically changed the therapeutic paradigm of ccRCC, and has 
resulted in increased response rates in patients with metastatic ccRCC 3-6.  
Axitinib, a novel oral tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 has been 
recently investigated in 52 patients with metastatic ccRCC who failed prior systemic therapy with 
Interferon- or Interleukin-2 7. Responses were seen in 23 patients (44.2%), with two patients achieving 
complete response and one patient without prior nephrectomy having partial shrinkage of the primary 
renal tumor. Axitinib has also been investigated in 62 patients with metastatic ccRCC refractory to 
sorafenib 8, and partial response was observed in 22.6% of patients, with 80% experiencing some degree 
of tumor shrinkage. As such, axitinib appears to be a promising agent in the treatment of metastatic 
ccRCC.  
We will be using the tyrosine kinase inhibitor axitinib up to 36 hours prior to radical 
nephrectomy in order to maximize the exposure time and potential benefit from this drug. This 
approach has been shown to be safe. Recently, Hellenthal et al 9 reported on a prospective trial of 3 
months of the tyrosine kinase inhibitor sunitinib in 20 patients with renal cell carcinoma prior to radical 
nephrectomy. In 15 patients, sunitinib was stopped 1 day prior to surgery, and no surgical complications 
were attributable to sunitinib treatment. This is consistent with our experience 10, as we have not found 
a significant difference in surgical complications when comparing patients who received targeted 
therapy prior to radical nephrectomy with those who have not received any preoperative therapy.  
Neoadjuvant therapy in the non-metastatic setting has the potential of improving overall 
survival, as seen from trials in non-metastatic bladder cancer 11. To date, there are no published 
prospective trials of neoadjuvant targeted therapy prior to radical nephrectomy in patients without 
metastases. The use of axitinib in patients with ccRCC prior to radical nephrectomy has the potential of 
decreasing tumor size (which might allow us to perform a partial nephrectomy rather than a radical 
nephrectomy-thereby preserving renal function), regression of invasion into adjacent organs, regression 
of tumor venous thrombi, therefore improving surgical margins and treatment outcomes. In addition, 
collection of blood and tissue for molecular and genetic analysis is possible using this neoadjuvant 
approach, which will provide valuable information about molecular correlates of tumor response to 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
targeted therapy. Finding molecular correlates of activity or resistance to axitinib will allow us in future 
trials to select the appropriate patients to receive neoadjuvant therapy.  
 
2. Protocol Drug 
2.1. Axitinib 
2.1.1. Dosage 
Axitinib is given orally at a starting dose of 5mg twice daily (BID) with food. Dosage 
modifications will be discussed below. 
2.1.2. Pharmacokinetics and Pharmacodynamics 
Axitinib administered in the fed state is absorbed rapidly, with peak plasma 
concentrations occurring within 2 to 6 hours. Plasma concentrations declined with a 
terminal plasma half-life between 2 and 5 hours. Axitinib plasma PK reached steady 
state within 15 days. At the phase II dose of 5 mg BID given in the fasted state, the 
between-patient coefficient of variation for AUC0-24 on cycle 1, day 15 was 90%; the 
corresponding coefficient of variation for Cmax was 63%. Both the rate and extent of 
absorption were higher in the fasted state. Peak concentrations occurred 1 to 2 hours 
after dosing in the fasted state, and there was a median 49% increase in plasma 
exposures compared with the fed state. Plasma half-life was not changed appreciably in 
fed and fasted states.  
In the presence of the potent proton-pump inhibitor rabeprazole, the rate of 
absorption of axitinib was decreased, but the extent of absorption was unaffected. 
Because of the minimal change in plasma exposure in the presence of rabeprazole, the 
effect of antacids on axitinib absorption was not considered to be clinically significant.  
Twelve-hour urinary collections obtained on days 1 and 29 (cycle 2, day 1) 
demonstrated that < 1% of the administered dose appeared as unchanged drug in the 
urine regardless of dose, which indicates that the majority of drug elimination was 
through systemic metabolism.  
Soluble plasma proteins (VEGF, fibroblast growth factor, tumor necrosis factor-
alpha, and matrix metalloproteinases 2 and 9) evaluated as exploratory markers related 
to VEGFR signal transduction pathways did not show any variation with treatment. 
2.1.3. Side Effects Profile 


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The most common side effects (all grades) are hypertension, diarrhea, fatigue, 
nausea, hoarseness, anorexia, dry skin, and weight loss.  
 
 
3. Inclusion and Exclusion Criteria 
3.1. Study Population   
A total of 24 patients with clear cell renal cell carcinoma clinical stage T2-T3bN0M0 will be 
treated in this study with an estimated accrual of 3 patients per month. Please see section 6 for 
statistical considerations.  We will enroll additional patients to allow for screen failures after 
biopsy results, or patient withdrawal. 
 
3.2. Inclusion Criteria 
3.2.1. Locally advanced renal cell carcinoma without evidence of metastatic disease with 
absence of adjacent organ invasion or retroperitoneal adenopathy (cT2-T3b, N0, M0). 
Patients with retroperitoneal lymph nodes ≤ 2 cm in size each are considered N0. 
3.2.2. Predominant clear cell histology on pre-treatment biopsy of the primary tumor. 
3.2.3. Patient should be candidate for curative radical nephrectomy. 
3.2.4. ECOG Performance Status 0-1. 
3.2.5. Patient must provide signed informed consent. 
3.2.6. Male or female, age≥ 18 years. 
3.2.7. Adequate renal function: serum creatinine level ≤ 1.5 x ULN or calculated creatinine 
clearance (as estimated by GFR using the MDRD formula) is ≥ 60 ml/min. 
3.2.8. Adequate hepatic function: alkaline phosphatase ≤ 1.5 x ULN; total bilirubin, AST, and 
ALT ≤ 1.5 x ULN; INR <1.3 (or <3 if on anticoagulant therapy). 
3.2.9. Adequate bone marrow function: ANC ≥ 1.5 x 109/L; Platelets ≥ 100 x 109/L; Hb >9 g/dL. 
3.2.10. Urinary protein <100 on urinalysis (equivalent to <2+ by urine dipstick). If urinalysis 
protein ≥ 100 (equivalent to dipstick is ≥2+) then a 24-hour urine collection can be done 
and the patient may enter only if urinary protein is <2 g per 24 hours. 
3.2.11. No hormonal therapy, chemotherapy, immunotherapy, or any other systemic therapy 
for a malignancy in the 5 years prior to current study enrollment. 
3.2.12. Women of childbearing potential (defined as a female subject who is not surgically 
sterilized, not at least 1 year postmenopausal) must have negative urine or serum 


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pregnancy test within 4 weeks of enrollment and again on the day of starting therapy and 
she and/or her partner must utilize birth control while on therapy.  
3.2.13. Male (defined as a male subject who has not been surgically sterilized) or female 
patients of child-producing potential must agree to use adequate contraception (e.g. IUD, 
condom plus spermicide, diaphragm, or cervical cap plus spermicide) or medical 
contraception as of date of study enrollment and for 1 month after last dose of axitinib.  
Subjects who are not currently sexually active must agree and consent to use one of the 
above-mentioned methods should they become sexually active while participating in the 
study. 
 
3.3. Exclusion Criteria 
3.3.1. Evidence of metastatic disease, adjacent organ invasion, retroperitoneal adenopathy on 
pre-treatment imaging.  In addition, patients with inferior vena cava thrombi extending to 
the atrium or with evidence of Budd-Chiari Syndrome (hepatic dysfunction) will not be 
eligible for the protocol. 
3.3.2. Patients who undergo embolization of their primary tumor 
3.3.3. Previous treatment for their primary renal tumor, including prior chemotherapy, 
immunotherapy, targeted therapy, radiation therapy, cryotherapy, radiofrequency 
ablation or embolization. 
3.3.4. Active malignancies other than renal cell carcinoma and/or history of other malignancy 
within the last 5 years, except for adequately treated cone-biopsied in situ carcinoma of 
the cervix or basal or squamous cell carcinoma of the skin. 
3.3.5. Uncontrolled hypertension (BP>140/90 on medications)  as documented by 2 baseline 
blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure 
readings must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be 
≤90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are 
eligible. 
3.3.6. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 
inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, 
erythromycin, telithromycin, clarithromycin, indinavir, saquinavir, ritonavir, nelfinavir, 
nefazodine, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine). 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
3.3.7. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 
or CYP1A2 inducers (ie, carbamazepine, dexamethasone, felbamate, omeprazole, 
phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. 
John’s wort). 
3.3.8. Active gastrointestinal bleeding. 
3.3.9. Malabsorption syndromes such as celiac disease, cystic fibrosis, inflammatory bowel 
disease, systemic sclerosis, and carcinoid syndrome. 
3.3.10. Known HIV or Hepatitis C status. 
3.3.11. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose 
anticoagulants for maintenance of patency of central venous access devise or prevention 
of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is 
allowed. 
3.3.12. Active seizure disorder or evidence of brain metastases, spinal cord compression, or 
carcinomatous meningitis.  
3.3.13. A serious uncontrolled medical disorder or active infection that would impair their 
ability to receive study treatment. 
3.3.14. Any of the following within the 12 months prior to study drug administration: 
myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, 
symptomatic congestive heart failure, cerebrovascular accident or transient ischemic 
attack and 6 months for deep vein thrombosis or pulmonary embolism 
3.3.15. Withdrawal of consent. 
3.3.16. Unwillingness or inability to comply with mandated pre-treatment biopsy or therapeutic 
regimen. 
 
4. Trial Objectives 
4.1. Primary Objective 
Assess objective response rate following the administration of axitinib for 12 weeks in patients 
with locally advanced biopsy-proven clear cell renal cell carcinoma prior to undergoing radical 
nephrectomy.  
4.2. Secondary Objectives 


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4.2.1. Study the safety, tolerability, and feasibility of Axitinib in patients with locally advanced 
biopsy-proven clear cell renal cell carcinoma prior to undergoing radical nephrectomy. 
4.2.2. Assess disease-free survival and overall survival in patients with locally advanced biopsy 
proven clear cell renal cell carcinoma treated with 12 weeks of neoadjuvant Axitinib 
followed by radical nephrectomy. 
4.2.3. Collect renal tissue, blood (serum, plasma, DNA, and PBMC), and urine for future 
correlative biomarker studies. 
 
5. Assessment of Response 
CT scans of the chest and abdomen will be evaluated by a urologist and an expert genitourinary 
radiologist. The urologist (investigator assessment) and the radiologist (independent assessment) 
will perform the tumor measurements.  Response will be determined by the radiologist assessment. 
Tumor measurements will be documented in the tumor measurement form (one of the CRFs) and 
medical record. GURU will be used as electronic case report forms (CRF). RECIST version 1.0 criteria 
will be used as follows to quantify response to therapy: 
 
Complete Response (CR): Complete disappearance of renal mass. 
 
Partial Response (PR): At least a 30% decrease in the largest diameter (LD) of the renal mass 
taking as reference the baseline largest diameter. 
 
Progressive disease (PD): At least a 20% increase in the LD of the renal mass taking as 
reference the LD of the renal mass recorded since the treatment started. PD will also include 
development of any biopsy-proven metastatic disease. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the LD since the treatment started. 
 
Objective response rate (ORR) is defined as CR+PR.  
 
ORR will be evaluated when CT abdomen is done after 12 weeks of treatment (see Table 4). 
 
PD will be evaluated when CT abdomen is done after 7 weeks and 12 weeks of treatment 
(see Table 4). 
 
6. Statistical Considerations 
6.1. Statistical Considerations for Primary Objective 


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The primary objective of this study is to assess objective response rate (ORR) following 
the administration of axitinib for 12 weeks in patients with locally advanced biopsy-proven clear 
cell renal cell carcinoma prior to undergoing radical nephrectomy.   
 
Twenty-four patients will be treated in this study.  We plan to abort recruitment should 
we have reason to believe that axitinib does not provide minimal efficacy, defined as Pr[ORR ≥ 
20% | data] < 5%. We also plan to stop recruitment should we have reason to believe that it 
may be harmful, defined as Pr[PD > 20% | data] > 80%, where PD is progressive disease. We will 
monitor study patients using the Bayesian approach of Thall 12. ORR will be evaluated at week 12 
following initiation of treatment and PD will be evaluated at week 7 and week 12 following 
initiation of treatment. 
 
For calculating our stopping criteria and operating characteristics for futility and disease 
progression, we assume that ORR ~ Beta(0.4, 1.6) and PD ~ Beta(0.4, 1.6).  The prior for both 
ORR and PD has a mean of 20% and a standard deviation of 23%. 
 
We will continually evaluate patients for excessive PD as they are being enrolled. We 
will begin evaluating for minimal ORR after the first 18 patients have been treated and 
evaluated for responses.  Given that those patients who have PD will be immediately terminated 
from the study treatment to have a nephrectomy, we do not feel that delaying evaluation for 
futility until 18 patients are treated will jeopardize patient wellbeing.  Once the minimum 
number of patients has been treated and assessed for ORR and PD, we will continue to assess 
both outcomes after each additional patient has been evaluated.  
The trial will be stopped for futility (low ORR) if  
 [# of patients with ORR / # of patients evaluated at Week 12] ≤ 1/18. 
Likewise, the trial will be stopped for excessive PD if 
 [# of patients with PD / # of patients evaluated at Week 7 and 12] ≥ 3/6, 4/9, 5/13, 6/17, 7/21. 
 
To illustrate the use of these stopping rules, suppose 18 patients are treated in this 
study and evaluated for response and only 1 had ORR. We would close the study for lack of 
efficacy. If 2 patients out of the first 18 respond, then an additional 6 patients will be treated for 
a total of 24 patients. Likewise, if 6 out of 17 patients had PD, we would close the study for 
excessive PD. 
 
The operating characteristics for the futility monitoring rule are shown in Table 1 and for 
the PD monitoring rule are shown in Table 2.  The operating characteristics in Table 1 do not 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
account for early stopping due to excessive PD; likewise, the operating characteristics in Table 2 
do not account for early stopping due to futility.  
 
We plan to stop recruitment if we observe 2 treatment-related deaths. Treatment-
related deaths are defined as deaths directly caused by study drug while the patients are taking 
the study drug, or intraoperatively, or within 30 days after nephrectomy, and the decision to 
classify the deaths as directly caused by study drug will be made by the study Principal 
Investigator. Perioperative mortality for patients undergoing radical nephrectomy is estimated 
to be between 1% and 4% 13-15.  The operating characteristics associated with this decision 
criterion are shown in Table 3.  These probabilities were derived by running 1,000 simulations. 
 
We also plan to stop recruitment if two or more patients a) cannot undergo radical 
nephrectomy as a result of participating in the study, or b) experience a delay in time to radical 
nephrectomy of more than 6 weeks from last axitinib dose, or c) experience inadequate healing 
post-operatively defined as fascial dehiscence requiring reoperation, or d) experience severe 
bleeding post-operatively defined as bleeding requiring reoperation.  
 
Table 1.  Operating Characteristics of the ORR Futility Monitoring Rule 
Success Rate 
Probability of Stopping Early 
Sample Size 
P25 
P50 
P75 
0.05 
0.775 
18 
18 
18 
0.10 
0.455 
18 
24 
24 
0.15 
0.221 
24 
24 
24 
0.20 
0.106 
24 
24 
24 
0.25 
0.039 
24 
24 
24 
 
Table 2.  Operating Characteristics of the Excessive PD Monitoring Rule 
Success Rate 
Probability of Stopping Early 
Sample Size 
P25 
P50 
P75 
0.10 
0.056 
24 
24 
24 
0.15 
0.165 
24 
24 
24 
0.20 
0.346 
12 
24 
24 
0.25 
0.537 
8 
19 
24 
0.30 
0.724 
6 
11 
24 
 
Table 3. Operating Characteristics of the Treatment-Related Mortality Stopping Rule 
πtreatment-related mortality 
Probability of Stopping Early 
Sample Size 
P25 
P50 
P75 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
0.005 
0.012 
24 
24 
24 
0.01 
0.033 
24 
24 
24 
0.02 
0.083 
24 
24 
24 
0.04 
0.268 
23 
24 
24 
0.07 
0.505 
14 
24 
24 
0.1 
0.708 
10 
17 
24 
0.2 
0.976 
5 
8 
13 
 
 
Based on operating characteristics of the ORR futility monitoring rule (Table 1), we have 
a 10.6% chance of closing the study early if the ORR truly is only 20%.     
 
Once we have completed the study we will estimate the objective response rate for 
axitinib with a 90% credible interval. We will also report the posterior probability that the 
objective response rate is more than 20%. If this posterior probability is greater than 80%, we 
will conclude that axitinib was successful and therefore merits further study as a neoadjuvant 
therapy in this patient population.  This would mean that axitinib would be considered 
successful if 7 or more patients had ORR. 
 
6.2. Statistical Considerations for Secondary Objectives 
6.2.1. To examine the safety of axitinib, we will tabulate reported adverse events (adverse 
events will be recorded per CTCAE v4.0).   
6.2.2. To examine the tolerability of axitinib, we will use the FKSI-15 (Functional Assessment of 
Cancer Therapy-Kidney Specific Index-15, Appendix E) questionnaire and compare changes 
in response between different time points. 
6.2.3. We will evaluate disease-free survival by plotting Kaplan-Meier curves and estimating 
median recurrence-free survival.  Time to death or recurrence will be defined as the time 
from treatment start until death, recurrence or progressive disease, whichever comes first.  
Patients who did not die, recur or have progressive disease will be censored at date of last 
follow-up.  These will be compared to contemporary, matched (2:1 matching, for age 
group, stage and grade), historical controls. Although small differences in recurrence-free 
and overall survival might not be detected in this current trial, this information will help us 
when designing future large trials with this particular agent. 
 
 


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7. Treatment Plan (Table 4) 
7.1. Pre-treatment screening 
7.1.1. Patients will undergo routine staging evaluation to include CT chest and abdomen with 
renal protocol, to evaluate extent of local disease and rule out the presence of metastatic 
disease.  If the patient had these CT scans done at an outside facility within 4 weeks of 
enrollment in the trial, then these CT scans may not need to be repeated at MD Anderson, 
as long as the actual CD or DVD of the films are available (and not just the report) and as 
long as the protocols used for the CT scans were similar to those at MD Anderson (i.e. 
renal protocol with intravenous contrast needs to be used). If the CD or DVD is from an 
outside facility, it has to be reviewed by our urologist and/or radiologist here to check the 
quality of the images (for example, if the CT scan was done within 4 weeks of screening, 
but was done without intravenous contrast, the investigators might decide to repeat the 
CT scan prior to starting study treatment). If only a report is available, the CT scans will 
need to be repeated at MD Anderson to be eligible for the study. Bone scan and CNS 
imaging will be done at the discretion of the attending physician for patients with 
indications to do so (elevated alkaline phosphatase, bone pain for bone scan, and CNS 
symptoms for CNS imaging). An EKG will be done.  
7.1.2. CBC, CMP (sodium, potassium, chloride, carbon dioxide, calcium, glucose, BUN, 
creatinine, magnesium, phosphorus, lactate dehydrogenase, AST, ALT, alkaline 
phosphatase, total and direct bilirubin, albumin, total protein), PT, PTT, TSH, free T3, free 
T4, and urinalysis will be obtained within 4 weeks of study enrollment. A pregnancy test 
will be done for women of childbearing potential within 4 weeks of enrollment and again 
on the day of starting therapy as explained in Section 3.2. 
7.1.3. A history, physical examination, medication list (Appendix J), ECOG Performance Status, 
Adverse Events, and EKG will be performed and recorded in the medical record within 4 
weeks of study enrollment as noted in Table 4.   
7.1.4. Patients that meet eligibility criteria will undergo image-guided biopsy (18G core needle 
biopsy x 4 cores and touch prep-1 core for pathologic diagnosis, 3 optional cores for tissue 
banking) of their primary tumor to establish the presence of clear cell histology. 
 
7.1.5. If a prospective patient has untreated hypertension at presentation, the patient will be 
placed on a medical regimen to control the hypertension, prior to enrollment (Enrollment 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
means when the patient meets all the study eligibility criteria and is ready to be registered 
in CORe step 2). 
 
7.2. Treatment Phase 
7.2.1. Eligible patients will provide written informed consent. 
7.2.2. Prior to the initiation of therapy, a surgical date will be established.  
7.2.3. Treatment Assignment: Each patient will receive a total of 12 weeks of axitinib. Patients 
will take the last dose of axitinib 1.5 days prior to surgery. 
7.2.4. Adverse events monitoring and reporting:  
7.2.4.1. Adverse events: 
7.2.4.1.1. The investigator is responsible for determining the attribution of adverse events to 
study drug. 
7.2.4.1.2.  Adverse events will be documented in the medical record and entered into the 
 
case report form according to the Recommended Adverse Event Recording 
 
Guidelines for Phase II protocol (see table below). 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
 
7.2.4.1.3. 
Adverse events will be assessed at each patient visit, documented in the medical record, and 
entered into the CRFs. Adverse events should be treated appropriately. Such treatment may 
include changes in axitinib treatment including possible interruption or discontinuation, 
starting or stopping concomitant treatments, changes in the frequency or nature of 
assessments, hospitalization, or any other medically required intervention. Once an adverse 
event is detected, it should be followed until its resolution, and assessment should be made at 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
each visit of any changes in severity, the suspected relationship to the axitinib, the 
interventions required to treat it, and the outcome. In addition,  Pfizer requires reporting of 
serious adverse events on the M.D. Anderson SAE forms. Reporting of adverse events will be 
done according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
The following items will be recorded at least: 
-Event description 
-Date of onset of AE 
-CTCAE grade/severity (1,2,3,4,5) 
-Relationship to treatment with axitinib (unrelated, unlikely, possible, 
probable, highly probable/definite) 
-Action taken (none, temporarily discontinued agent, drug treatment 
given/specify, permanently discontinued agent, non-drug treatment 
given/specify, hospitalization) 
-Date of AE stop  
-Outcome (recovered without sequelae, recovered with sequelae, 
ongoing, worsened, death)  
-Serious AE (yes, no) 
7.2.4.2. Serious Adverse events (SAE):  
7.2.4.2.1. 
SAE reporting-SAEs will be recorded on a SAE form (Appendices G and H), in addition to the 
CRF AE documents. SAEs will be reported within 24 hours to Pfizer (Please see Pfizer SAE 
reporting guidelines in the appendix section)  
7.2.4.2.2. 
SERIOUS ADVERSE EVENT REPORTING – M. D. Anderson Cancer Center: 
The following SAE Reporting Requirements, since this is an MDACC sponsored IND 
study, and all SAEs must be reported to IND Sponsor representative – the IND Office - 
according to the following: 
7.2.4.2.2.1. A serious adverse event is – any adverse drug experience occurring at 
any dose that results in any of the following outcomes: 
- 
Death 
- 
A life-threatening adverse drug experience – any adverse 
experience that places the patient, in the view of the initial 
reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse 


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experience that, had it occurred in a more severe form, might 
have caused death 
- 
Inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
- 
A persistent or significant disability/incapacity – a substantial 
disruption of a person’s ability to conduct normal life functions 
- 
A congenital anomaly/birth defect 
 
7.2.4.2.2.2. In this protocol, we will not report those hospitalizations resulting from 
routine treatment not associated with any deterioration in condition, 
treatment for a pre-existing condition that is unrelated to axitinib and has 
not worsened since the start of axitinib; or for treatment on an 
emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 
 
7.2.4.2.2.3. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse 
(21 CFR 312.32): 
- 
Important medical events as defined above, may also be 
considered serious adverse events. Any important medical 
event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Office . 
- 
All events occurring during the conduct of a protocol and 
meeting the definition of a SAE must be reported to the IRB in 
accordance with the timeframes and procedures outlined in 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
“University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy on Reporting Serious Adverse Events”.  
Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND office, regardless of 
attribution (within 5 working days of knowledge of the event). 
- 
All life-threatening or fatal events, expected or unexpected, and 
regardless of attribution to the study drug, must have a written 
report submitted within 24 hours (next working day) of 
knowledge of the event to the IND office 
- 
The MDACC “Internal SAE Report Form for Prompt Reporting” 
will be used for reporting to the IND office. 
- 
Serious adverse events will be captured from the time the 
patient signs consent until 30 days after the last dose of drug. 
Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
- 
Additionally, any serious adverse events that occur after the 30 
day time period that are related to the study treatment must be 
reported to the IND office. This may include the development of 
a secondary malignancy. 
7.2.4.2.2.4. Reporting to FDA: 
- 
Serious adverse events will be forwarded to FDA by the IND 
Office, according to 21 CFR 312.32. 
7.2.4.2.2.5. It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
7.2.5. Axitinib Starting Dose: Patients will receive up to 12 weeks of axitinib orally. Axitinib is 
started at a dose of 5mg BID (twice each day) taken orally with food. Dose adjustments, 
including dose increase or dose reduction should be based on adverse events experienced 


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by the individual patient. Axitinib should be taken beginning on day 1 of the study. Doses 
should be taken approximately 12 hours apart. Patients should be instructed to take their 
doses at approximately the same times each day. Patients should be instructed that if they 
vomit anytime after taking a dose, that 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, otherwise, it should be skipped. If doses are 
missed or vomited, this must be indicated in the source documents and CRFs.  A pill diary 
(Appendix J) will be provided where the patient will record the date, time (AM or PM), and 
dose of axitinib taken, as well as the blood pressure measurement prior to axitinib intake 
(Appendix J). Available axitinib dose levels are listed below. 
 
Dose Level 
Dose 
Dispensed As 
+2 
10 mg BID 
2 X 5 mg Tablets BID 
+1 
7 mg BID 
1 X 5 mg Tablet BID  +  2 X 1mg Tablets BID 
0 (Starting Dose) 
5 mg BID 
1 X 5 mg Tablet BID 
-1 
3 mg BID 
 3 X 1mg Tablets BID 
-2 
2 mg BID 
2 X 1mg Tablets BID 
7.2.6. Axitinib dose modifications during trial: Patients will receive axitinib at a starting dose of 
5 mg orally twice daily until disease progression, unmanageable toxicity, withdrawal of 
consent occurs, or until 1.5 days prior to surgery.  
7.2.6.1. Axitinib dose increase: Because previous studies indicated variable drug levels in 
patients, the axitinib dose will be increased in a step-wise fashion from 5 mg twice 
daily to 7 mg twice daily, then to 10 mg twice daily, in the absence of axitinib-related 
toxicity greater than or equal to grade 2 for a continuous 2-week period and in the 
absence of hypertension (defined as two blood pressure [BP] measurements of > 
150/90 mmHg taken in the clinic > 1 hour apart) at any point during study. The 
clinical judgment of the treating physician should be exercised in up-titrating the 
axitinib dose. 
7.2.6.2. Axitinib dose modifications for adverse events (other than hypertension and 
proteinuria): 
7.2.6.2.1. 
Patients developing axitinib-related CTCAE Grade 1 adverse events may have their dose 
increased to next dose level. 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
7.2.6.2.2. 
Patients developing axitinib-related CTCAE Grade 2 adverse events should have their dose 
continued at the same dose level.  
7.2.6.2.3. 
Patients developing axitinib-related CTCAE Grade ≥ 3 adverse events should have their dose 
reduced as indicated in section 7.2.6.2.6 
7.2.6.2.4. 
If patients need to have their axitinib treatment interrupted for 2 or more continued-week 
period due to unmanageable toxicities or any other reason, their axitinib treatment will be 
permanently discontinued and considered treatment failures. Patients will then proceed to 
surgery to have their kidney tumors removed. 
7.2.6.2.5. 
Patients removed from treatment for intolerable toxicity should still be followed with 
regular tumor assessments (every 4 months for 1 year, every 6 months for the next 2 years and 
every 12 months for one more year) until disease progression or start of new treatment, and 
for survival thereafter until study completion. 
7.2.6.2.6. 
The criteria for dose modification for study-drug-related adverse events  are summarized in 
the table below: 
CRITERIA FOR DOSE MODIFICATION FOR AXITINIB-RELATED ADVERSE EVENTS OTHER THAN 
HYPERTENSION OR PROTEINURIA 
Related Adverse Events 
INTERVENTION 
Grade 1 
Increase to next dose level, or maintain if already at 
the maximum dose 
Grade 2 
Continue at same dose level 
Grade 3 nonhematologic treatment-related 
toxicity* or Grade 3 hematologic toxicity 
Decrease dose to one lower dose level 
Grade 4 hematologic treatment-related 
toxicity** 
Interrupt dosing; re-start at one lower dose level as 
soon as improvement to CTCAE Grade ≤2 occurs 
within 2 weeks. If a patient requires dose reduction 
below 2 mg BID when above fails, consideration 
should be given to stop axitinib if this recurs. 
Grade 4 nonhematologic treatment-related 
toxicity 
Stop Axitinib 
* Patients who develop Grade 3 nonhematologic toxicities that are controlled with symptomatic 
medications or Grade 3 asymptomatic biochemistry laboratory abnormalities may be continued at the 
same dose level at the discretion of the investigator. 
** Patients who develop Grade 4 lymphopenia or Grade 4 asymptomatic biochemistry laboratory 
abnormality may continue study treatment without interruption. 
7.2.6.3. Axitinib dose-reduction for hypertension: 
7.2.6.3.1. 
Electronic BP monitors will be provided to each patient for home use. Instructions to use 
them will be provided (Appendix F) and demonstration of their use will be done in the visit 


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prior to starting axitinib intake. Patients will self-monitor BP at home twice daily (before each 
axitinib dose). All BP measurements will be recorded in a diary (Appendix J) and brought to the 
clinic at each clinic visit. Patients will be instructed to inform their physicians in the event of 
systolic BP greater than 150 mmHg or diastolic BP greater than 100 mmHg, or if they develop 
symptoms related to elevated BP (e.g. headache or visual disturbance). During normal business 
hours the patient will call the urology research nurse for instructions. Outside of normal 
business hours, the patient will call the urologist on call through the page operator, and inform 
the urologist that they are enrolled in the axitinib trial. The urologist on call will then contact 
one of the axitinib study members (Dr. Wood, Dr. Matin, Dr. Tannir or Dr. Jonasch) for further 
instructions. Written contact information will be provided to each patient prior to initiation of 
axitinib (Appendix I) 
7.2.6.3.2. 
New or additional antihypertensive therapy should be started if 2 BP readings, preferably 
taken in the clinic and separated by at least 1 hour, show the following: 2 systolic BP readings 
greater than 150 or 2 diastolic BP readings greater than 100 mm Hg. Alternately, the dose of 
existing antihypertensive medication(s) may be increased. If the patient is already on maximal 
antihypertensive treatment, the axitinib dose should be reduced by 1 dose level. 
7.2.6.3.3. 
Patients who have 2 systolic BP readings, separated by at least 1 hour, greater than 160 mm 
Hg, or 2 diastolic BP readings, separated by at least 1 hour, greater than 105 mm Hg, should 
have treatment with axitinib held. (Note: if axitinib is held, patients receiving antihypertensive 
medications should monitor closely for hypotension and restart axitinib at one lower dose level 
as soon as BP is <150/100 mm Hg. Plasma half-life of axitinib is 2 – 6 hours and BP usually 
decreases within 1-2 days following dose interruption.) Treatment with axitinib should be 
restarted at 1 lower dose level as soon as the systolic blood pressure reduces to less than 150 
mm Hg and the diastolic BP reduces to less than 100 mm Hg. 
7.2.6.3.4. 
Patients who develop recurrent systolic hypertension (2 BP readings separated by at least 1 
hour show systolic pressure >150 mm Hg) or recurrent diastolic BP >100 mm Hg following 
previous axitinib dose reduction should undergo another dose reduction by one dose level. 
7.2.6.3.5. 
Patients removed from treatment for intolerable toxicity should still be followed with 
regular tumor assessments (every 4 months for 1 year, every 6 months for the next 2 years and 
every 12 months for one more year) until disease progression or start of new treatment, and 
for survival thereafter until study completion.  Guidance on dose interruption and reduction for 
hypertension is summarized in the table below. 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
7.2.6.3.6. 
The antihypertensive medications (if the patient is taking any) will be tapered after axitinib 
is stopped, in order to maintain a blood pressure level that is less or equal to 140/90. Once the 
patient is at this blood pressure level, his blood pressure/blood pressure medications will be 
managed by his primary care physician. 
HYPERTENSION MANAGEMENT PLAN FOR AXITINIB 
Degree of Blood Pressure Elevation 
Management 
Systolic Pressure 
 
 
OR 
Diastolic Pressure 
 
2 BP readings separated 
by at least 1 hour show 
systolic pressure >150 
mm Hg 
2 BP readings 
separated by at least 1 
hour show diastolic 
pressure >100 mm Hg 
If not on maximal antihypertensive 
treatment, institute new or additional 
antihypertensive medication and maintain 
dose of axitinib. 
If on maximal antihypertensive treatment, 
reduce axitinib to one lower dose level. 
2 BP readings separated 
by at least 1 hour show 
systolic pressure >160 
mm Hg 
 
OR 
2 BP readings 
separated by at least 1 
hour show diastolic 
pressure >105 mm Hg 
Interrupt dosing*; adjust antihypertensive 
medication; as soon as BP is less than 
150/100 mm Hg, restart axitinib at one lower 
dose level. 
Recurrent hypertension 
following previous dose 
reduction (2 BP readings 
separated by at least 1 
hour show systolic 
pressure >150 mm Hg) 
 
 
OR 
Recurrent diastolic BP 
>100 mm Hg (2 BP 
readings separated by 
at least 1 hour) 
following previous dose 
reduction 
Repeat axitinib dose reduction by one lower 
dose level. If a patient requires dose 
reduction below 2 mg BID, interrupt dosing 
adjust antihypertensive medication; as soon 
as BP is less than 150/100 mm Hg, restart 
axitinib. Consideration should be given to 
stop axitinib if this recurs. 
* If axitinib is held, patients receiving antihypertensive medications should monitor closely for hypotension. 
Plasma half-life of axitinib is 2 – 6 hours and BP usually decreases within 1-2 days following dose interruption. 
7.2.6.4. Axitinib dose-reduction for proteinuria: 
7.2.6.4.1. 
If urinalysis shows protein qualitative level ≥ 100 (equivalent to ≥ 2+ proteinuria on dipstick), 
perform 24-hour urine collection. Dosing may continue while waiting for test results. 
[Equivalence of protein qualitative levels on urine dipstick and urinalysis are as follows: 1+ on 
dipstick is equivalent to 30 on urinalysis, 2+ on dipstick is equivalent to 100 on urinalysis, 3+ on 
dipstick is equivalent to 300 on urinalysis, and 4+ on dipstick is equivalent to >2000 on 
urinalysis] 
7.2.6.4.2. 
If < 2 g proteinuria/24 hour is reported, continue dosing at the same dose level. 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
7.2.6.4.3. 
If ≥ 2 g proteinuria/24 hours is reported, hold dosing and repeat 24 hour urine collection for 
proteinuria and creatinine clearance (interval at investigator discretion) until proteinuria is < 2 
g/24 hours. Restart axitinib at the same dose or one lower dose level at discretion of the 
investigator.  
7.2.6.4.4. 
Patients removed from treatment for intolerable toxicity should still be followed with 
regular tumor assessments (every 4 months for 1 year, every 6 months for the next 2 years and 
every 12 months for one more year) until disease progression or start of new treatment, and for 
survival thereafter until study completion.   
7.2.7. Concomitant therapy 
7.2.7.1. The patient will provide a list of medications taken within 4 weeks prior to 
enrollment, and will provide a new list during each clinic visit while being treated 
with axitinib. The name, dose, date of start, date of stop (if use for short term), 
indication of the medication will be listed. (Appendix J) 
7.2.7.2. The patient should not start a new prescription medication or over-the-counter 
medication before consulting with the study investigator, except in the case of a 
medical emergency.  
7.2.7.3. No other cancer/investigational therapies should be started during the current 
study without consulting with the study investigator. 
7.2.8. Treatment intake monitoring 
7.2.8.1. The patient will be provided with a pill diary to record date of treatment, day of 
treatment, time of treatment, dose. Missed doses will be recorded as well. (Appendix 
J) 
7.2.8.2. Pill counting. The patient will bring the axitinib bottle(s) when coming for a clinical 
visit. Pills will be counted by nurse/provider and recorded on a CRF and medical 
records. 
7.2.8.3. Unused or expired axitinib pills will be disposed per MDACC institutional policy. 
7.2.9. Treatment Start-Eligible patients will start treatment within 4 weeks of enrollment.  
7.2.10. A history, physical examination, medication list (Appendix J), ECOG Performance Status, 
Adverse Events, FKSI-15 questionnaire (Appendix E) will be performed and recorded in the 
medical record and appropriate CRFs on weeks 3, 7, and 12. An EKG will be performed and 
the results recorded in the medical record and appropriate CRFs on weeks 3 and 12. 


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7.2.11. Laboratory studies that include CBC, CMP, PT, PTT, UA will be obtained prior to starting 
axitinib, then at week 3, week 7, and week 12 after starting axitinib. In addition, blood 
studies for TSH, free T3, and free T4 will be performed prior to starting axitinib, and then 
blood studies for TSH will be performed at week 3, week 7, and week 12 after starting 
axitinib. With each blood draw, 4 tubes of research blood will be drawn and processed for 
DNA, serum, plasma, and PBMC isolation for correlative studies, after the patient has 
provided informed consent.  
7.2.12. Imaging: CT scans of the chest and abdomen (renal protocol) will be obtained on week 7 
and week 12 of therapy.  Patients with evidence of disease progression by RECIST version 
1.0 at week 7 (primary or metastatic) will be considered treatment failures and their 
axitinib treatment will be permanently discontinued. Subsequently, their surgery will be 
performed earlier than initially planned. The urologist (investigator assessment) and the 
radiologist (independent assessment) will perform the tumor measurements. Response 
will be determined by the radiologist assessment. Tumor measurements will be 
documented in the tumor measurement form (one of the CRFs) and medical record. 
7.2.13. Surgery: Following successful completion of presurgical therapy, patients will undergo 
radical nephrectomy (open or laparoscopic at the surgeon’s discretion), with 
retroperitoneal lymph node dissection.  Extent of lymph node dissection will be recorded 
in the operative record and should include the ipsilateral nodes from renal hilum to aortic 
bifurcation, as well as the interaortocaval nodes from renal hilum to aortic bifurcation.  
Primary tumor specimens will be immediately sent to pathology on ice for further 
processing and correlative study specimen harvest.  Routine perioperative parameters will 
be recorded and will include operative approach, operative time, estimated blood loss, 
ease of surgical dissection, comment on tissue planes, intraoperative complications (with 
grade), post-operative complications (with grade), blood transfusions, length of ICU stay (if 
applicable), length of hospital stay, perioperative mortality (within 30 days of surgery). The 
operating urologist will make a decision based on their extensive surgical expertise if these 
adverse events are attributable to axitinib or not. These events will certainly be monitored 
and recorded by the operating urologist, and discussed with the IND if they arise. 
 
7.3. Post-treatment follow-up 


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7.3.1. Patients will be seen at week 19 (+/- 1 week) and evaluated with CT chest and abdomen 
(renal protocol), full laboratory analysis (CBC, CMP), collection of blood and urine for 
research, and full history and physical examination.  Evidence of disease recurrence [If a 
patient develops any evidence of biopsy-proven RCC after axitinib/surgery (in the form of 
local disease or distant disease), the patient will be labeled as having disease recurrence] 
or treatment related morbidity will be recorded.  Pathology will be reviewed and will be 
assessed for histology, Fuhrman grade, percentage tumor viability, pathologic tumor size, 
presence of venous, extracapsular, sinus, or nodal involvement. 
7.3.2. A history, physical examination, medication list (Appendix J), ECOG Performance Status, 
Adverse Events, FKSI-15 questionnaire (Appendix E) will be performed and recorded in the 
medical record and appropriate CRFs on week 19. 
7.3.3. Patients will be followed with similar evaluations every 4 months (+/- 2 weeks) for the 
first year, then every 6 months (+/- 2 weeks) for the next 2 years, , then yearly (+/- 1 
month) until year 5 postoperatively.  Evidence of recurrence or treatment related 
morbidity will be recorded. 
 
8. Tissue, Blood, and Urine Banking 
8.1. Tissue-Kidney biopsy specimen and kidney surgical specimen will be collected 
8.1.1. Kidney biopsy specimen. A total of 4 adequate biopsy cores are needed. Each core 
should undergo touch prep by cytopathologist to ensure biopsy quality (ie, malignant cell 
present with minimal necrosis/hemorrhage). More cores will be obtained if touch prep 
shows inadequate diagnosis (to obtain a total of 4 adequate cores). 
8.1.1.1. One core will be fixed for pathologic evaluation and sent for pathology department 
for review prior to starting treatment. 
8.1.1.2. Three cores will be immediately placed in 3 separate cryotubes, labeled 
appropriately, and stored at -70° to -80°C for future use. 
8.1.1.3. All 4 touch prep slides will be labeled appropriately, and stored at room 
temperature for future use. 
8.1.2. Kidney surgical specimen:  
8.1.2.1. Tissues from final kidney surgical specimen (4 pieces of tumor, 5-10mm diameter 
each; and 4 pieces of normal appearing kidney cortex, 5-10mm diameter each) will 


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be collected in the pathology department. Each piece will be placed in a separate 
cryotube, labeled appropriately, and stored at -70° to -80°C for future use. 
8.1.2.2. In accordance with pathology standards, several blocks of tissue will be fixed in 
formalin and embedded in paraffin, and stored at room temperature for future use. 
8.2. Blood 
8.2.1. Four different tubes will be collected at specified visits (Table 4), processed, labeled 
appropriately, and stored in aliquots at -70° to -80°C for future use. 
8.2.1.1. Tube 1 (8cc): PAXgene Blood DNA tube to collect DNA 
8.2.1.2. Tube 2 (8cc): BD Vacutainer CPT tube to collect plasma (Sodium Citrate) and PBMC 
8.2.1.3. Tube 3 (10cc): BD Vacutainer EDTA tube to collect plasma (K2 EDTA) and PBMC 
8.2.1.4. Tube 4 (10cc): BD Vacutainer Serum tube to collect serum 
8.3. Urine 
8.3.1. 30-50cc fresh voided urine obtained will be collected at specified visits (Table 4), 
processed, labeled appropriately, and stored in aliquots at -70° to -80°C for future use. 
8.4. Blood and urine collection for research are optional but extremely valuable for the study. These 
samples will be used in the future to study predictors of response to therapy with axitinib. 
 
9.  Good Clinical Practice 
9.1. Informed Consent: 
The investigator/team will explain to the patient the nature of the clinical trial, its goal, potential 
benefits and risks. The patient will be informed that participation in the trial is voluntary, and 
that withdrawal is allowed at any time of the study, and that withdrawal will not affect 
subsequent medical treatment or relation with treating investigator/team. The informed 
consent is a document written in non-technical language. The patient will need to read the 
consent, ask pertinent questions, sign and date prior to starting study treatment. Separate 
consents will be obtained for required preoperative biopsy. 
9.2. Institutional Review Board (IRB): 
Prior to enrolling the first patient in this study, the protocol, related documents, and the 
informed consent forms will be reviewed by the Departmental Research Committee, the Clinical 
Research Committee, and the IRB. Pertinent amendments to the protocol will need to be 
approved by the IRB and the IND Sponsor – IND Office. 
9.3. Ethical Conduct of Study 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
This study will be conducted according to GCP, US 21 Code of Federal Regulations (CFR) Part 50 
(Protection of Human Subjects); US 21 CFR Part 56 (IRBs); US 21 CFR Part 54 (Financial 
Disclosure); International Conference on Harmonization (ICH) Guidance for Industry, E6 GCP: 
Consolidated Guidance; the Nuremberg Code; and, where applicable, the 1996 version of the 
Declaration of Helsinki (World Medical Association Declaration of Helsinki, 1996). 
9.4. Patient Confidentiality: 
All information collected during the study will be recorded in case report forms (CRF) and placed 
in a patient-specific folder. The information in the CRFs will then be put into a research database 
at M.D. Anderson Cancer Center. This database will identify the patient by a study number. The 
study number will be assigned by the research nurse, and all subsequent research records will 
contain the study number only.  The link between the study number and patient identifiers will 
be kept in a limited access database with password protection. The informed consent will be 
kept in the medical record.  The research records will be kept in the research nurse office at 
M.D. Anderson Cancer Center, and will be accessible to the Principal Investigator, the 
collaborators, and the research staff as designated by the Principal Investigator. Strict 
adherence to HIPAA regulations will be maintained at all times.  The research subject will not be 
identified in any reports on this study.  The results will be identified by the patient's study 
number.  Only authorized personnel such as members of the University of Texas M.D. Anderson 
Cancer Center Institutional review board, Principal Investigator, Co-Investigators, collaborators, 
and research staff will be allowed to access the data.  Data [abdominal CT scans, age, gender, 
race, height, weight, body mass index, serum albumin (both before and after treatment with 
axitinib), serum total protein (both before and after treatment with axitinib), current disease 
status, response to axitinib treatment, complications related to axitinib treatment or surgery, 
performance status, pathologic tumor stage, pathologic tumor grade, and tumor size] from this 
study may also be shared and used in protocol PA15-0949. 
 
 
 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
Table 4. Summary of protocol studies 
Studies 
Pre-
treatment* W1 
W3 
W5 
W7 
W9 W12 W13 
W19 
(±1w) 
Q4M 
x 1Y 
(±2w) 
Q6M 
x 2Y 
(±2w) 
Q12M 
X 2Y 
(±1M) 
History & Physical 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Medication list 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
ECOG PS 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
FKSI-151 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Adverse Events 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Nurse phone call2 
 
 
 
X 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
X 
 
 
 
X 
 
 
 
 
 
Routine labs 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
CMP3 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
PT, PTT 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
TSH 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Free T3, free T4 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Pregnancy test 
(urine or serum) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Study blood# 
 
 
 
 
 
 
 
 
 
 
 
 
PAXgene DNA 
X4 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Red top 
X4 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Purple top 
X4 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
CPT 
X4 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Study urine# 
X4 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Imaging 
 
 
 
 
 
 
 
 
 
 
 
 
CT chest 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
CT abdomen 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI brain5 
X5 
 
 
 
 
 
 
 
 
 
 
 
Bone scan6 
X6 
 
 
 
 
 
 
 
 
 
 
 
Pathology 
 
 
 
 
 
 
 
 
 
 
 
 
Percutaneous 
biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
Final pathology 
 
 
 
 
 
 
 
X 
 
 
 
 
Nephrectomy 
 
 
 
 
 
 
 
X 
 
 
 
 
Axitinib 
 
-----------------------X---------------------
- 
 
*Evaluations need to be completed within 4 weeks of study enrollment  
 #Blood and urine collection for research are optional but extremely valuable for the study. These samples will be 
used in the future to study predictors of response to therapy with axitinib 
1 FKSI-15, Functional Assessment of Cancer Therapy-Kidney Specific Index-15 (Appendix E) 
2 Nurse phone call will mainly assess adverse events and BP measurements 


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CG Wood et al. Phase II Trial Of Neoadjuvant Axitinib In Locally Advanced Clear Cell Renal Cell Carcinoma 
3 CMP includes sodium, potassium, chloride, carbon dioxide, calcium, glucose, BUN, creatinine, magnesium, 
phosphorus, lactate dehydrogenase, AST, ALT, alkaline phosphatase, total and direct bilirubin, albumin, total 
protein 
4 The blood samples for research can be drawn on W1-prior to first intake of axitinib-if it was not drawn at 
enrollment 
5 If CNS symptoms are noted 
6 If alkaline phosphatase is abnormal or if bone pain is present 
W=week, M=month, Y=year, Q=every 


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