Conditions: Renal Cell Carcinoma Metastatic Renal Cell Carcinoma Non-metastatic Renal Cell Carcinoma
Keywords: Neoadjuvant Venous Tumour Thrombus Axitinib Mayo Classification Nephrectomy Thrombectomy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
NAXIVA is a study of axitinib in patients with metastatic and non-metastatic renal cell carcinoma with venous invasion. Patients will be given axitinib (twice daily) for 8 weeks (at an escalated dose) and the response of the venous invasion will be assessed.

Blood, urine and tumour tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response.

The primary objective is to assess the response of the thrombus to axitinib. Its thought that axitinib will reduce the extent of the thrombus in the inferior vena cava will reduce the extent of surgical intervention.

Detailed description:
NAXIVA is a single arm, single agent, open label, phase II feasibility study of axitinib in patients with both metastatic and non-metastatic renal cell carcinoma of clear cell histology. 20 patients will be recruited from multiple centres within the United Kingdom.

Patients who have signed informed consent and who have met all eligibility criteria will be registered into the trial.

The starting dose of axitinib will be 5mg BID and escalated to 7mg BID and then 10mg BID. A dose modification assessment will take place every 2 weeks in clinic during the 8 week pre-surgical treatment period and will be dependent on tolerability of treatment. Patients will follow an aggressive axitinib dose escalation process within the 8 week period to a maximum of 10mg BID. Patients should stop axitinib a minimum of 36 hours and a maximum of 7 days prior to surgery in week 9.

Blood, urine and tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response. Nephrectomy and IVC tumour thrombectomy will be planned for all patients on the trial.

Response to axitinib in VTT, primary tumour and any RECIST measureable lesion will be correlated with changes in molecular markers.

Patients will be followed up in clinic at 6 \& 12 weeks post surgery.

Arms:
arm 1: Axitinib - oral tablet twice daily for 8 weeks prior to surgery. Starting dose 5mg.

Interventions: intervention 1: Axitinib Oral Tablet
Intervention descriptions: intervention 1: Axitinib is an oral VEGF-receptor inhibitor. Patients are prescribed a starting dose of 5mg twice daily, escalating to 10mg in absence of dose limiting toxicities and blood pressure.

Doses should be taken approximately 12 hours apart and patients should be instructed to take their doses at approximately the same times each day with or without food as per instruction. On clinic days only, patients will be advised to fast for 6 hours prior to their clinic visit.

Patients should be advised to stop axitinib treatment a minimum of 36 hours and maximum of 7 days prior to week 9 nephrectomy and thrombectomy surgery.

Dose adjustments, including dose increase or dose reduction, are permitted and should be based on clinical judgement and the guidelines provided in the protocol.

Protocol document:
Prot_ICF_000.pdf: 
  
 
NAXIVA 
 
 
PHASE II NEOADJUVANT STUDY OF AXITINIB FOR 
REDUCING EXTENT OF VENOUS TUMOUR THROMBUS IN 
CLEAR CELL RENAL CELL CANCER WITH VENOUS 
INVASION (NAXIVA) 
 
 
Version number: 1.2 
 
Date: 22nd September 2017 
 
 
 
 
Main Sponsor: Common Services Agency (CSA) 
 
Funders: Pfizer Limited UK 
 
Trial Coordinating Centre: Scottish Clinical Trials Research Unit (SCTRU),  
                                              NHS National Services Scotland, Edinburgh. 
 
 
 
 
ISRCTN: 
ISRCTN96273644 
EudraCT Number: 
2017-000619-17 
REC reference: 
17/EE/0240 
 
 
 
 
 
Protocol authorised by: 
 
Name: Mr Grant Stewart 
 
 
Role in Trial:  Chief Investigator 
 
 
Signature:           
                                                   Date: 22/09/2017 
 
 


 
 
 
 
 
 
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KEY CONTACTS 
 
Chief Investigator 
Mr Grant Stewart 
University of Cambridge 
Academic Urology Group, Box 43,  
Addenbrooke's Hospital, Cambridge Biomedical Campus, Hill's Road, Cambridge, CB2 0QQ 
 
Co-Chief Investigator  
Professor Robert Jones 
University of Glasgow 
Suite 3A, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN 
 
Translational Lead 
Dr Sarah Welsh 
University of Cambridge 
Department of Oncology, Box 143, Addenbrooke’s Hospital, Hill’s Road, Cambridge, CB2 0QQ 
 
Sponsor 
The Common Services Agency 
NHS National Services Scotland, Gyle Square, 1 South Gyle Crescent 
Edinburgh, EH12 9EB 
 
Funder 
Pfizer Limited UK 
Walton Oaks, Dorking Road, Walton-on-Hill 
Tadworth, Surrey, KT20 7NS 
 
Trial Coordination  
Scottish Clinical Trials Research Unit 
NHS National Services Scotland 
Gyle Sqaure, 1 South Gyle Crescent, Edinburgh EH12 9EB 
NSS.NAXIVA@nhs.net  
 
 
TRIAL DEVELOPMENT GROUP 
Mr Grant Stewart 
University of Cambridge 
Dr James Larkin 
The Royal Marsden Hospital 
Professor Robert Jones 
University of Glasgow 
Professor Thomas Powles 
Bart’s Cancer Institute 
Mr Grenville Oades 
Beatson West of Scotland Cancer Centre 
Mr Michael Aitchison 
The Royal Free Hospital 
Professor David Nicol 
The Royal Marsden Hospital 
Dr Kate Fife 
Addenbrooke’s Hospital, Cambridge 
Dr Iosif Mendichovszky 
University of Cambridge 
Dr Ferdia Gallagher 
Addenbrooke’s Hospital, Cambridge 
Dr Sarah Welsh 
University of Cambridge 
Alison Fielding 
Consumer Representative 
Mr Robert Hill 
SCTRU 
Mrs Tracy McEleney 
SCTRU 
Mrs Niki Couper 
SCTRU 
Any questions relating to this protocol should be addressed in the first instance to the NAXIVA Team 
within SCTRU: 
Email: NSS.NAXIVA@nhs.net 
Telephone: 0131 275 7178 
Fax: 0131 275 7512 


 
 
 
 
 
 
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SYNOPSIS  
 
Protocol ID 
NAXIVA 
 
Protocol Title 
Phase II Neoadjuvant study of AXItinib for reducing extent of 
venous tumour thrombus in clear cell renal cell cancer with Venous 
invAsion (NAXIVA) 
 
Development Phase 
Phase II Feasibility 
 
Primary Endpoint 
The percentage of evaluable patients with an improvement in the 
Mayo classification. 
 
       Mayo Classification; 
 
Level 0: thrombus limited to the renal vein 
 
Level 1: into IVC <2cm from renal vein ostium level 
 
Level 2: IVC extension >2cm from renal vein ostium and 
below hepatic vein 
 
Level 3: thrombus at the level of or above the hepatic veins 
but below the diaphragm 
 
Level 4: thrombus extending above the diaphragm. 
 
Secondary Endpoints 
% change in surgical approach. 
% change in venous tumour thrombus (VTT) height. 
Response rate (RECIST). 
Evaluation of morbidity assessed by Clavian-Dindo classification. 
 
Study Design 
NAXIVA is a single arm, single agent, open label, phase 2 feasibility 
study of axitinib in patients with both metastatic and non-metastatic 
renal cell carcinoma of clear cell histology prior to nephrectomy and 
thrombectomy. 
 
Patient Accrual 
20 patients will be recruited over a 24 month period at 7 sites across 
the UK. 
 
Interim Analysis 
Will be performed after thirteen patients have been recruited. If no 
patients show an improvement in their Mayo classification the trial 
will be stopped for futility.  
 


 
 
 
 
 
 
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TABLE OF CONTENTS 
 
1. INTRODUCTION ............................................................................................................... 7 
1.1. BACKGROUND............................................................................................................................... 7 
1.2. INVESTIGATIONAL MEDICINAL PRODUCT .................................................................................... 7 
1.3. PRE-CLINICAL DATA .................................................................................................................... 7 
1.4. CLINICAL DATA ............................................................................................................................ 7 
1.5. TRIAL RATIONALE ........................................................................................................................ 9 
2. TRIAL OBJECTIVES .......................................................................................................11 
3. TRIAL DESIGN ................................................................................................................11 
3.1. GENERAL DESIGN ....................................................................................................................... 11 
3.2. INCLUSION CRITERIA .................................................................................................................. 11 
3.3. EXCLUSION CRITERIA ................................................................................................................. 12 
3.4. ENDPOINTS ................................................................................................................................. 13 
4. TREATMENT ...................................................................................................................13 
4.1. TREATMENT SCHEDULE .............................................................................................................. 13 
4.2. DOSE MODIFICATIONS ................................................................................................................ 14 
4.3. DURATION OF TREATMENT ........................................................................................................ 16 
4.4. CONCOMITANT THERAPY ........................................................................................................... 16 
4.5. COMPLIANCE WITH TREATMENT ................................................................................................ 17 
4.6. DRUG SUPPLIES AND LABELLING ............................................................................................... 17 
4.7. DRUG STORAGE ACCOUNTABILITY ............................................................................................ 18 
5. ASSESSMENT OF EFFICACY ........................................................................................20 
5.1. TREATMENT AND EXAMINATION SCHEDULE ............................................................................. 20 
5.2. SCHEDULE OF ASSESSMENTS ...................................................................................................... 21 
5.3. WITHDRAWAL OF SUBJECTS ....................................................................................................... 27 
6. TRANSLATIONAL RESEARCH ......................................................................................27 
7. PHARMACOVIGILANCE .................................................................................................28 
7.1. DEFINITIONS ............................................................................................................................... 28 
7.2. RECORDING OF ADVERSE EVENTS ............................................................................................. 29 
7.3. RECORDING AND REPORTING OF SERIOUS ADVERSE EVENTS ................................................... 29 
7.4. DEVELOPMENTAL SAFETY UPDATE REPORT.............................................................................. 30 
7.5. PREGNANCIES ............................................................................................................................. 30 
8. DATA MANAGEMENT ....................................................................................................31 
8.1. DATA COLLECTION ..................................................................................................................... 31 
8.2. RECORD KEEPING AND ARCHIVING............................................................................................ 31 
9. STATISTICS ....................................................................................................................31 
9.1. SAMPLE SIZE ............................................................................................................................... 31 
9.2. ANALYSIS PLAN .......................................................................................................................... 31 
9.3. END OF STUDY ............................................................................................................................ 32 
10. ACCESS TO SOURCE DATA/ DOCUMENTS ...............................................................32 
11. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................32 


 
 
 
 
 
 
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11.1. MONITORING VISITS ................................................................................................................. 32 
11.2. DATA MONITORING AND ETHICS COMMITTEE ......................................................................... 32 
11.3. TRIAL STEERING COMMITTEE .................................................................................................. 33 
12. ETHICAL CONSIDERATIONS .......................................................................................33 
12.1. PATIENT CONFIDENTIALITY ..................................................................................................... 33 
12.2. INFORMED CONSENT ................................................................................................................ 33 
13. RESEARCH GOVERNANCE .........................................................................................34 
14. FINANCING AND INSURANCE .....................................................................................35 
15. PUBLICATION POLICY .................................................................................................35 
16. REFERENCE LIST .........................................................................................................36 
APPENDIX 1 - ECOG & KARNOFSKY PERFROMANCE STATUS .......................................................... 39 
APPENDIX 2  – CAUSALITY ................................................................................................................ 40 
APPENDIX 3A – INVESTIGATOR STATEMENT (SCTRU COPY) .......................................................... 40 
APPENDIX 3B – INVESTIGATOR STATEMENT (INVESTIGATOR COPY) ............................................... 41 
APPENDIX 4 – MAIN STUDY; PATIENT INFORMATION SHEET AND INFORMED CONSENT .................. 42 
APPENDIX 5 –TRANSLATIONAL; PATIENT INFORMATION SHEET AND INFORMED CONSENT ......... 42  
APPENDIX 6 – TRANSLATIONAL RESEARCH STUDIES ....................................................................... 59 
APPENDIX 7– THE PRINCIPLES OF ICH GOOD CLINICAL PRACTICE ................................................. 66 


 
 
 
 
 
 
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GLOSSARY OF ABBREVIATIONS 
 
AE 
AIDS 
ALT 
AR 
AST 
BID 
BP 
ccRCC 
Adverse Event 
Acquired Immunodeficiency Syndrome 
Alanine Transaminase 
Adverse Reaction 
Aspartate Transaminase 
Twice a day 
Blood Pressure 
Clear Cell Renal Cell Cancer 
CI 
CRF 
CRP 
CRUK 
CSA 
CT 
CTCAE 
ct DNA 
DCE 
Chief Investigator 
Case Report Form 
C-Reactive Protein 
Cancer Research United Kingdom 
Common Services Agency 
Computed Tomography 
Common Toxicity Criteria for Adverse Events 
Circulating Tumour DNA 
Dynamic Contrast Enhanced 
DMC 
DWI 
EDTA 
EMT 
EU 
Data Monitoring Committee 
Diffusion Coefficient 
Ethlenediaminetetraacetic Acid 
Epithelial Mesenchymal Transition  
European Union 
GCP 
GP 
HIV 
Good Clinical Practice 
General Practitioner 
Human Immunodeficiency Virus 
ICH 
IC50 
International Conference on Harmonisation 
50% Inhibitory Concentration 
IMP 
IVC 
LDH 
M0 
M1 
Investigational Medicinal Product 
Inferior Vena Cava 
Lactate Dehydrogenase 
Non-metastatic 
Metastatic 
MHRA 
mRCC 
Medicines and Healthcare products Regulatory Agency 
Metastatic Renal Cell Carcinoma 
MRI 
MSKCC 
NSCLC 
ORR 
PBS 
PCR 
PDGF-R 
PI 
PIL 
PMBC 
PRES 
PSA 
QP 
RCC 
R&D 
REC 
RECIST 
Magnetic Resonance Imaging 
Memorial Sloan Kettering Cancer Centre 
Non Small Cell Lung Cancer 
Objective Response Rate 
Phosphate Buffered Saline 
Protein: Creatinine Ratio 
Platelet-Derived Growth Factor Receptors 
Principal Investigator  
Patient Information Leaflet 
Peripheral Blood Mononuclear Cells 
Posterior Reversible Encephalopathy Syndrome 
Prostrate-specific antigen 
Qualified Person 
Renal Cell Cancer 
Research and Development 
Research Ethics Committee 
Response Evaluation Criteria in Solid Tumours 
SAE 
SCTRU 
Serious Adverse Event 
Scottish Clinical Trials Research Unit 


 
 
 
 
 
 
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SDV 
SmPC 
Source Data Verification 
Summary of Product Characteristics  
SOP 
Standard Operating Procedures 
SUSAR 
TKI 
Suspected Unexpected Serious Adverse Reaction 
Tyrosine Kinase Inhibitor 
TMG 
Trial Management Group 
TSC 
TSH 
TTP 
TV 
UKCRC 
ULN 
VEGF 
VEGFR 
VTT 
Trial Steering Committee 
Thyroid Stimulating Hormone 
Thrombotic Thrombocytopenic Purpura 
Tumour Thrombus Volume 
United Kingdom Clinical Research Collaboration 
Upper Limits of Normal 
Vascular Endothelial Growth Factor 
Vascular Endothelial Growth Factor Receptor 
Venous Tumour Thrombus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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1. INTRODUCTION 
 
1.1. Background 
Venous tumour thrombus (VTT) extension into the renal vein and/or inferior vena cava (IVC) 
occurs in 4-15% cases of renal cell cancer (RCC) (1). If the patient is fit enough to undergo 
surgery, in an attempt to excise all disease with curative intent, the surgical risk is high due 
to the need to perform a cavotomy and/or open heart surgery to excise the VTT (5-15% 
mortality) (1). Complications are established to increase with the height of the VTT (1). After 
such surgery, the 5 year survival rates are poor; ~40-65% in non-metastatic RCC to 0-17% 
for patients with concomitant metastatic RCC (2, 3). As such, the concept of using targeted 
therapies, which are standard of care in metastatic RCC, to downstage the VTT prior to 
extirpative surgery is appealing. If it were possible to reduce the extent of the surgery an 
individual patient with RCC VTT required it is likely morbidity and mortality would be reduced 
and potentially survival time improved.  
 
1.2. Investigational Medicinal Product 
Axitinib is a potent oral VEGFR2 and 3 inhibitor at picomolar concentrations and VEGFR1, 
PDGFRs and c-KIT inhibitor at low nanomolar concentrations. In phase II clinical trials, 
axitinib has shown efficacy in sorafenib and cytokine refractory mRCC patients. A recently 
reported phase III trial, showed superiority over sorafenib as second line therapy (4), leading 
to the licensing of axitinib in this indication by the United States Food and Drug 
Administration (FDA) agency in January 2012. Axitinib was subsequently licensed for the 
same indication by the European Medicines Agency. Furthermore, the efficacy of axitinib is 
under evaluation in other tumour types, and has shown activity in lung (5), thyroid (6), and 
pancreatic (7) cancers, and melanoma (8). 
 
1.3. Pre-Clinical Data 
In vitro, axitinib inhibits cellular phosphorylation of VEGFR2 and 3 with an IC50 of about 0.2 
nmol/L. It has a higher IC50 for VEGFR1 (1.2 nmol/L), PDGFR-β (1.6 nmol/L), PDGFR-α (5 
nmol/L) and c-KIT (1.7 nmol/L). It reduces phosphorylation of downstream signalling 
molecules mediated by vascular endothelial growth factor (VEGF) in a rapid and dose-
dependent manner, including Akt, endothelial nitric oxide synthase and extracellular signal 
regulated kinase (ERK).  
In mouse xenografts, twice daily oral axitinib inhibited the primary tumour and controlled 
metastases in human melanoma (M24mwt), colorectal cancer (HCT-116) and RCC (SN12C) 
models. Within axitinib treated tumours, there was reduced CD31 and Ki-67 staining and 
increased caspase-3 staining. Microscopic examination of tumour vasculature in preclinical 
models of pancreatic islet cell tumours and Lewis lung carcinomas has shown that axitinib 
reduces patency and flow. Axitinib has its greatest effects on endothelial cells and 
fenestrated vessels, resulting in normalisation of the surviving tumour vasculature. 
 
1.4. Clinical Data 
1.4.1 Efficacy Data 
 
Phase I  
In an initial phase I study, 3 of 36 patients had partial responses determined by Response 
Evaluation Criteria in Solid Tumours (RECIST) (9) including 2 patients with RCC and 1 
patient with adenoid cystic carcinoma (10). In a Japanese phase I trial, none of 12 recruited 
patients had a partial response but 3 patients had stable disease at 24 weeks, seen in one 
patient each with colorectal carcinoma, thymic cancer and non-small cell lung cancer 
(NSCLC) (11).  


 
 
 
 
 
 
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Phase II: Axitinib in Cytokine-refractory Metastatic RCC  
In a single arm, open label, phase II trial in cytokine-refractory mRCC, axitinib was 
administered at a starting dose of 5mg twice daily in the fasted state as 28 day treatment 
cycles until disease progression or significant toxicity (12). Fifty-two patients were recruited 
with a median age of 59 years and performance status 0 or 1. Forty-nine patients (95%) had 
previously undergone a nephrectomy and none of the patients had previously received 
tyrosine kinase inhibitors (TKIs). All patients had clear cell histology, except one patient who 
had papillary carcinoma. The objective response rate (ORR) was 44.2% (95% CI: 30.5-
58.7%); there were 2 complete and 21 partial responses. Twenty-two patients had stable 
disease for at least 8 weeks, including the patient with papillary carcinoma. Four patients 
had early progression and 3 patients could not be assessed for response. The median 
thrombotic thrombocytopenic purpura (TTP) was 15.7 months and median overall survival 
was 29.9 months. The median duration of axitinib therapy was 9.4 months and median dose 
was 8.83 mg/day, as 15 patients had dose reductions for adverse events (AE) including 
fatigue, hypertension and diarrhoea. Axitinib was discontinued due to adverse events in ten 
patients. The most frequent grade 1-4 axitinib related adverse events were diarrhoea, 
hypertension, fatigue, nausea and hoarseness. The most common grade 3-4 adverse events 
were hypertension (15.4%), diarrhoea (9.6%) and fatigue (7.7%). Thirty patients had axitinib 
induced hypertension, eight of whom had grade 3-4 hypertension. Hypertension was 
resistant to anti-hypertensive therapy in 8 patients, seven of whom had hypertension at 
baseline. There were no detectable haematological toxicities. Four patients had treatment 
related proteinuria which resolved once axitinib was stopped. 
 
Phase II: Axitinib in Sorafenib Refractory Metastatic RCC  
In a single arm, open label, phase II study, patients with sorafenib refractory mRCC received 
a starting dose of axitinib 5mg twice daily with food until disease progression or 
unmanageable toxicity (13). Sixty-two patients were recruited; all had undergone prior 
nephrectomy and 59 patients had clear cell /mixed histology. Median age was 60 years and 
all patients were performance score of 0 or 1. The most common prior therapies in addition 
to sorafenib were sunitinib and cytokine therapy, received by 14 (22.6%) and 38 (61.3%) 
patients, respectively.  
The ORR was 22.6% (95% CI 12.9-35.0%), with 14 patients experiencing a partial response 
and no complete responses. Tumour responses were observed in patients who received 5 
mg twice daily or higher, and also in patients whose dose was reduced to below 5 mg twice 
daily. Patients who had a partial response received doses ranging from <4mg to 9-10mg 
twice daily. Eleven patients (17.8%) had stable disease. The median progression-free 
survival was 7.4 months (95% CI 6.7-11.0 months) and median overall survival was 13.6 
months (95% CI 8.4-18.8 months).  
The most common grade 3-4 adverse events included hypertension (16.1%), fatigue 
(16.1%), hand-foot syndrome (16.1%), dyspnoea (14.5%) and diarrhoea (14.5%). Twelve 
patients stopped axitinib due to treatment related adverse events. Two patients developed 
congestive heart failure, both of whom had a history of cardiovascular disease, and two 
patients had cerebral haemorrhages during the study. One of the latter patients was 
subsequently diagnosed with a cerebral metastasis at the site of haemorrhage. Most 
haematological toxicities were mild or moderate (grade 1 or 2) except grade 3 lymphopaenia 
experienced by 9 of 55 evaluable patients (16.4%). 
 
1.4.2 Safety Data 
 
Phase I 
The primary dose limiting toxicity in the initial phase I trial was hypertension (10); in most 
cases it responded to anti-hypertensive therapy and resolved after axitinib was stopped. The 
incidence and severity of hypertension was dose-dependent, all patients with axitinib-


 
 
 
 
 
 
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induced hypertension at dose 5mg twice daily were managed with standard anti-
hypertensives. Prior to blood pressure monitoring two patients had uncomplicated seizures 
in the absence of brain metastases at doses 10mg and 20mg twice daily, these may have 
been related to hypertensive crises.  
Three bleeding events were reported during the phase I study. A patient with central NSCLC 
had a fatal haemoptysis attributed to axitinib. A patient with peripheral NSCLC had grade 1 
haemoptysis while taking axitinib which was subsequently stopped. Two weeks later the 
patient had grade 4 haemoptysis and died, this patient’s death was reported as secondary to 
disease progression and concurrent infection. Finally, there was 1 episode of grade 1 rectal 
bleeding.  
Asymptomatic proteinuria was detected in seven of the first ten patients. Consequently, 
patients with proteinuria >0.5gram/24 hours were not recruited and treatment reviews were 
required for all patients with proteinuria ≥1gram/24 hours. These amendments reduced the 
incidence and severity of proteinuria. 
 
Thrombocytopenia was the only haematological toxicity in the phase I trial, with grade 2 
thrombocytopenia affecting one patient taking 20mg twice daily.  
 
Phase II  
The commonest non-haematological adverse events grade 1-4 reported in phase II axitinib 
monotherapy trials were hypertension, fatigue, diarrhoea, anorexia, nausea and hoarseness. 
The main grade 3-4 adverse events were similar, except hand-foot syndrome and proteinuria 
were also reported. Most adverse events were manageable. Hypertension usually 
responded to anti-hypertensive therapy and resolved once axitinib was stopped.  
The starting dose in all but one of the phase 2 studies conducted to date was 5mg twice 
daily of axitinib. In one metastatic breast cancer study, axitinib dose was titrated up from a 
starting dose of 5mg twice daily in 1–3mg increments in patients tolerating axitinib. Those 
subjects who could tolerate axitinib with no adverse events related to axitinib above CTCAE 
(14) grade 2 for consecutive 2 week periods were permitted to increase their dose step-wise 
to 7mg twice daily and then to 10mg twice daily, unless their BP was >150/90mm Hg or the 
subject was receiving antihypertensive medication. All studies ongoing at the time of writing 
allow axitinib dose reductions to as low as 2mg twice daily for treatment-related adverse 
events. Except for an increase in hand-foot syndrome and slight increase in the incidence of 
hypertension, it appears that patients whose dose is titrated to between 6-10mg twice daily 
doses do not experience increased toxicities if they have previously tolerated 5mg twice 
daily starting dose. Axitinib dose titration will be permitted within NAXIVA, consistent with 
previous clinical trial protocols and the drug development programme for axitinib. 
 
1.5. Trial Rationale 
There is no level I or II evidence of neoadjuvant studies of targeted therapies in non-
metastatic RCC VTT or upfront therapies in metastatic RCC VTT. There is level III evidence 
of mixed populations of RCC VTT patients (including both metastatic and non-metastatic 
patients) treated with a heterogeneous group of drug treatments (15, 16). The results of 
these studies suggest that regression in VTT is limited to sunitinib therapy (seen in 
3/12=25% patients; regression not seen for bevacizumab, temsirolimus or sorafanib). With 
sunitinib treatment none of the patients (0/12) had an increase in the VTT level (15).  
 
A recent prospective phase II of 12 weeks neoadjuvant axitinib in ccRCC T2-T3b, has been 
reported by Karam and colleagues (17). All of the patients in this study were cT3a (i.e. there 
were no patients with VTT). It was possible to titrate all patients up to 10mg axitinib with no 
grade 4/5 toxicities. 100% of patient’s tumours showed response (46% patients had partial 
response, and 54% stable disease) and the median reduction in primary tumour diameter 
was 28% by week 12. The median tumour diameter reduced from 10cm to 6.9cm. The vast 
majority of reduction in tumour size had occurred at 7 weeks of axitinib treatment.  


 
 
 
 
 
 
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The results of these small studies in non-metastatic RCC patients suggest that neoadjuvant 
TKI treatment of RCC patients is safe. However, the effect of these drugs on the extent of 
the VTT and the surgical approach that must be applied has not been confirmed. Authors in 
this field agree that a prospective trial is required to answer this important clinical question 
(15,16,18). 
 
In NAXIVA we will study the response of VTT to axitinib. The primary outcome is percentage 
of patients with reduction in the Mayo Classification (19). This study will address the 
feasibility of patient recruitment in this setting. In order to ensure adequate recruitment both 
metastatic and non-metastatic patients will be recruited to assess the effect of axitinib 
therapy on the extent of the tumour thrombus, rather than to primarily assess a prolonged 
survival. A reduction in the extent of the VTT, as assessed by the Mayo classification, will 
potentially result in less extensive and less morbid surgical approach with immediate patient 
benefits of reduced operative mortality/morbidity, potential shorter hospital stay and shorter 
recuperation period to return to full activities of daily living. There is also potential for a 
longer disease free survival in patients treated with axitinib prior to nephrectomy and tumour 
thrombectomy. The risks of the treatment of patients with VTT with axitinib over an 8 week 
period include progression of their disease (from operable to non-operable or non-metastatic 
to metastatic). However, based on the studies outlined above there is no evidence that 
progressive disease will occur over this period of time. Treating patients with axitinib over an 
8 week period may also increase the incidence of adverse events which could have a 
significant impact on the patient’s fitness for surgery. This risk will be minimised as dose 
reduction and axitinib cessation will be managed as per section 4. 
 
Axitinib has been chosen for this study as it is a potent TKI with proven effect in non-
metastatic ccRCC (17). The dose regimen (starting at 5mg bd, increasing dose up to 10mg 
twice daily (BID), as rapidly as possible, as tolerated by patients) is a well established 
regimen in metastatic ccRCC and was shown to be effective in the previous non-metastatic 
ccRCC neoadjuvant study (18). 8 weeks has been chosen as the treatment duration as in 
the study by Karam et al maximum effect on the primary tumour size was observed by 7 
weeks and no significant further advantage was seen by continuing treatment to 12 weeks.  
 
Patients having biopsy proven ccRCC will be included in this study, as this is histological 
subtype of RCC shown to have a benefit from axitinib therapy. Patients with VTT confined to 
the renal vein (cT3a) will be included as they would benefit from a reduction in the extent of 
the VTT, regressing from the renal vein back into the kidney, as this would allow curative 
surgery by laparoscopic rather than more morbid open surgical approaches. Patients with 
more extensive IVC VTT (infrahepatic, intrahepatic or atrial) will be included, as for patients 
in each of these groups reducing the extent of the thrombus i.e. from intrahepatic to 
infrahepatic would potentially reduce extent of surgery and the associated surgical morbidity. 
Both non-metastatic and metastatic patients will be eligible for recruitment as both groups of 
patients are likely to benefit, in terms of reduction of level of VTT and surgical morbidity, if 
axitinib shows efficacy in this patient cohort. It is accepted that there may be different 
biological processes at play in these 2 cohorts. However, this will be further explored in a 
fully powered phase 3 randomised control trial, if this phase 2 trial is positive.   
 
 
 
 
 
 
 


 
 
 
 
 
 
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2. TRIAL OBJECTIVES 
Aims: to assess the reduction in the Mayo Venous Tumour Thrombus Classification of 
patients with clear cell renal cell cancer who have a renal vein or inferior vena cava venous 
tumour thrombus treated with neoadjuvant (non-metastatic patients) or upfront (metastatic 
patients) axitinib therapy.  
 
Primary outcomes:  
 
The percentage of evaluable patients with an improvement in the Mayo 
Classification. 
 
Mayo Classification; 
 
Level 0: thrombus limited to the renal vein 
 
Level 1: into IVC <2cm from renal vein ostium level 
 
Level 2: IVC extension >2cm from renal vein ostium and below hepatic vein 
 
Level 3: thrombus at the level of or above the hepatic veins but below the diaphragm 
 
Level 4: thrombus extending above the diaphragm. 
 
Secondary outcomes:  
 
% change in surgical approach 
 
% change in VTT height 
 
Response rate (RECIST) 
 
Evaluation of surgical morbidity assessed by Clavian-Dindo classification 
 
 
3. TRIAL DESIGN 
3.1. General Design 
NAXIVA is a single arm, single agent, open label, phase II feasibility study of axitinib in 
patients with both metastatic and non-metastatic renal cell carcinoma of clear cell histology. 
20 patients will be recruited from multiple centres within the United Kingdom. 
 
Patients who have signed informed consent and who have met all eligibility criteria will be 
registered into the trial.  
 
The starting dose of axitinib will be 5mg BID and escalated to 7mg BID and then 10mg BID. 
A dose modification assessment will take place every 2 weeks in clinic during the 8 week 
pre-surgical treatment period and will be dependent on tolerability of treatment. Patients will 
follow an aggressive axitinib dose escalation process within the 8 week period to a maximum 
of 10mg BID. Patients should stop axitinib a minimum of 36 hours and a maximum of 7 days 
prior to surgery in week 9. 
 
Blood, urine and tissue samples will be taken prior to and during therapy to evaluate 
biomarkers of treatment response. Nephrectomy and IVC tumour thrombectomy will be 
planned for all patients on the trial. 
Response to axitinib in VTT, primary tumour and any RECIST measureable lesion will be 
correlated with changes in molecular markers. 
 
Patients will be followed up in clinic at 6 & 12 weeks post surgery.  
 
3.2. Inclusion Criteria 
1. 
Age ≥ 18. 
2.  
Histologically proven clear cell RCC. 
3. 
Immediate resection of the primary tumour considered technically possible. 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 12 of 66
 
 
 
4.  
Suitable for and willing to undergo nephrectomy (either cytoreductive or with curative 
intent) 
5. 
cT3b, cT3c, cT3a (main renal vein) 
6. 
N0, N1, or Nx 
7. 
M0, or M1  
8.         ECOG performance status 0 – 1 
9.     Urinalysis <2+ protein. If dipstick is ≥2+ then a 24-hour urine collection should be 
performed and the patient may enter NAXIVA only if urinary protein is <2g per 24 
hours. 
10.    All female patients with reproductive potential must have a negative serum or urine 
pregnancy test within a maximum of 14 days prior to starting trial treatment. 
 
3.3. Exclusion Criteria 
1. 
For M1 patients: poor risk on Memorial Sloan Kettering Cancer Centre (MSKCC) 
score and deemed suitable for cytoreductive nephrectomy at time of enrolment. 
2. 
The presence of active second malignancy. Patients will be eligible if they have 
adequately treated basal cell carcinoma, squamous cell skin cancer, in situ cervical 
cancer, stable prostate cancer or if treated with curative intent for any other cancer 
with no evidence of disease for 2 years. Patients with prostate cancer will be 
permitted entry if not receiving treatment and prostrate-specific antigen (PSA) is not 
rising. 
3. 
Women who are pregnant or are breastfeeding. Female patients must be surgically 
sterile, be postmenopausal, or must agree to use effective contraception during the 
period of therapy and up to 1 week after treatment.  
Male patients must be surgically sterile or must agree to use effective contraception 
during the period of therapy and for 6 months after completion of study drug (Patients 
who do not meet this will not be are not eligible).  
4. 
Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine 
or pulmonary disease other than directly related to RCC.  
5. 
Gastrointestinal abnormalities including: a. inability to take oral medication; b. 
requirement for intravenous alimentation; c. prior surgical procedures affecting 
absorption including total gastric resection; d. treatment for active peptic ulcer 
disease in the past 6 months; e. active gastrointestinal bleeding, unrelated to cancer, 
as evidenced by hematemesis, hematochezia or melena in the past 3 months without 
evidence of resolution documented by endoscopy or colonoscopy; f. malabsorption 
syndromes. 
6. 
Current use or anticipated need for treatment with drugs that are known potent 
CYP3A4 inhibitors (see section 4.4, concomitant therapy).  
7. 
Current use, or anticipated need for treatment with, drugs that are known CYP3A4 
inducers or substrates for CYP1A2 (see section 4.4, concomitant therapy).  
8. 
Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose 
anticoagulants for maintenance of patency of central venous access device or 
prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular 
weight heparin is allowed.  
9. 
Active seizure disorder, spinal cord compression, or carcinomatous meningitis.  
10. 
Any of the following within 12 months prior to study entry: myocardial infarction, 
uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive 
heart failure, cerebrovascular accident or transient ischemic attack.  
11. 
Uncontrolled hypertension (>160/100 mmHg despite optimised antihypertensive 
treatment). 
12. 
Known human immunodeficiency virus (HIV) or acquired immunodeficiency 
syndrome (AIDS)-related illness.  
13. 
ALT or AST ≥ 1.5 x ULN; Bilirubin ≥ 1.5 x ULN.  
14. 
Serum creatinine ≥ 1.5 x ULN 


 
 
 
 
 
 
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15. 
Neutrophil count < 1.0 x 109/L; platelet count < 100 x 109/L; Hb ≤ 90g/L. 
16. 
Known severe hepatic impairment (Child-Pugh class C) 
17. 
Known hypersensitivity to axitinib or any of its excipients. Specifically patients with 
hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose 
malabsorption should not enter the study. 
 
 
3.4. Endpoints 
Primary: 
 
The percentage of evaluable patients with an improvement in the Mayo 
Classification. 
 
Mayo Classification; 
 
Level 0: thrombus limited to the renal vein 
 
Level 1: into IVC <2cm from renal vein ostium level 
 
Level 2: IVC extension >2cm from renal vein ostium and below hepatic vein 
 
Level 3: thrombus at the level of or above the hepatic veins but below the diaphragm 
 
Level 4: thrombus extending above the diaphragm. 
 
Secondary: 
 
% change in surgical approach 
 
% change in VTT height 
 
Radiological response (RECIST) 
 
Evaluation of morbidity assessed by Clavian-Dindo classification 
 
Primary Safety Endpoints 
Thirteen patients will be recruited at first; if at least 1 patient has an improvement in the 
Mayo classification a further 7 patients would be recruited (to the final total of 20 patients 
who have received study drug), to receive study drug.  At least 3 patients showing 
reductions in Mayo score are required for a positive trial.  The early stopping rules are:  
(1) If a single M0 patient progresses to the point where surgery is no longer possible, 
then recruitment of new patients will be suspended following a review by the data 
monitoring committee (DMC). 
(2) If a single M0 patient becomes M1 recruitment of new patients will be suspended 
following a review by the DMC. 
(3) If in 3 patients the VTT extends but patients remain surgically resectable the trial will 
close. If the VTT has extended the patient will be expedited and operated on as soon 
as possible. 
 
Where there is diagnostic doubt at site, the week 3 MRI abdomen scans (and CT chest for 
M0 patients) a central review will be conducted to determine if a patient has progressed as 
per RECIST 1.1 criteria. In addition those particular patient cases will be discussed on an 
individual basis by the trial steering committee (TSC). 
The central review for final analysis will be conducted by radiologists based at 
Addenbrooke’s Hospital.  
 
 
4. TREATMENT 
4.1. Treatment Schedule 
Patients should start axitinib treatment on day 1, week 1 of the study and continue for 8 
weeks. 
Patients will be prescribed 1 pack (28 tablets) of 5mg BID at week 1. Patients will then be 
prescribed further axitinib every 2 weeks following the dose modification schedule detailed in 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 14 of 66
 
 
 
section 4.2 (depending on toxicities and blood pressure). Doses should be taken 
appropriately 12 hours apart and patients should be instructed to take their doses at 
approximately the same time each day with or without food as per instruction. On clinic days 
only, patients will be advised to fast for 6 hours prior to their clinic visit.  
Patients should be advised to stop axitinib treatment a minimum of 36 hours and maximum 
of 7 days prior to week 9 surgery and tissue collection. 
If a patient vomits or misses a dose, an additional dose should not be taken. The next 
prescribed dose should be taken at the usual time. If the patient reports having missed a 
dose or vomiting, this should be recorded in the source documents and case report forms 
(CRFs). 
 
4.2. Dose Modifications 
Dose Level 
Dose 
Dispensed As 
+2 
10mg BID 
2 x 5mg tablets BID (2 x 5mg packs) 
 
+1 
7mg BID 
1 x 5mg tablet BID + 2 x 1mg tablets 
BID (1x 5mg + 2 x 1mg packs) 
 
0 (starting dose) 
5mg BID 
1 x 5mg tablet BID (1 x 5mg pack) 
 
-1 
3mg BID 
3 x 1mg tablets BID (3 x 1mg packs) 
 
-2 
2mg BID 
2 x 1mg tablets BID (2 x 1mg packs) 
 
 
Dose Escalation 
Patients who tolerate axitinib with no adverse events related to study drug above CTCAE 
grade 2 for a consecutive 2 week period should follow the aggressive dose escalation 
schedule above and have their dose increased by one dose level to a maximum of 10 mg 
BID. The only exception to this would be if the patient’s blood pressure (BP) is >150/90 mm 
Hg or the patient is receiving antihypertensive medication. If the patient is receiving 
antihypertensive medication and a dose escalation is clinically indicated this should be 
considered by the onsite clinical team.  
 
Dose Interruption and Reduction 
Patients experiencing non-haematological drug reactions greater than CTCAE Grade 2 or 
haematological reactions greater than CTCAE Grade 3 should undergo dose modification. 
The current version of the Summary of Product Characteristics (SmPC) should be used to 
assess whether any adverse event is attributable to the drug.  
Axitinib should be stopped in the event of significant toxicity and restarted if appropriate 
when toxicities have resolved. If the patient has had an interruption of axitinib more than 2 
weeks, it must be discussed with the Chief Investigator (CI) before the patient restarts study 
drug.  
Patients permanently removed from treatment for intolerable toxicity should receive a post 
treatment CT scan assessed according to RECIST 1.1 criteria, and should revert to standard 
of care.  
 
The criteria for dose modification for axitinib related adverse events are summarised in the 
table below:  
 
Criteria for dose modification for axitinib- related adverse events (other than 
hypertension or proteinuria) 
 
Related Adverse Events 
Intervention 
Any grade: bleeding where medical 
Temporarily interrupt the axitinib dose. 


 
 
 
 
 
 
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intervention is required 
Any grade: posterior reversible 
encephalopathy syndrome (PRES) 
Patients with signs or symptoms should 
temporarily interrupt or permanently 
discontinue axitinib treatment. In case of 
severe or persistent arterial hypertension 
and symptoms suggestive of posterior 
reversible encephalopathy syndrome, a 
diagnostic brain magnetic resonance image 
(MRI) should be considered. If PRES is 
confirmed, the patient should permanently 
discontinue axitinib. 
Grade 1 
Continue at same dose level 
Grade 2 
Continue at same dose level 
Grade ≥3 non-haematologic treatment-
related toxicity or Grade 4 haematologic 
toxicity (other than those below) 
Interrupt dosing; re-start at one lower dose 
level as soon as improvement to CTCAE 
Grade≤2. If patient requires dose reduction 
below 2mg BID, contact SCTRU for 
discussion prior to implementation. 
Grade 4 lymphopaenia 
Continue at the same dose level at the 
discretion of the investigator. 
 
Axitinib dose reduction guidance for hypertension 
 
Degree of Blood Pressure Elevation 
Management 
Systolic Pressure 
 
Diastolic Pressure 
 
2 consecutive BP 
readings show systolic 
pressure >150 mmHg 
OR 2 BP readings 
separated by at least 
1 hour show diastolic 
pressure >90 mmHg 
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 consecutive BP 
readings show systolic 
pressure >160 mmHg 
OR 2 BP readings 
separated by at least 
1 hour show diastolic 
>100 mmHg 
Interrupt dosing *; adjust 
antihypertensive medication; as 
soon as BP is less than 150/90 
mmHg, restart axitinib at one lower 
dose level. 
Recurrent hypertension 
following previous dose 
reduction (2 
consectutive BP 
readings show systolic 
pressure >150 mmHg) 
OR Recurrent dBP>90 
mmHg (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, contact SCTRU for discussion. 
* If dose is interrupted, patients receiving antihypertensive medications should monitor 
closely for hypotension.  
 
Axitinib Dose reduction for Proteinuria   
 
If dipstick shows ≥2 proteinuria, perform 24 hour urine collection or urinary 
protein:creatinine ratio (PCR). Dosing may continue while waiting for test results.  
 
If < 2g proteinuria/24 hour or urinary PCR < 200mg/mmol is reported, continue 
dosing at the same dose level.  
 
If ≥ 2g proteinuria/24 hours or urinary PCR ≥ 200mg/mmol is reported, withhold dose 
and repeat 24 hour urine collection or urinary PCR (interval at investigator discretion) 
until proteinuria is < 2 g/24 hours or urinary PCR < 200mg/mmol. Restart axitinib at 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 16 of 66
 
 
 
the same dose or one lower dose level at discretion of the investigator. Monitor renal 
function in accordance with standard practice. 
 
Dose re-escalation  
Re-escalation back to the previous dose level is permitted in the absence of grade ≥3 
haematologic or grade ≥2 non-haematologic treatment-related toxicity in the previous 4 
weeks of treatment.  
 
Axitinib dose interruption for surgery or surgical procedures 
If major surgery or an interventional procedure (e.g. endoscopy) which is not part of NAXIVA 
study is required, treatment with axitinib must be interrupted a minimum of 36 hours and a 
maximum of 7 days before the procedure and the patient’s blood pressure should be 
monitored closely for hypotension. Patients may resume axitinib seven days after minor 
surgery and 2-3 weeks after major surgery, assuming the wounds have completely healed. 
The decision to resume axitinib therapy after surgery should be based on clinical judgment 
of adequate wound healing. 
 
4.3. Duration of Treatment 
Treatment with study drug should be discontinued if it is considered to be in the best interest 
of the patient. Reasons for treatment discontinuation include: 
 
Disease progression 
 
Occurrence of intolerable side effects 
 
Pregnancy 
 
Patient withdrawal of consent or non-compliance 
 
4.4. Concomitant Therapy 
Axitinib is metabolised primarily by liver enzymes, in particular CYP3A4. All medication 
considered necessary for the patients’ welfare and which is not expected to interfere with the 
evaluation of the study drug may be given at the discretion of the investigator. Concomitant 
medications must be recorded in the patients’ source documentation, as well as the 
appropriate pages of the CRF. 
 
Contraindicated concurrent medications include: 
Agents known to induce CYP3A4 or CYP1A2 
including but not limited to:  
Agents known to inhibit CYP1A2, CYP2C19 
or CYP3A4 including but not limited to: 
 
o Amobarbital,  
o Carbamazepine,  
o Dexamethasone,  
o Felbamate,  
o Nevirapine,  
o Omeprazole,  
o Phenobarbital,  
o Phenytoin,  
o Primidone,  
o Rifabutin,  
o Rifampicin,  
o St John’s wort  
o Amitriptyline  
o Amprenavir,  
o Artemisinin, 
o Atazanavir,  
o Atazanavir,  
o Cimetidine,  
o Ciprofloxacin,  
o Clarithromycin,  
o Delavirdine  
o Enoxacin, 
o Erythromycin,  
o Ethinyl,  
o Fluvoxamine, 
o Fosamprenavir  
o Grapefruit juice,  
o Imipramine  
o Indinavir,  


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 17 of 66
 
 
 
o Itraconazole,  
o Ketoconazole,  
o Lopinavir,  
o Mexiletine, 
o Miconazole,  
o Nelfinavir,  
o Ritonavir,  
o Saquinavir,  
o Tacrine,  
o Telithromycin,  
o Thiabendazole, 
o Ticlopidine.  
o Verapamil,  
o Zileuton 
 
 
Other approved or investigational systemic anticancer treatments, including 
chemotherapy, hormone therapy and immunotherapy. 
 
 
Other investigational drugs. 
 
The use of potent antacids such as proton pump inhibitors (except those listed above) and 
histamine H2 antagonists is permissible, if medically necessary. However, patients requiring 
chronic antacid therapy should avoid their use for 2 hours before and for 2 hours after taking 
axitinib tablets.  
 
The contraindicated medications detailed above may only be used in exceptional 
circumstances and following written confirmation from SCTRU of the CI’s approval. 
 
The current version of the SmPC should be used to assess whether any other concomitant 
medications are permissible. 
 
Other supportive medicines such as thyroid replacement therapy, anti-emetics and anti-
diarrhoeal medicines are permitted in accordance with local practice.  
 
4.5. Compliance with Treatment 
The study drug must not be used outside the context of the NAXIVA protocol. 
 
Patients must be asked to bring all their trial medication every time they attend the clinic for 
the purposes of treatment compliance assessment and drug accountability. Every effort 
should be made to encourage patients to return the unused medication and empty packs. 
The unused tablets should be collected by the investigator/study nurse and counted to 
ascertain patient compliance, medication will then be returned to pharmacy for drug 
accountability prior to destruction according to local practices. Drug accountability and 
destruction records should be maintained by the local pharmacy. 
 
4.6. Drug Supplies and Labelling 
Drug Supply 
Axitinib is supplied free of charge by Pfizer to Tayside Pharmaceuticals as 1mg and 5mg 
immediate release film-coated tablets and supplied in blister packs. Each 1mg and 5mg 
carton will contain 56 tablets (four blister sheets of 14 tablets per pack).  
 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 18 of 66
 
 
 
Tayside Pharmaceuticals will repack 2 intact blister sheets of 14 tablets each into a new 
carton along with the patient information leaflet (PIL) for each strength of axitinib. Each 
carton will then be labelled as per approved label. Release of the re-packaged drug will be 
carried out by a Qualified Person (QP) at Tayside Pharmaceuticals. IMP will then be 
dispatched to sites. The schedule of responsibilities for this arrangement is detailed in the 
contract between Tayside Pharmaceuticals and the sponsor. 
 
SCTRU will arrange for a supply of axitinib to be sent from Tayside Pharmaceuticals to the 
relevant pharmacy department following centre initiation. Local R&D approval and a study 
agreement must be in place before any drug can be shipped to sites.  
 
Sites will receive an initial supply of axitinib after completion of site initiation. Each site will 
receive; 2x 5mg pack as a starting dose and 3x 1mg packs of axitinib to cover any 
unexpected dose adjustments within the first 2 weeks of the patient schedule.  
SCTRU will closely monitor axitinib supply at sites however sites will be expected to notify 
SCTRU when stock is required as per the NAXIVA Pharmacy Manual. A trial specific order 
form will be included in the pharmacy pack. Sites must have a minimum of 1x 5mg pack and 
3x 1mg packs of axitinib in stock during the recruitment period. 
 
Labelling 
All study drug supplied by Pfizer will be re-packaged and labelled according to Annex 13 of 
the ‘Good Manufacturing Practice’. The drugs will be re-packaged, labelled, QP released 
and distributed by Tayside Pharmaceuticals to sites. 
 
4.7. Drug Storage Accountability 
Storage 
Axitinib should be stored in the original package in order to protect from moisture and should 
be stored at controlled room temperature (between 15°C and 30°C). The local pharmacy is 
responsible for ensuring that the study medication is stored in an appropriate secured area. 
Study treatment must be kept out of the reach and sight of children.  
 
Accountability 
The investigator or a delegated individual (e.g. pharmacist) must ensure that the study drug 
is stored and dispensed in accordance with hospital standard operating procedures and 
applicable regulatory requirements.    
 
The medication provided for this study is for clinical trial use only as directed. Drug 
distribution and accountability logs will be provided to the site in a pharmacy pack. It is the 
investigator’s responsibility to establish a system for handling the investigational product to 
ensure that: 
 
Deliveries of investigational products from Pfizer via Tayside Pharmaceuticals are 
correctly received by a responsible person (e.g. pharmacist or suitable pharmacy 
designee) and are handled and stored correctly and safely. 
 
Investigational products are dispensed only to study participants, and in accordance 
with the protocol. 
 
Participants return any unused investigational product and all empty packs to the 
investigator. 
 
A dispensing record (which will include the identification of the participant to whom 
the investigational product was dispensed, the date of dispensing, the quantity of 
investigational product dispensed, and the date and quantity of any unused 
investigational product returned to the pharmacy) is accurately maintained.  Any 
discrepancies must be accounted for on the appropriate form.   
 


 
 
 
 
 
 
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In the case that any study drug is damaged, please contact SCTRU for reconciliation and 
replacement. 
 
At the termination of the study or at the request of the sponsor, all unused drugs will be 
accounted for and destroyed locally at the study sites. Certificates of delivery and destruction 
or return must be signed and copies retained in the Investigator Site File. 
 
Accountability records must be completed and any study drug remaining at the end of the 
trial must be destroyed according to the sites local standard procedures. 
 
 
 
 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 20 of 66 
 
 
 
5. ASSESSMENT OF EFFICACY 
 
5.1. Treatment and Examination Schedule 
 
 
 
Activity 
Screening 
(Up to 4 weeks 
prior to 
enrolment) 
Pre-treatment 
Day 1, Week 1 
Week 3 
Week 5 
Week 7 
Week 9 
Week 9 (min 36 
hours after 
stopping 
axitinib) 
6 week post 
surgery follow 
up 
12 week post 
surgery follow 
up 
Confirmation of histological diagnosis of ccRCC via image guided biopsy (5 cores: 1 for 
diagnosis and 4 cores for research as per appendix 6) 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Physical examination including ECOG & Karnofsky performance status, body weight, height, 
temperature, blood pressure², heart rate, respiratory rate. 
X 
X¹ 
X 
X 
X 
X 
 
X 
X 
Haematology, coagulation, glucose, renal and liver function, serum calcium, CRP and LDH. 
X 
X¹ 
X 
X 
X 
X 
 
X 
X 
Urinalysis for protein 
X 
X¹ 
X 
X 
X 
X 
 
 
 
Serum Thyroid Function Tests (Free T4 and TSH) 
X 
X¹ 
X 
X 
X 
 
 
 
 
Pregnancy Test (serum or urine) if applicable  
X 
 
 
 
 
 
 
 
 
CT Chest, Abdomen and Pelvis for IVC VTT and primary tumour assessment using RECIST 1.1 
and Mayo classification 
X (all) 
 
 
 
 
X (M1 
only) 
 
 
X (all) 
CT Chest to check for development of metastasis 
 
 
X (M0 
only) 
 
 
X (M0 
only) 
 
 
 
Contrast enhanced MRI abdomen 
X 
 
X 
 
 
X 
 
 
 
Blood samples and urine sample for biomarker analysis 
 
X 
X 
X 
X 
X 
 
 
X 
Assessment of compliance with study medication 
 
 
X 
X 
X 
X 
 
 
 
Dispense axitinib 
 
X 
X 
X 
X 
 
 
 
 
Dose Escalation (5 to 7 to10mg BID) (depending on toxicities and blood pressure) ³ 
 
 
X 
X 
X 
 
 
 
 
Stop axitinib (minimum 36 hours, maximum 7 days prior to surgery) 
 
 
 
 
 
X 
 
 
 
Assessment of concomitant medications 
 
X 
X 
X 
X 
 
 
 
 
Assessment of symptoms (CTCAE V4) 
X 
X 
X 
X 
X 
X 
 
X 
X 
Nephrectomy and IVC tumour thrombectomy  
 
 
 
 
 
 
X 
 
 
¹ Laboratory and clinical assessments day 1 week 1 may be omitted if conducted within previous 7 days as part of screening assessment (apart from blood and urine for biomarker analysis).  
²Blood pressure readings are required at each time point and should be taken by a healthcare professional using an appropriate calibrated machine.  
³Aggressive increasing of axitinib dose at each to ensure effective dose reached in window period. 


 
 
 
 
 
 
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5.2. Schedule of Assessments 
5.2.1. Screening Procedures 
 
Screening procedures within 4 weeks prior to study enrolment. 
 
Clinical assessment 
o Signed informed consent 
o Medical history 
o ECOG & Karnofsky performance status (appendix 1) 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4)  
 
 
Histological assessment 
o Confirmation of diagnosis of ccRCC via image guided biopsy (5 cores should 
be taken for diagnosis/research as per the ‘translational research studies’ in 
appendix 6) 
 
 
Laboratory determinations 
o FBC, coagulation, glucose, renal and liver function, serum calcium, C - 
reactive protein (CRP) and Lactate Dehydrogenase (LDH). 
o Urinalysis 
o Serum thyroid function tests (Free T4 and Thyroid stimulating hormone 
(TSH)). 
o Pregnancy Test (serum or urine) if applicable (must be performed a maximum 
of 14 days prior to receiving 1st dose of axitinib) 
 
 
Radiological assessment  
o CT thorax, abdomen and pelvis for IVC VTT and primary tumour assessment 
using RECIST 1.1 criteria and the Mayo classification  
o Diffusion/ contrast enhanced MRI abdomen 
 
5.2.2. Study Enrolment  
 
The participant’s research nurse and/or doctor will screen the participant to ensure that they 
meet the trial eligibility criteria, after obtaining participant consent for any additional trial 
procedures. 
 
Patients will be enrolled centrally with the Scottish Clinical Trials Research Unit (SCTRU). An 
eligibility and enrolment checklist must be completed prior to enrolment. Enrolment should 
take place within 72 hours prior to the planned start date of axitinib. 
 
 
 
 
 
 
Once consent has been obtained and eligibility confirmed the participant should be 
enrolled by emailing the NAXIVA team at the Scottish Clinical Trials Research Unit: 
SCTRU enrolment email:  NSS.SCTRU@nhs.net    


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 22 of 66
 
 
 
Referring to the NAXIVA site instructions, the following information will be required at 
enrolment; 
 
 
Name of hospital, consultant and person enrolling the patient 
 
Confirmation that the patient has given written informed consent for trial participation 
and the provision of biological samples. 
 
Confirmation that the patient is eligible for the trial by completion of the eligibility 
checklist. 
 
Patients initials, date of birth, sex, NHS/CHI number and date of proven clear cell 
RCC (metastatic/ non-metastatic). 
 
Proposed start date of axitinib (must be within 72 hours of enrolment). 
 
The site will inform the participants General Practitioner (GP) of the participants enrolment, if 
the participant gives consent to do so. 
 
It may be possible for participants to be recruited into other clinical trials, but this should be 
discussed with the CI via SCTRU before this is considered. 
 
5.2.3. Pre-treatment Assessment day 1, week 1 (within 7 days) 
 
 
Laboratory determinations* 
o FBC, coagulation, glucose, renal and liver function, serum calcium, CRP and 
LDH 
o Urinalysis 
o Serum thyroid function tests (Free T4 and TSH) 
o Blood and urine samples for biomarker analysis (NB. patients should be 
asked to fast for 6 hours prior to urine analysis, and to not take axitinib until 
after their bloods have been sampled for the biomarker analyses) 
 
 
Clinical assessment* 
o ECOG & Karnofsky performance status (appendix 1) 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4) 
o Assessment for concomitant medications. 
 
*Laboratory and clinical assessments day 1 week 1 may be omitted if conducted within 
previous 7 days as part of screening assessment (apart from blood and urine for biomarker 
analysis).  
 
 
Radiological assessment  
o CT thorax, abdomen and pelvis for IVC VTT (all patients) and primary tumour 
assessment using RECIST 1.1 criteria and the Mayo classification (is not 
required if CT carried out at screening/diagnosis)  
Imaging to be acquired following intravenous contrast medium assuming no 
contraindications. Thin slice (at least 2mm) imaging will be acquired as an 
arterial phase in the throax and as a portal venous phase of the abdomen and 
pelvis. 


 
 
 
 
 
 
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o Diffusion/ contrast enhanced MRI abdomen (all patients), (is not required if 
contrast enhanced MRI carried out at screening/diagnosis) 
Thin slice (or volumetric imaging) will be acquired of the kidneys and adjacent 
IVC to include the tumour thrombus and proximal normal IVC to allow 
reconstruction of the VTT in axial and coronal planes. Sequences may 
include: 
 
T2-weighted imaging  
 
T1-weighted imaging with and without fat saturation 
Following intravenous contrast injection of a suitable gadolinium-based 
contrast agent as a dynamic acquisition 
 
Diffusion weighted imaging 
Non-contrast MR venography of the renal veins and IVC including the tumour 
thrombus and normal venous lumen adjacent to the thrombus 
The patient may be asked to undergo breathing strategies to enhance imaging 
(eg. breathhold, valsalva). 
 
 
Pharmacy 
o Dispense axitinib  
 
5.2.4. Assessment at day 1, week 3 (within 7 days) 
 
 
Laboratory determinations 
o FBC, coagulation, glucose, renal and liver function, serum calcium, CRP and 
LDH 
o Urinalysis 
o Serum thyroid function tests (Free T4 and TSH) 
o Blood and urine sample for biomarker analysis (NB. patients should be asked 
to fast for 6 hours prior to urine analysis) 
 
 
Clinical assessment 
o ECOG & Karnofsky performance status (appendix 1) 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4) 
o Assessment for concomitant medications 
o Assessment of compliance with study medication 
o Dose evaluation and escalation (where appropriate) 
 
 
Radiological assessment  
o CT chest for IVC VTT (M0 patients only) to check for development of 
metastasis 
o Diffusion/ contrast enhanced MRI abdomen (all patients) 
 
 
Pharmacy 
o Dispense axitinib (dose modification as per section 4.2 if applicable) 
 


 
 
 
 
 
 
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         5.2.5. Assessment at day 1, week 5 (within 7 days) 
 
 
Laboratory determinations 
o FBC, coagulation, glucose, renal and liver function, serum calcium, CRP and 
LDH 
o Urinalysis 
o Serum thyroid function tests (Free T4 and TSH) 
o Blood, urine sample for biomarker analysis (NB. patients should be asked to 
fast for 6 hours prior to urine analysis) 
 
 
Clinical assessment 
o ECOG & Karnofsky performance status (appendix 1) 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4) 
o Assessment for concomitant medications 
o Assessment of compliance with study medication 
o Dose evaluation and escalation (where appropriate) 
 
 
Pharmacy 
o Dispense Axitinib (dose modification as per section 4.2 if applicable) 
 
 5.2.6. Assessment at day 1, week 7 (within 7 days) 
 
 
Laboratory determinations 
o FBC, coagulation, glucose, renal and liver function, serum calcium, CRP and 
LDH 
o Urinalysis 
o Serum thyroid function tests (Free T4 and TSH) 
o Blood and urine sample for biomarker analysis (NB. patients should be asked 
to fast for 6 hours prior to urine analysis) 
 
 
Clinical assessment 
o ECOG & Karnofsky performance status (appendix 1) 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4) 
o Assessment for concomitant medications 
o Assessment of compliance with study medication 
o Dose evaluation and escalation (where appropriate) 
 
 
Pharmacy 
o Dispense axitinib (dose modification as per section 4.2 if applicable) 


 
 
 
 
 
 
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5.2.7. Assessment at day 1, week 9 (within 7 days) 
 
 
Laboratory determinations 
o FBC, coagulation, glucose, renal and liver function, serum calcium, CRP and 
LDH 
o Urinalysis 
o Blood and urine sample for biomarker analysis (NB. patients should be asked 
to fast for 6 hours prior to urine analysis) 
 
 
Clinical assessment 
o ECOG & Karnofsky performance status 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4) 
o Assessment of compliance with study medication 
 
 
Radiological assessment  
o CT thorax, abdomen and pelvis (M1 patients) for IVC VTT and primary tumour 
assessment using RECIST 1.1 criteria and the Mayo classification 
 
o CT chest (M0 patients) for IVC VTT to check for development of chest 
metastasis. 
 
o Diffusion/ contrast enhanced MRI abdomen (all patients) 
 
The patient should stop axitinib a minimum of 36 hours and a maximum 7 days prior to 
surgery; no further study drug should be dispensed. 
 
5.2.8. Surgery day 2-7, week 9 (+/- 7 days) 
 
 
Surgery 
o Nephrectomy and IVC tumour thrombectomy 
 
The surgeon should complete the surgery CRF on the day of surgery. 
 
5.2.9. Follow up assessment- 6 weeks post surgery (within 7 days) 
 
 
Laboratory determinations 
o FBC, coagulation, glucose, renal and liver function, serum calcium, CRP and 
LDH 
 
 
Clinical assessment 
o ECOG & Karnofsky performance status (appendix 1) 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 


 
 
 
 
 
 
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o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4) 
 
5.2.10. Follow up assessment- 12 weeks post surgery (within 7 days) 
 
 
Laboratory determinations 
o FBC, coagulation, glucose, renal and liver function, serum calcium, CRP and 
LDH 
o Blood and urine sample for biomarker analysis (NB. patients should be asked 
to fast for 6 hours prior to urine analysis) 
 
 
Clinical assessment 
o ECOG & Karnofsky performance status (appendix 1) 
o Body weight 
o Height 
o Blood pressure 
o Heart rate 
o Respiratory rate 
o Temperature 
o Symptom assessment (CTCAE V4) 
 
 
Radiological assessment  
o CT thorax, abdomen and pelvis (all patients) for restaging. 
 
5.2.11. Imaging 
 
 
All imaging data will be collated centrally. 
 
CT and RECIST assessment will be undertaken locally.  
 
MRI assessment will be undertaken at a single site to ensure consistency. 
 
Radiological endpoints 
 
Primary 
 
The VTT position in relation to the IVC for the Mayo classification will be performed 
using a combination of both MRI and CT.  
 
Secondary 
 
RECIST 1.1 criteria will be used for CT evaluation 
 
Exploratory 
 
The following exploratory endpoints may also be evaluated on MRI 
o VTT volume will be calculated using the thin slice MRI images reconstructed 
where appropriate. A small group of readers will undertake this and where 
possible automated segmentation will be used for consistency. 
o Change in the maximum VTT length using coronal MRI reconstructions 
o Apparent Diffusion Coefficient (DWI) changes over time of both the whole 
tumour and VTT. 
o Textural features of the whole tumour and VTT on MRI as a measure of 
heterogeneity, as well as changes in heterogeneity during treatment. This will 
be measured using semi-automated proprietary software where possible. 


 
 
 
 
 
 
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5.3. Withdrawal of Subjects 
Patients discontinue from the study for reasons such as safety, non-compliance or 
withdrawal of consent, etc.  These patients will continue to be followed up for efficacy and 
safety as per protocol, unless they are lost to follow up, deceased or withdrew consent to the 
study.  The bio-samples collected during the study will continue to be used for translational 
research. 
 
Patients may withdraw from the study at any point; no further data collection will take place, 
and will be censored at the point of withdrawal this should be indicated on the case report 
form (CRF) as per completion guidelines. 
 
Patients who consent to the trial but do not start trial treatment will be withdrawn from the 
trial. These patients will not be followed up as part of the study and will be expedited to 
surgery as per standard practice. 
For any patient that did not start study treatment, a further patient would be enrolled to the 
trial to maintain the target number of patients for analysis. 
 
6. Translational Research 
Tissue, blood and urine will be collected at baseline (all sample types), throughout the 8 
week treatment period (blood and urine) and at surgery (all sample types). A minimum 
requirement will be access to a formalin-fixed, paraffin-embedded tumour block (excess to 
diagnostic requirements) from the patient biopsy and nephrectomy. Where the institutional 
infrastructure exists the following samples will be collected: fresh frozen tissue (biopsy and 
nephrectomy), fresh tissue (biopsy and nephrectomy) plasma, buffy coat, urine, and 
peripheral blood mononuclear cells (PBMCs). The analysis streams will be as follows, with 
the aim of identifying molecular correlates to the clinical outcomes of this study.  
 
6.1. Circulating tumour DNA (ctDNA) 
In view intratumoural heterogeneity, the use of tumour tissue for the development of 
prognostic and predictive biomarkers in ccRCC is challenging (20). Circulating tumour DNA 
(ctDNA) has been established to represent the tumour biology and may be superior to tissue 
as heterogeneity will be negated (21). Obtaining ctDNA from blood from patients with VTT is 
the ideal platform on which to validate ctDNA in RCC because of the high likelihood of DNA 
shedding from the tumour directly into the circulation. Furthermore, the change in ctDNA 
profiles from baseline to treatment phase to post-treatment phase may be informative 
regarding markers of tumour response.  
 
6.2. Metabolomics 
It is well established that there is a strong metabolic basis to ccRCC. The presence of the 
Warburg effect has revealed several novel targets for treatment or tumour surveillance (22). 
Metabolites will be assayed in urine, blood and tissue across the various time points of the 
NAXIVA study to assess the use of these molecules in patients with VTT and with axitinib 
therapy.  
 
6.3. Predictive biomarker studies 
There has been previous identification of a prognostic biomarker signature for response to 
sunitinib. The same biomarker profile will be validated for axitinib using the matched biopsy 
and nephrectomy tumour tissue samples obtained in this study.  
 


 
 
 
 
 
 
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6.4. Comparative study of IVC VTT in untreated and treated patients  
Dovetailing in with ongoing studies looking at the invasive front of the IVC VTT in TKI naïve 
patients, the VTT samples from NAXIVA will be assessed using the same biomarker pipeline 
specifically searching for evidence in alterations in EMT or invasion profiles. The hypothesis 
being that treatment with axitinib abrogates some of the invasive features of the VTT.  
 
6.5. Imaging   
There is little published data on the best imaging method for assessing the IVC VTT. USS, 
CT and MRI are all currently used in different centres. Surgical outcome studies have shown 
that patients with solid VTT will have a superior oncological outcome compared to friable 
VTT, yet there are no radiological data on how to make this assessment. A non-invasive 
imaging biomarker of VTT composition would help to guide surgery in patients with 
borderline fitness. Textural analysis of the serial CT and MRI scans undertaken as part of 
NAXIVA will be performed and compared to the surgical outcome to assess if VTT 
composition and the effect of drug on VTT can be determined on imaging. Renal vein and 
IVC VTT volumes will be measured using MR venography techniques developed in 
Cambridge and % changes in post-contrast enhancement within the thrombus will be 
assessed from dynamic contrast-enhanced MRI (DCE-MRI) data. Exploratory analyses will 
include: changes in total tumour volume in the renal vein and IVC (CT and MRI); changes in 
the degree of enhancement after intravenous contrast administration (MRI); changes in 
imaging heterogeneity (texture) of the renal and IVC VTT (CT and MRI); differentiation of 
solid from friable IVC VTT using MR venography and physiological manoeuvres (Valsalva). 
 
6.6. Immune Analysis 
It is known that RCC is a typical immunogenic tumour with immune mechanisms known to 
play an important role in its natural history.  Recent studies have also shown that TKI 
treatment can influence the immune system and, importantly, changes in the immune 
response may affect response and survival.  The immune aim to identify immune- and 
cytokine-based signatures in PBMCs, plasma and urine which predict response to axitinib 
treatment in RCC patients.  These studies will also provide important information about the 
effect of axitinib on the immune system in RCC, and vice versa, including providing 
comprehensive analysis of how peripheral immune cell populations and cytokines vary 
during treatment with axitinib, and whether they correlate with other markers of response and 
resistance in RCC patients.  Importantly, it will also provide essential immunological 
information to inform biologically driven, rational, scheduling of future studies examining 
combinations of axitinib and immunotherapy. 
  
 
7. PHARMACOVIGILANCE 
 
7.1. Definitions 
Adverse Event (AE): An adverse event (AE) is any untoward medical occurrence in a 
patient which does not necessarily have a causal relationship with the study treatments or 
procedures. An adverse event can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with a treatment or procedure, whether or not considered related. 
Adverse Reaction (AR): All noxious and unintended responses related to a study 
treatment or procedure should be considered adverse drug reactions. 


 
 
 
 
 
 
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Serious Adverse Event (SAE): Any untoward medical occurrence in a patient that 
 
a) Results in death 
b) Is life-threatening 
c) Requires hospitalisation or prolongation of existing hospitalisation 
d) Results in persistent or significant disability or incapacity 
e) Consists of a congenital anomaly or birth defect 
f) Is otherwise considered to be medically significant by the investigator 
 
The term “life-threatening” refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe. 
 
Hospitalisations planned prior to enrolment in the trial or for social reasons should not 
normally be considered as SAEs unless the hospitalisation has to be prolonged.  
Treatment in an emergency room of less than 24 hours or on an out-patient basis that 
does not meet any other serious criteria should not be considered as an SAE. 
Hospitalisation for nephrectomy is not considered a SAE where this goes ahead as 
planned within the trial. Prolonged hospitalisation, however, should be reported as SAE. 
Suspected Unexpected Serious Adverse Reaction (SUSAR): A suspected unexpected 
serious adverse reaction (SUSAR) is an adverse reaction that is classified as serious and 
it is suspected that it is caused by a study treatment or procedure. The nature, severity or 
outcome of this adverse reaction also must not be consistent with the current version of 
the SmPC for the treatment or procedure.  
7.2. Recording of Adverse Events 
All related Adverse Reactions will be recorded in the Case Report Form. Any Adverse 
Reaction considered unrelated will not be recorded.  
All adverse reactions that occur after the signing of written informed consent and within 30 
days after the final study treatment will be recorded on the appropriate CRF page.  The 
exception to this would be any event occurring after signing the informed consent and prior to 
commencing study treatment that is considered unrelated to trial procedures.  In addition any 
events occurring more than 30 days after final study treatment that are deemed to be related 
to the study drug should be notified to SCTRU as detailed in section 7.4. 
 
Any medical conditions or diseases present prior to signing of informed consent should only 
be considered an adverse event if there is a worsening of the condition. 
 
Please refer to Appendix 2 for details on the Causality. 
 
7.3. Recording and Reporting of Serious Adverse Events 
Contact Details for Reporting SAEs 
 
SCTRU Fax:   
+44 131 275 7512 (preferred method) 
 
SCTRU Telephone:  +44 131 275 7276 (Mon – Fri 9am-4pm) 
                            Or:  +44 131 316 4278 (Mon – Fri 9am-4pm) 
 


 
 
 
 
 
 
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All serious adverse events that occur after the signing of written informed consent and within 
30 days after the final study treatment will be recorded on the SAE report form.  The 
exception to this would be any event occurring after signing the informed consent and prior to 
commencing study treatment that is considered unrelated to trial procedures.  In addition any 
events occurring more than 30 days after final study treatment that are deemed to be related 
to the study drug should be notified to SCTRU as above. 
 
The SAE report form must be signed by the Principal Investigator (PI) of the centre involved 
and faxed to SCTRU within 24 hours of first becoming aware of the event.  All initial SAE 
reports should contain the following minimum information: 
 
Reporter information 
 
At least one subject identifier (trial number/patient initials) 
 
Event term 
 
Assessment of relatedness 
 
Serious criteria 
 
A fax or email receipt will be sent to the relevant centre by SCTRU to acknowledge receipt of 
the SAE report form, and SCTRU will notify the CI. 
 
All SAEs will be forwarded to the CI by SCTRU for assessment of expectedness against the 
current SMPC.  Any SAE that is deemed to be both related and unexpected (i.e. a SUSAR) 
will be notified to the appropriate Competent Authorities and Research Ethics Committees 
within 7 days of becoming aware of the event for fatal or life threatening events and 15 days 
for all other serious events. 
SUSARs should be reported to the Research Ethics Committee (REC) accompanied by the 
‘safety reports to the REC covering form’.  The coordinator of the REC should acknowledge 
receipt of the safety report within 30 days by signing and returning a copy of the covering 
form. 
SCTRU will then notify the CI and the PI’s at all of the participating centres of the occurrence 
of all SUSARs. 
 
Hospitalisations planned prior to enrolment in the trial or for social reasons should not 
normally be considered as SAEs unless the hospitalisation has to be prolonged.  Treatment 
in an emergency room of less than 24 hours or on an out-patient basis that does not meet 
any other serious criteria should not be considered as an SAE. 
 
7.4. Developmental Safety Update Report 
An Annual Safety Report will be submitted to the appropriate Competent Authorities and 
Ethics Committees, once a year for the duration of the trial.  The time frame for the report 
starts with the date of first authorisation by a competent authority in an EU member state and 
the report should be submitted within 60 days of the anniversary of first authorisation. 
 
7.5. Pregnancies 
Any pregnancy in a trial participant or their partner that occurs during study participation 
should be reported to SCTRU within 24 hours of becoming aware of its occurrence, using the 
contact details in Section 7.3.  The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary abortion, details of birth and presence or absence of any 
birth defects, congenital abnormalities or maternal or newborn complications. Any birth 
defects or congenital abnormalities must be reported as SAEs.  
 


 
 
 
 
 
 
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8. DATA MANAGEMENT 
All data will be handled, computerised and stored in accordance with the Data Protection Act 
1998 and NHS National Services Scotland Confidentiality Guidelines. 
 
8.1. Data Collection 
Data generated will be collected by SCTRU. SCTRU will be responsible for checking the 
data, and validating it.  The data collected will include: 
 
initial clinical details at registration 
 
drug administration (CTIMPs) 
 
concomitant medications 
 
adverse events 
 
survival/ recurrence details 
 
surgical techniques 
 
tumour measurements 
 
vena cava thrombus measurement 
 
Dose escalation details 
 
8.2. Record Keeping and Archiving 
SCTRU will store study documentation until the end of patient follow up.  The documentation 
will then be archived according to current legislative requirements.  
 
 
9. STATISTICS 
9.1. Sample Size 
The aim is to recruit 20 patients over a 24 month period. A Simon two stage minimax design 
to distinguish a <5% from a >25% improvement in the Mayo classification requires 20 
patients (90% power, 10% 1-sided). Thirteen patients would be recruited at first stage; if at 
least 1 patient had an improvement in the Mayo classification a further 7 patients would be 
recruited (to the final total of 20 patients).    
 
9.2. Analysis Plan 
The main analysis will be conducted on the “as-treated” population. All patients who receive 
study drug will be included in the interim and final analysis. Any patient who withdraws from 
the study prior to receiving drug will not be included in the analysis. At least 3 patients 
showing a reduction in Mayo Classification would produce a positive trial. 
 
Interim Analysis  
An interim analysis will be performed after thirteen patients have been recruited. If no 
patients have show an improvement in their Mayo classification the trial will be stopped for 
futility. If at any point in the study 3 patients have a progression of their thrombus (increase in 
Mayo classification) but remain surgically resectable the trial will be stopped. (Probability of 
seeing 3 or more progressions if true progression rate <5% is <7.5%). There is no formal 
stopping rule for efficacy. 
 
The primary analysis will be made on the “treated” population, with patients being included in 
the analysis only if they have received at least one dose of the drug. In order to assess the 
impact of any biases an analysis of the “intention to treat” population will also be carried out. 


 
 
 
 
 
 
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This will include all patients who are registered as eligible for the trial, regardless of whether 
or not the subsequently received study medication. 
 
Final Analysis  
The final analysis will be performed once the end of study has been declared and will include 
summaries of the % of evaluable patient with improvement in the Mayo classification; % 
change in surgical approach; the response rates as determined by RECIST criteria V1.1 and 
an evaluation of morbidity utilising the Clavien-Dindo classification system. 
 
The dose of axitinib delivered will be summarised with the median and range of total dose 
being presented. Adverse events will be classified using CTCAE V4 and the worst grade for 
each toxicity will be summarised.  
 
9.3. End of Study 
This study will end when the below criteria are deemed complete by the sponsor; Last patient 
last visit (12 week post surgery follow up) complete and the database is clean and frozen for 
analysis. 
 
 
10. ACCESS TO SOURCE DATA/ DOCUMENTS 
The investigator, by accepting to participate to this protocol, agrees to co-operate fully with 
any quality assurance visit undertaken by third parties, including representatives from the 
Sponsor, SCTRU, national and/or foreign regulatory authorities or company supplying the 
product under investigation, as well as to allow direct access to documentation pertaining to 
the clinical trial (including CRFs, source documents, hospital patient charts and other study 
files) to these authorised individuals. 
 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control will be maintained through adherence to appendix 7, Good Clinical Practice 
(GCP) and the coordinating centre’s SOPs.  The coordinating centre will monitor receipt of 
CRFs and evaluate incoming CRFs for compliance with the protocol, inconsistencies and 
missing data. 
 
11.1. Monitoring Visits 
We have allowed for site visits in the UK to enable monitoring by SCTRU to check patient 
consent forms, confirm compliance with the protocol and complete source data verification 
(SDV) on the patient data as defined in the Data Monitoring Plan.  Higher levels of monitoring 
will be performed, if requested, by the Data Monitoring Committee, or if the investigators, the 
Trial Management group or Trial Steering Committee identify particular safety issues. 
 
11.2. Data Monitoring and Ethics Committee 
An independent Data Monitoring Committee (DMC) will be established and will meet 6 
monthly in the first instance and annually thereafter (and at any other time at the committee’s 
discretion). There will be an extra meeting of the committee after 13 patients have been 
recruited. None of the committee members will be involved in the trial. The committee will 
receive regular reports from SCTRU. It will submit its comments and recommendations to the 
Trial Steering Committee and Trial Management Group (TMG). 
 


 
 
 
 
 
 
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11.3. Trial Steering Committee 
A trial steering committee will be established to provide overall supervision of the trial, in 
particular; trial progress, adherence to protocol, patient safety, and consideration of new 
information. The committee will meet 3 monthly in the first instance and then 6 monthly 
thereafter. The committee will then meet 3 monthly during close out/ final analysis. 
 
 
12. ETHICAL CONSIDERATIONS 
Ethical approval by the East of England – Cambridge Committee will be required before the 
trial can be started. 
The trial will be carried out according to GCP guidelines as defined by paragraph 28 and 
Schedule 1 Part 2 of the Medicines for Human Use (Clinical Trials) Regulations, 2004, and 
the Clinical Trials Directive (2001/20/EC) elsewhere in the European Union and follow the 
principles of research governance. 
 
The use and storage of human tissue will be carried out in accordance with The Human 
Tissue Act (2004) and The Human Tissue (Scotland) Act (2006).  Human Tissues is defined 
as any material which has come from a human body that consists of, or includes human cells 
and includes blood and other bodily fluids. 
 
12.1. Patient Confidentiality 
The patient’s full name, date of birth, hospital number and NHS number (Community Health 
Index and/or hospital number in Scotland) will be collected to enable tracing through national 
records.  The personal data recorded on all records will be regarded as confidential, and to 
preserve each patient’s anonymity, only their initials and date of birth will be recorded on 
CRFs. The patients will be identified within the CRFs by the use of a unique trial number 
allocated to them upon entry into the study.  
The PI (or delegate) at each site must keep a log of patients’ trial numbers, names, 
addresses and hospital numbers.  The PI must ensure that patient confidentiality is 
maintained and that all trial documents (e.g. consent forms) are maintained in strict 
confidence. 
 
SCTRU will maintain the confidentiality of all patient data and will not reproduce or disclose 
any information by which patients could be identified.  Patients will only be referred to by Trial 
Number, Initials and Date of Birth in any essential trial related correspondence, including 
Case Report Forms and Serious Adverse Event Reports. 
 
All patient identifiable data will be handled, computerised and stored in accordance with the 
Data Protection Act 1998 and NHS National Services Scotland Confidentiality Guidelines. 
 
12.2. Informed Consent 
All patients will be informed of the aims of the study, the possible adverse events, the 
procedures and possible hazards to which they will be exposed, and the mechanism of 
treatment allocation.  They will be informed as to the strict confidentiality of their patient data, 
but that their medical records may be reviewed for trial purposes by authorized individuals 
other than their treating physician. It will be emphasized that the participation is voluntary and 
that the patient is allowed to refuse further participation in the protocol whenever they want.  
This will not prejudice the patient’s subsequent care.  
 


 
 
 
 
 
 
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Documented informed consent must be obtained for all patients included in the study before 
they are enrolled.  This must be done in accordance with the national and local regulatory 
requirements and must conform to guidelines on Good Clinical Practice.  That is, “the written 
informed consent form should be signed and personally dated by the patient or by the 
patient’s legally acceptable representative”.   
 
Copies of the patient information sheets and consent forms are provided in appendices 4 & 
5.  
 
All Patient Information Sheets & Informed Consent Forms will be version controlled and 
dated and this information will always be stated in any communication with ethics 
committees. 
 
 
13. RESEARCH GOVERNANCE 
 
Sponsor (CSA) – The sponsor will have overall responsibility for the design, co-ordination 
and management of the study. These include: 
 
 
Trial authorisation including responsibility for the protocol and obtaining approvals 
 
Ensuring that the trial is conducted according to GCP guidelines (22,23) 
 
Assessment of SAEs and providing a prompt response as to whether the SAE is a 
SUSAR. 
 
Clinical Trials Unit – The sponsor has delegated the responsibility for overall project 
management, data management and monitoring to Scottish Clinical Trials Research Unit, 
NHS National Services Scotland 
Responsibilities include: 
a. Assistance with completion of the IRAS form and REC communication 
b. Production of trial specific documentation (i.e. CRFs) 
c. Facilitating set up of trial centres 
d. Data management 
e. Monitoring 
f. Pharmacovigilance – Reporting of SARs / SUSARs 
 
Statistical Analysis – A Principal Information Analyst, based at SCTRU, Edinburgh will 
undertake the final analysis arising for this study. 
  
Local Project Teams – These will consist of Surgeons and/or Oncologists (responsible for 
introducing the patient to the study and ensuring eligibility and consent), Research Nurse 
(responsible for patient recruitment, obtaining consent and co-ordination of all aspects of 
data collection), Pathologists (responsible for tissue sample analysis), Radiologists and 
Radiographers (responsible for completing MRI and CT scans to protocol). Centres are 
specifically responsible for conducting the trial in accordance with the protocol, Standard 
Operating Procedures (SOPs), the trial agreement and Good Clinical Practice. 
 
Trial Steering Committee and Data Monitoring and Ethics Committee – The Common 
Services Agency (CSA) will act as study sponsor. Central study co-ordination, data 
collection, monitoring and organisation of the data for the statistical analyses will be 
undertaken by Scottish Clinical Trials Research Unit, NHS National Services Scotland, which 
has processes in place to ensure that the study will not open to recruitment until appropriate 


 
 
 
 
 
 
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approvals and authorisations have been obtained from the independent research ethics 
committee, and NHS Research and Development departments (R&D). The Trial Steering 
Committee (TSC), including members of the research team and an radiologist, oncologist, 
statistician, and lay members, will be responsible for the progress and conduct of the study 
and convene annually. A Trial Management Group will meet quarterly. A Data Monitoring and 
Ethics Committee (DMC) will convene 6 monthly, to review all data including adverse events 
and review the stopping policy for the trial, if necessary. Specific issues that will be looked at 
include: tolerability of initial dose, dose reductions, toxicities (including interaction of the mild 
increased bleeding risk), imaging & review schedules.  
 
Laboratories – Accredited local laboratories shall be used for all on-study tests.  Samples 
from the translational research will be transferred to a central laboratory based at the 
University of Cambridge. The details of the sampling, storage and shipping protocols are 
covered in appendix 6 and the NAXIVA laboratory manual in accordance with all prevailing 
regulatory requirements. 
 
 
14. FINANCING AND INSURANCE  
This study is funded by Pfizer Limited and endorsed by Cancer Research UK (CRUK). 
Indemnity for participating hospitals is provided by the usual NHS indemnity arrangements.  
 
 
15. PUBLICATION POLICY 
All presentations and publications relating to the trial must be authorized by the Trial 
Management Group.  The main trial results will be published in the name of the trial in a 
peer-reviewed journal, on behalf of all collaborators. The manuscript will be prepared by Trial 
Management Group, representatives from SCTRU, NHS National Services Scotland and 
high accruing clinicians. The trials offices and all participating Centers and clinicians will be 
acknowledged in this publication. Any data that might detrimentally affect the progress of the 
trial will not be released prior to the end of the trial. No investigator may present or attempt to 
publish data concerning their patients, which is directly relevant to the questions posed in the 
trial, until the main results have been published. 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 36 of 66
 
 
 
REFERENCE LIST 
 
1. Kirkali Z, Van Poppel H. A critical analysis of surgery for kidney cancer with vena cava 
invasion. Eur. Urol. 2007;52(3):658–662. 
 
2. Parra J et al. Oncological outcomes in patients undergoing radical nephrectomy and vena 
cava thrombectomy for renal cell carcinoma with venous extension: a single-centre 
experience. Eur. J. Surg. Oncol. J. Eur. Soc. Surg. Oncol. Br. Assoc. Surg. Oncol. 
2011;37(5):422–428. 
 
3. Lambert EH et al. Prognostic risk stratification and clinical outcomes in patients 
undergoing surgical treatment for renal cell carcinoma with vascular tumor thrombus. Urology 
2007;69(6):1054–1058. 
 
4. Rini, B.I., et al., Axitinib versus sorafenib as second-line therapy for metastatic renal-cell 
carcinoma (mRCC): Results of phase III AXIS trial, in American Society of Clinical Oncology. 
2011, Journal of Clinical Oncology: Chicago, USA. p. Abstr 4503. 
 
5. Schiller, J.H., et al., Efficacy and safety of axitinib in patients with advanced non-small-cell 
lung cancer: results from a phase II study. J Clin Oncol, 2009. 27(23): p. 3836-41. 
 
6. Cohen, E.E., et al., Axitinib is an active treatment for all histologic subtypes of advanced 
thyroid cancer: results from a phase II study. J Clin Oncol, 2008. 26(29): p. 4708-13. 
 
7. Kindler, H.L., et al., Axitinib plus gemcitabine versus placebo plus gemcitabine in patients 
with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. 
Lancet Oncol, 2011. 12(3): p. 256-62. 
 
8. Fruehauf, J., et al., Multicenter, phase II study of axitinib, a selective second-generation 
inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with 
metastatic melanoma. Clin Cancer Res, 2011. 17(23): p. 7462-9. 
 
9. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
 
10. Rugo, H.S., et al., Phase I trial of the oral antiangiogenesis agent AG-013736 in patients 
with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol, 2005. 23(24): 
p. 5474-83. 
 
11. Mukohara, T., et al., Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating 
hormone, and biomarkers: a phase I study in Japanese patients. Cancer Sci, 2010. 101(4): 
p. 963-8. 
 
12. Rixe, O., et al., Axitinib treatment in patients with cytokine-refractory metastatic renal-cell 
cancer: a phase II study. Lancet Oncol, 2007. 8(11): p. 975-84. 
 
13. Rini, B.I., et al., Phase II Study of Axitinib in Sorafenib-Refractory Metastatic Renal Cell 
Carcinoma. Journal of Clinical Oncology, 2009. 27(27): p. 4462-4468. 
 
14. NCICTCAE. NCI Common Terminology Criteria for Adverse Events (CTCAE) v.4 data 
files 2010; Available from: http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 37 of 66
 
 
 
 
15. Cost NG et al. The impact of targeted molecular therapies on the level of renal cell 
carcinoma vena caval tumor thrombus. Eur. Urol. 2011;59(6):912–918. 
 
16. Bigot P et al. Neoadjuvant targeted molecular therapies in patients undergoing 
nephrectomy and inferior vena cava thrombectomy: is it useful? World J. Urol. 
2014;32(1):109–114. 
 
17. Karam JA et al. Phase 2 Trial of Neoadjuvant Axitinib in Patients with Locally Advanced 
Nonmetastatic Clear Cell Renal Cell Carcinoma. Eur. Urol. 2014;66(5):874-880  
 
18. Bex A, Clarke N. Targeted caval cytoreduction: solid foundations or shifting sands? Eur. 
Urol. 2011;59(6):919–920; discussion 921–922. 
 
19. Blute, M.L., et al., The Mayo Clinic experience with surgical management, complications 
and outcome for patients with renal cell carcinoma and venous tumour thrombus. BJU Int. 
2004;94(1):33-41 
 
20. Stewart G et al. Sunitinib Treatment Exacerbates Intratumoral Heterogeneity in 
Metastatic Renal Cancer. Clin Cancer Res. 2015;21(18):4212-4223 
 
21. Murtaza M et al. Non-invasive analysis of acquired resistance to cancer therapy by 
sequencing of plasma DNA. Nature 2013;497(7447):108–112. 
 
22. Srinivasan R, Ricketts CJ, Sourbier C, Linehan WM. New Strategies in Renal Cell 
Carcinoma: Targeting the Genetic and Metabolic Basis of Disease. Clin Cancer Res. 
2015;21(1):10–17. 
 
23. Frezza C et al. Haem oxygenase is synthetically lethal with the tumour suppressor 
fumarate hydratase. Nature 2011;477(7363):225–228. 
 
 
 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 38 of 66
 
 
 
Appendix 1 – ECOG and Karnofsky Performance Scores  
 
 
 
 
 
Karnofsky Status 
Karnofsky 
Score 
 
ECOG 
Grade 
ECOG Status 
Normal, no complaints. 
100 
0 
Fully active, able to carry on all pre-
disease performance without 
restriction. 
Able to carry on normal 
activities. Minor signs or 
symptoms of disease. 
90 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or 
sedentary nature, e.g., light house 
work, office work. 
Normal activity with effort. 
80 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or 
sedentary nature, e.g., light house 
work, office work. 
Care for self. Unable to carry 
on normal activity or to do 
active work. 
70 
2 
Ambulatory and capable of all self 
care but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
Requires occasional 
assistance, but able to care 
for most of his needs. 
60 
2 
Ambulatory and capable of all self 
care but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
Requires considerable 
assistance and frequent 
medical care. 
50 
3 
Capable of only limited self care, 
confined to bed or chair more than 
50% of waking hours. 
Disabled. Requires special 
care and assistance. 
40 
3 
Capable of only limited self care, 
confined to bed or chair more than 
50% of waking hours. 
Severely disabled. 
Hospitalisation indicated 
though death nonimminent. 
30 
4 
Completely disabled. Cannot carry 
on any self care. Totally confined to 
bed or chair. 
Very sick. Hospitalisation 
necessary. Active supportive 
treatment necessary. 
20 
4 
Completely disabled. Cannot carry 
on any self care. Totally confined to 
bed or chair. 
Moribund. 
10 
4 
Completely disabled. Cannot carry 
on any self care. Totally confined to 
bed or chair. 
Dead. 
0 
5 
Dead. 
 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 39 of 66
 
 
 
 
Appendix 2 – Causality 
 
The assignment of causality should be made by the investigator responsible for the care of 
the patient, using the definitions in the table below. 
If any doubt about the causality exists the investigator should inform the Trials Centre who 
will notify the Chief Investigator.   
In the case of discrepant views on causality between the investigator and others, the case 
will be discussed by all parties.  In the event that no agreement is made, the MHRA will be 
informed of both points of view.  
 
Description of causality of adverse events 
 
 
 
 
Possibly Related: 
No 
 
Unrelated 
There is no evidence of any causal 
relationship. 
 
 
 
 
Unlikely 
There is little evidence to suggest there is a 
causal relationship (e.g. the event did not 
occur within a reasonable time after 
administration of the trial medication).  There 
is another reasonable explanation for the 
event (e.g. the patient’s clinical condition, 
other concomitant treatment). 
 
 
 
 
 
 
 
 
 
Possibly Related: 
Yes 
 
 
 
 
Possible 
There is some evidence to suggest a causal 
relationship (e.g. because the event occurs 
within a reasonable time after administration 
of the trial medication).  However, the 
influence of other factors may have 
contributed to the event (e.g. the patient’s 
clinical condition, other concomitant 
treatments). 
 
 
Probable 
There is evidence to suggest a causal 
relationship and the influence of other factors 
is unlikely. 
 
 
Definitely 
There is clear evidence to suggest a causal 
relationship and other possible contributing 
factors can be ruled out. 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 40 of 66
 
 
 
 
Appendix 3a – Investigator Statement (SCTRU Copy) 
 
 
NAXIVA 
 
 
 
PHASE II NEOADJUVANT STUDY OF AXITINIB FOR REDUCING EXTENT OF 
VENOUS TUMOUR THROMBUS IN CLEAR CELL RENAL CELL CANCER WITH 
VENOUS INVASION (NAXIVA) 
 
 
 
Principal Investigator Declaration 
 
 
 
I acknowledge receipt of version 1.2 dated 22nd September 2017 of 
the NAXIVA trial protocol (REC approved17th October 2017) and I 
agree to perform this trial in accordance with this version of the 
protocol and Good Clinical Practice. 
 
I understand that the safety of the patient is my first concern 
 
 
 
Print Name:  
-------------------------------------------------------- 
Hospital: 
 
-------------------------------------------------------- 
Signed: 
 
-------------------------------------------------------- 
Date:  
 
-------------------------------------------------------- 
 
 
 
Please return this copy to: NAXIVA Trial Coordinator 
Scottish Clinical Trials Research Unit, 
Gyle Square, 
1 South Gyle Crescent, 
Edinburgh, 
EH12 9EB 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 41 of 66
 
 
 
  
Appendix 3b – Investigator Statement (Investigator Copy) 
 
 
NAXIVA 
 
PHASE II NEOADJUVANT STUDY OF AXITINIB FOR REDUCING EXTENT OF 
VENOUS TUMOUR THROMBUS IN CLEAR CELL RENAL CELL CANCER WITH 
VENOUS INVASION (NAXIVA) 
 
 
 
 
Principal Investigator Declaration 
 
 
 
 
I acknowledge receipt of version 1.2 dated 22nd September 2017 of 
the NAXIVA trial protocol (REC approved 17th October 2017) I agree 
to perform this trial in accordance with this version of the protocol and 
Good Clinical Practice. 
 
I understand that the safety of the patient is my first concern 
 
 
 
Print Name:  
-------------------------------------------------------- 
Hospital: 
 
-------------------------------------------------------- 
Signed: 
 
-------------------------------------------------------- 
Date:  
 
-------------------------------------------------------- 
 
 
 
 
 
 
 
Please retain this copy and file in Investigator Site File. 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 42 of 66
 
 
 
Appendix 4 – Main Study Patient Information Sheet and Informed Consent 
 
[To be printed on hopsital headed paper] 
 
PATIENT INFORMATION SHEET- Main Study 
 
‘NAXIVA’ 
 
Phase II neoadjuvant study of axitinib for reducing extent of venous tumour thrombus 
in clear cell renal cell cancer with venous invasion 
 
EudraCT No: 2017-000619-17 
 
 
 
 
 
ISRCTN96273644 
IRAS ID: 223309 
 
PIS Version: 1.2 
Version Date: 22nd September 2017 
 
 
 
Invitation Paragraph 
You are being invited to take part in a research study.  Before you decide if you want to take 
part it is important for you to understand why the research is being done, how your 
information will be used, what the study will involve and the possible benefits, risks and 
discomforts.  Please take time to read the following information carefully and discuss it with 
your relatives, friends or GP if you wish.   
 
Please ask if there is anything that is not clear or if you would like further information. 
 
Main Components of Study 
 
1. 
What is the purpose of the study? 
 
We want to see if combining standard surgical treatment with a type of drug called a tyrosine 
kinase inhibitor can stop the growth of the tumour in patients with the type of cancer that you 
have. Tyrosine kinase inhibitors are a type of drug that act by blocking certain proteins called 
tyrosine kinases. These proteins tell the cancer cells to grow. Previous studies have 
suggested that tyrosine kinase inhibitors may slow or stop the growth and in some cases 
may reduce the size of the tumour.  
 
In the NAXIVA study, axitinib is the tyrosine kinase inhibitor, which is being tested. The drug 
is already used after surgery for some patients who have metastatic disease. We want to 
see if giving the drug before surgery (neoadjuvant) would be effective in preventing cancer 
cells from growing or causing them to shrink. If this happens it may mean that patients need 
less extensive surgery.   
 
2. 
Why have I been invited to take part? 
 
You have been invited to take part in this study because you have kidney cancer that may 
be suitable for treatment with a type of drug called tyrosine kinase inhibitor before your 
surgery.  Approximately 20 other kidney cancer patients like you will be asked to take part in 
the study, in up to 7 hospitals across the UK. 
 
 
 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 43 of 66
 
 
 
3. 
 Do I have to take part? 
 
No, it is up to you to decide whether or not to take part.  If you do choose to take part, you 
will be asked to sign an informed consent form and you will be given a copy to keep together 
with this information sheet.  For your safety your GP will be informed of your participation in 
this study.   
 
If you do not wish to take part in the study, you do not have to give a reason. You will not be 
disadvantaged in any way, and it will not affect the standard of care you receive.  This also 
applies if you initially decide to take part and then change your mind at a later date.  Your 
doctor will discuss your treatment options at that time: you do not need to take part in the 
study to be offered the standard treatment, which is surgery within 4-6 weeks without a 
tyrosine kinase inhibitor. 
 
4. 
What will happen to me if I decide to take part? 
 
Before you are entered onto the NAXIVA study you will have a biopsy taken of your kidney 
cancer along with a series of scans, tests and examinations to confirm that you are eligible 
to take part in the study. This will be done approximately 1 to 4 weeks before you start taking 
any study medication.  
 
When it’s confirmed that you are eligible to take part in the trial you will be seen and 
examined in clinic before being given your first prescription of axitinib tablets to take at home 
twice a day. You will be prescribed axitinib at each clinic visit before surgery. After this, you 
will be seen and examined in clinic weeks 3, 5, 7 and 9 prior to surgery. You will then be 
followed up at clinic 6 and 12 weeks after surgery. 
 
At each visit you will have routine blood samples of approximately 40ml (3 tablespoons) 
taken. You will also have your blood pressure checked and be asked to provide a urine 
sample for dipstick testing.  
At each visit, you will be asked about your health and any other medications you are taking. 
You will also be asked about any side effects or problems you may be having with the study 
medication. 
 
At the beginning of the study CT and MRI scans will be performed.  Following this, you will 
be assessed to see how the kidney cancer is responding to the study drug. This will be done 
by subsequent CT/MRI scans at weeks 3 & 9 prior to surgery.  If your cancer has not spread 
to other parts of the body (non-metastatic or M0), you will have a CT scan in week 3. If your 
cancer has already spread to other parts of your body (metastatic or M1) you will not need 
this scan. These scans will give your study doctor clearer pictures of the inside of your body.  
It is very likely that you will have had this type of scan already. 
 
You will stop the axitinib a minimum of 36 hours and a maximum of 7 days prior to surgery.  
Surgery will be performed at week 9.   
 
After you have completed treatment and surgery, you will be asked to return to clinic for a 
follow up visit, 6 & 12 weeks after surgery. This is so that your doctor can continue to check 
on your progress. At the follow up visit you will be asked about your health and about any 
new treatments you may be receiving. At your final study visit (12 weeks post surgery) you 
will have a further blood and urine test. 
 
At each visit, you will discuss your progress with your doctor alongside any scan results. 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 44 of 66
 
 
 
By consenting to NAXIVA you will be expected to attend 2 additional clinic visits compared 
with standard care; this is so the research staff can monitor your progress on the trial 
closely. Please find an overview of the trial visits in table 1. 
 
Table 1-Trial Visit Schedule 
 
 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5  
Visit 6 
Visit 7 
Visit 8 
 
1-4 weeks 
prior to 
study 
enrolment 
Week 1 Week 3 
Week 5 Week 7 Week 9 Week 9 6 
weeks 
post 
surgery 
12 
weeks 
post 
surgery 
Confirm eligibility  
X 
 
 
 
 
 
 
 
 
Examined in clinic 
X 
X 
X 
X 
X 
X 
 
X 
X 
Blood & Urine 
samples 
 
X 
X 
X 
X 
X 
 
 
X 
MRI scan 
X 
 
X 
 
 
X 
 
 
 
CT scan 
X 
 
X 
(M0 only) 
 
 
 
X 
 
 
X 
Axitinib 
Prescription 
 
X 
X 
X 
X 
 
 
 
 
Stop axitinib (min 
36 hours) prior to 
surgery 
 
 
 
 
 
X 
 
 
 
Surgery 
 
 
 
 
 
 
X 
 
 
 
5. 
What will I be asked to do? 
 
You will need to continue taking the daily tablets that are prescribed for you and to attend 
clinic visits at the time intervals as already mentioned.  
 
At each visit you will also be asked to return any medicine boxes you have (even if they are 
empty) and unused tablets to the hospital. 
 
Prior to each visit you will be asked to fast for 6 hours. This is to make sure that your tests 
can be interpreted correctly by your doctor.   
 
At each visit you will be asked to provide a urine sample for dipstick analysis. 
 
6. 
How long will I be on treatment for? 
 
Your course of axitinib will continue for 8 weeks until surgery. You will stop study treatment 
at a minimum of 36 hours and a maximum of 7 days prior to surgery. 
 
7. 
What other medicines or treatments could I have instead? 
 
Your doctor will discuss any alternative available treatments with you depending on what is 
best for you.  One option will likely be the current established treatment of urgent surgical 
removal. 
 
 
 
 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 45 of 66
 
 
 
8. 
Can I continue taking axitinib after the trial has ended? 
 
You will take your final axitinib before your surgery. After your surgery, your local hospital 
team will decide on the appropriate follow up treatment. Only patients whose cancer has 
already spread to other places may be offered another type of Tyrosine Kinase Inhibitor. 
 
 
9. 
What are the possible disadvantages and risks of taking part? 
 
One disadvantage is that you may be required to attend clinic more often than people who 
are not in the study. This is because the research staff may want to see you more often to 
check on your progress.  
 
You may also have to have additional blood and urine tests and also scans that you would 
not have if you were not on the study. Because you are in a clinical trial, we want all patients 
to have these tests/scans at the same time points.  
 
By taking part in the NAXIVA trial you will have an additional MRI scan and if your cancer 
has not spread you will also have an additional CT scan compared to if you were not taking 
part in NAXIVA. For both MRI and CT scans, you will receive an additional injection of a 
contrast agent. There is a small risk of side-effects from these contrast agents such as 
experiencing flu-like symptoms, a rash or difficulty breathing but, again, this risk is unlikely to 
be significant. These side effects occur in 2-3 people per 100 and the risk of experiencing a 
severe reaction occurs in 1 in 1000 people or fewer.  
 
Having an additional CT scan carries a risk of exposure to radiation; the lifetime risk of 
developing cancer from this radiation is approximately 1 in 1400. This small risk should be 
balanced against the normal lifetime risk of cancer which is approximately 1 in 3.  
There is no additional risk of exposure to radiation by having an additional MRI scan. 
 
Another disadvantage is of course that you may experience side effects from the medicines 
you will be taking (see section 11). 
 
10. 
What are the possible benefits of taking part?  
 
If you do wish to participate in this study we cannot be sure that there will be a direct benefit 
for you. Surgery for removing kidney cancer that has spread into the renal vein and/or 
inferior vena cava is major surgery with a risk of complications.  
 
Our hope is that axitinib will stop your cancer from growing which will improve surgical 
results by enabling your surgery to be a less extensive operation. This may mean a smaller 
incision and a less invasive operation on the inside of your abdomen. If this is the case, we 
hope for fewer complications (such as less blood loss and less chance of requiring a blood 
transfusion), a shorter hospital stay and faster recovery time at home. 
 
We also hope this research will teach us more about the type of cancer that you have and 
how it can be treated. This may enable us to improve the standard of treatment to help other 
patients with cancer in the future. 
 
11. 
What are the possible side effects of the medicines 
 
The study medication may cause some side effects. No one can predict whether you will 
have some, all or none of these, or how severe they may be.  It is important that you tell your 
study doctor or research nurse about any problems you have at each hospital visit. You can 


 
 
 
 
 
 
N A XI V A  
V er si o n 1. 2, 2 2 n d  S e pt e m b er 2 0 1 7                                                                     P a g e 4 6  of 6 6
 
 
 
t el e p h o n e eit h er  of  t h e m b et w e e n  vi sit s  if y o u  ar e  c o n c er n e d  a n d  y o u  will  fi n d t h eir t el e p h o n e 
n u m b er s  pri nt e d  at  t h e e n d  of  t hi s i nf or m ati o n s h e et.   
 
V er y  C o m m o n  si d e  eff e ct s  of  a xiti ni b   
( M or e  t h a n 1 0  i n 1 0 0  p e o pl e  h a v e  o n e  or  m or e  of  t h e s e si d e  eff e ct s)  
 
 Fl u -li k e s y m pt o m s  ( H e a d a c h e s, F ati g u e,  J oi nt   a n d  M u s cl e  p ai n)  
 L o s s  of  a p p etit e,  w ei g ht  l o s s 
 N a u s e a,  V o miti n g  a n d  Di arr h o e a  
 A  dr o p  i n t h e l e v el of  t h yr oi d h or m o n e s  ( h y p ot h yr oi di s m).  
 A  s or e  m o ut h , t o n g u e or  t hr o at 
 R ai s e d  bl o o d  pr e s s ur e  ( h y p ert e n si o n)   
 A n  i n cr e a s e d ri s k of  bl e e di n g,  i n cl u di n g n o s e bl e e d s  a n d  bl e e di n g  g u m s   
 S h ort n e s s  of  br e at h  a n d  a  c o u g h  
 T u m m y  ( a b d o mi n al) p ai n  
 C o n sti p ati o n  
 I n di g e sti o n  
 T a st e  c h a n g e s  or  l o s s of  t a st e 
 Pr ot ei n uri a  ( pr ot ei n i n t h e uri n e)  
 H a n d -f o ot s y n dr o m e  ( a s ki n  r e a cti o n o n  y o ur  h a n d s/f e et  w hi c h  m a y  c a u s e  p ai n,  s w elli n g,  
r e d n e s s, p e eli n g  s ki n,  bli st er s,  ti n gli n g or  n u m b n e s s  of  t h e h a n d s/f e et).  
 
C o m m o n  si d e  eff e ct s  of  a xiti ni b  
(B et w e e n  1  a n d  1 0  i n e v er y  1 0 0  p e o pl e  h a v e  o n e  or  m or e  of  t h e s e eff e ct s)  
 
 
Tir e d n e s s  a n d  br e at hl e s s n e s s  d u e  t o a  dr o p  i n r e d bl o o d  c ell s  ( a n a e mi a) 
 
A n o v er a cti v e t h yr oi d gl a n d ( H y p ert h yr oi di s m)  
 
D e h y dr ati o n  
 
S ki n  c h a n g e s  (r a s h or  r e d, dr y,  it c h y s ki n)  
 
H air  T hi n ni n g  ( Al o p e ci a) 
 
Di z zi n e s s  
 
Ri n gi n g  i n t h e e ar s  (ti n nit u s)  
 
L o w  l e v el s of  pl at el et s  i n t h e bl o o d  –  y o u  m a y  h a v e  n o s e bl e e d s,  or  bl e e di n g  g u m s  
aft er  br u s hi n g  y o ur  t e et h, or  y o u  m a y  h a v e  l ot s of  ti n y r e d s p ot s  or  br ui s e s  o n  y o ur  
ar m s  or  l e g s ( k n o w n a s  p et e c hi a e).  
 
Hi g h  l e v el s of  pl at el et s  l e a di n g t o bl o o d  cl ot s.  If it h a p p e n s  t o y o u,  y o u  will  h a v e  
tr e at m e nt t o t hi n y o ur  bl o o d,  di s s ol v e  a n y  cl ot s,  a n d  st o p  a n y  m or e  d e v el o pi n g.  
 
Mil d  eff e ct s  o n  t h e li v er a n d  ki d n e y s,  w hi c h  ar e  u nli k el y  t o c a u s e  a n y  s y m pt o m s  a n d  
will  u s u all y  g o  b a c k  t o n or m al  aft er  t h e tr e at m e nt e n d s.  Y o u  will  h a v e  r e g ul ar bl o o d  
t e st s t o c h e c k  h o w  y o ur  li v er a n d  ki d n e y s  ar e  w or ki n g.  
 
U n c o m m o n  si d e  eff e ct s  of  a xiti ni b  
(F e w er  t h a n 1  i n 1 0 0  p e o pl e  h a v e  t h e s e) 
 
A n i n cr e a s e d ri s k of g etti n g a n i nf e cti o n fr o m a dr o p i n 
w hit e bl o o d c ell s  
( N e utr o p e ni a) 
 
R e v er si bl e P o st eri or E n c e p h al o p at h y S y n dr o m e ( a r ar e br ai n di s or d er w hi c h m a y 
c a u s e hi g h bl o o d pr e s s ur e, h e a d a c h e, s ei z ur e s, vi si o n pr o bl e m s or bli n d n e s s, 
di z zi n e s s a n d c o nf u si o n).  It m a y b e r e v er si bl e if r e c o g ni s e d a n d tr e at e d pr o m ptl y.  If 
y o u d e v el o p a n y of t h e s e s y m pt o m s, y o u s h o ul d c o nt a ct y o ur d o ct or or ot h er 
h e alt h c ar e pr of e s si o n al i m m e di at el y.  
 
A s plit i n t h e w all of t h e b o w el ( b o w el p erf or ati o n) i s v er y r ar e b ut i s a s eri o u s si d e 
eff e ct if it h a p p e n s.  


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 47 of 66
 
 
 
 
12. 
What should I avoid whilst taking part in the study? 
 
The following should be avoided whilst taking axitinib as they may increase the chance of 
side effects;  
o 
Do not consume grapefruit or grapefruit juice 
o 
Do not take the following medications; 
- 
Ketoconazole & Itraconazole (used to treat fungal infections). 
- 
Clarithromycin, Erythromycin or Telithromycin (used to treat bacterial 
infections). 
- 
Atazanavir, Indinavir, Nelfinavir, Ritonavir or Saquinavir (used to treat HIV 
infections). 
- 
Nefazodone (used to treat depression). 
 
The following should be avoided whilst taking axitinib as they may reduce the effectiveness 
of axitinib; 
o 
Do not take the following medications; 
- 
Rifampicin, Rifabutin or Rifapentin (used to treat tuberculosis). 
- 
Dexamethasone (steroid medicine) 
- 
Phenytoin, Carbamazepine or Phenobarbital (anti-eplieptics to stop 
seizures and fits). 
- 
St John’s wort (herbal product used to treat depression). 
 
You should take special care whilst driving and speak to your doctor if you experience 
dizziness or feel tired whilst taking axitinib. 
 
13. 
Harm to the unborn child 
 
You will only have started in the study if you have completed a pregnancy test which gave a 
negative result. However, the medication in this study might harm an unborn child; therefore 
contraception should be used throughout the duration of the trial. If you think there is any 
chance you may be pregnant, or your partner has become pregnant it is important to let your 
study doctor or trials nurse know immediately.  
 
14. 
What will happen if I don’t want to continue with the study? 
 
If you agree to take part and then change your mind you can choose to withdraw at any time 
and you do not have to give a reason. Your decision will not affect the standard of care you 
receive. However, if you were to withdraw, we would like your permission to continue to 
collect information on your progress that is routinely recorded in your medical records. This 
is so that the overall quality of the study is not impaired.  
 
15. 
What if I have to stop participating in the study for another reason? 
 
Your study doctor may decide that continued participation in the study is no longer in your 
best interest and you may be withdrawn.   
 
For example, you may be withdrawn if the study medication is not working. Your doctor will 
be able to tell this from the MRI or other scans that you will have during the study. If this is 
the case, your doctor may decide that you should stop taking the study medication.  
 
You may also be removed from this study by your doctor if you are unable to follow the study 
schedule, if you develop other medical problems or conditions that would interfere with the 
study, or if the study procedures are found to be unsafe for you. If you are withdrawn, we 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 48 of 66
 
 
 
would still like your permission to collect information on your progress that is routinely 
recorded in your medical records. 
 
You may also be withdrawn if the study is stopped early for any reason. If this does happen, 
your doctor will discuss treatment options with you. 
 
16. 
What happens if there is new information about one of the medicines? 
 
Axitinib has been authorised for use in the treatment of kidney cancer in the UK since 2012. 
Sometimes during the course of a research project, new information becomes available 
about the medicines that are being studied.  If this happens, your study doctor will inform you 
and discuss whether you want to or should continue on study treatment.  
 
If you would prefer not to continue on the study, your doctor will make arrangements for your 
care to continue, and we would still like your permission to continue to collect information on 
your progress. If you decide that you do wish to continue in the study you may be asked to 
sign an updated consent form. 
 
17. 
What if there is a problem or something goes wrong? 
 
In the unlikely event that you are harmed by the study drug, indemnity for your hospital is 
provided by the usual NHS indemnity arrangements. 
 
If you are harmed due to someone’s negligence, the hospital in which you were treated 
would be liable on the part of hospital staff. Your legal rights are not affected by giving your 
consent to take part in this study. 
 
If you wish to complain, or have any concerns about any aspect of the way you have been 
approached or treated during the course of the study, the normal National Health Service 
complaints mechanisms will be available to you.  
 
Your progress will be watched closely and you will be offered whatever assistance is 
available to help you cope. 
 
18. 
Will my participation in the study be kept confidential? 
 
Yes. Your medical notes (paper or computerised) will, however, need to be seen by 
authorised members of the research team at your hospital and the Scottish Clinical Trials 
Research Unit (SCTRU), which is coordinating the study. There is also a possibility that your 
medical notes will be reviewed by regulatory authorities in the UK. 
 
Medical records of patients are maintained under strict confidentiality as required by law. 
Confidentiality will be maintained during and after your participation in the study in 
accordance with the Data Protection Act 1998. Data collected during the study will be stored 
and analysed by computer. It will be stored for a prolonged period (over 15 years).  
 
If you consent to take part in the study, only limited identifying information will be recorded, 
including your initials and date of birth.  You will be given a unique ‘code’ or study number 
when you enrol, which will be written on all forms relating to your participation in the study.  
These forms will be sent to the SCTRU with information about your treatment and progress 
in the study.   
 
In the unlikely event that you experience a serious side effect from the study medication we 
would pass the information to the drug manufacturer (Pfizer). Pfizer may use your data to 
submit reports to the regulatory authorities outside the European Union where the data 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 49 of 66
 
 
 
protections laws are not as stringent as the UK. By signing the trial informed consent form, 
you are authorising this access.  Please be aware, however, that all information about you 
will be treated as strictly confidential and nothing that might identify you will be revealed to 
any unauthorised third party.   
 
Once the study is complete the data collected will be processed and analysed by qualified 
personnel who will also respect the confidentiality and sensitivity of the data. Data obtained 
from the study may be archived, published in medical journals and presented at international 
meetings, even if you are excluded and do not participate in the study. In such cases your 
name will not be used so that confidentiality can be maintained. Your medical information 
may be held and processed on a computer. 
 
By consenting to participate in this study you understand that all data derived from this study 
or from the specimens or samples obtained from you is the property of the study sponsor. 
However, you have the right of access to information relating to yourself and if needed, 
correction of such information. You have certain rights, which may allow you to have access 
to information held about you, and to object or prevent certain processing of your information 
if it will cause you damage or distress. You understand that you may obtain access to such 
information through your study doctor. For further details on your rights and how you can 
enforce them, you should contact the study doctors at the study centre. 
 
19. 
Involvement of GP/family doctor  
 
We will inform your GP that you are taking part in this study. 
 
20. 
Expenses and Payments 
 
You will not receive any payment if you agree to take part in this study.  
 
21. 
What will happen to any samples that I give? 
 
To verify the initial diagnosis (performed by the pathologist in your hospital), your tumour 
might be reviewed by a second independent pathologist who will not necessarily be working 
in the hospital where you receive treatment. In some cases, a sample of your tumour biopsy, 
removed at the time of establishing the diagnosis or during a surgical procedure that you 
may undergo, might be used to perform additional examinations necessary to assure the 
correct diagnosis. 
 
While the samples should be considered a ‘gift’ they may be used for a range of research 
including commercial research and this research will include studies outside the UK. 
 
22. 
Will any genetic tests be done? 
 
Yes. Please see the translational research information sheet. 
 
23. 
What will happen to the results of the research study? 
 
Independent experts will review the progress of the research, and the results will be 
published in a respected medical journal as soon as there is enough information to be sure 
the results are reliable. The results may help to decide how to treat kidney cancer in the 
future. You will not be identified in any report or publication about the study. 
 
Your hospital will inform you when the results are known and will ask if you would like to see 
them. 
 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 50 of 66
 
 
 
24. 
Who is organising and funding the research?  
 
The Sponsor of the trial is the Common Services Agency or more commonly known as the 
NHS National Services Scotland.  The NAXIVA study is being coordinated by the SCTRU, in 
Edinburgh, which is an NHS National Services Scotland organisation that receives funding 
from the Scottish government. All treatment is provided by the NHS.  
 
For this trial, Pfizer, the manufacturer of axitinib, have provided this drug free of charge for 
patients taking part in this study, as well as providing funds to cover the costs of running the 
study.  
 
Your doctor will not receive any personal financial rewards for including you in this study.    
 
25. 
Who has reviewed the study? 
 
The NAXIVA study has been reviewed by Pfizer worldwide and endorsed by the Clinical 
Research Committee (CRC) of Cancer Research UK (CRUK). 
 
The NAXIVA study has also been reviewed for compliance with medical and ethical 
standards and for scientific value. It has been given a favourable ethical opinion by the East 
of England – Cambridgeshire and Hertfordshire Research Ethics Committee. 
 
26. 
Further information and contact details 
 
Your study doctor or research nurse will be happy to answer any questions you have about 
this study.  You can telephone them on the numbers shown below, or speak to them again 
when you come to the clinic.  
 
The Patient Advice and Liaison Service (PALS) is also avaliable to you. PALS offers 
confidential advice, support and information on health-related matters. They provide 
information on the NHS, the NHS complaints procedure and support groups outside of the 
NHS. You can ask your doctor/nurse for details of your nearest PALS alternatively you can 
search online at www.nhs.uk  
 
You will also be given a card with contact numbers on – please keep this card on you at all 
times in case of emergency. 
 
Your Study Doctor is:  
 
Contact Number: 
 
Your Research Nurse is: 
 
Contact Number: 
 
 
Thank you for reading this information sheet and for considering participating in this research 
study 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 51 of 66
 
 
 
[To be printed on hopsital headed paper] 
 
INFORMED CONSENT FORM 
 
‘NAXIVA’- Main study 
 
Phase II neoadjuvant study of axitinib for reducing extent of venous tumour thrombus 
in clear cell renal cell cancer with venous invasion. 
 
EudraCT No: 2017-000619-17 
 
                 
ISRCTN96273644   
IRAS ID: 223309           
 
Principal Investigator Name:  
Centre Number:  
 
Patient Trial Identification Number:  N 
 
 
 
 
 
 
 
 
      Please Initial 
 
I confirm that I have read and understood the information sheet dated 22nd September 
2017 version 1.2 for the NAXIVA study. I have had the opportunity to consider the 
information, ask questions and have had these answered satisfactorily.  
⁭ 
I understand that my participation is voluntary and that I am free to withdraw at any time 
without giving any reason, without my medical care or legal rights being affected.  
⁭ 
I understand that relevant sections of my medical notes and data collected during the 
study may be looked at by individuals from the Scottish Clinical Trials Research Unit, 
from regulatory authorities or from the NHS Trust, where it is relevant to my taking part 
in this research. I give permission for these individuals to have access to my records. 
⁭ 
I agree to my GP being informed of my participation in the NAXIVA study. 
 
I understand my initials, date of birth and CHI/NHS number will be given when I join the 
study and thereafter I will be identified by a unique subject number.  Any information 
passed to the regulatory authorities, drug manufacturers and organisations providing 
services on behalf of the sponsor will not identify me by name. 
⁭ 
I understand that the information collected about me will be used to support other 
research in the future, and may be shared anonymously with other researchers 
⁭ 
I understand that information held and maintained by the NHS and other central UK 
NHS bodies may be used to help contact me or provide information about my health 
status.  
⁭ 
I give permission for data collected during the study to be transferred for the purpose of 
Pfizer regulatory reports to associated researchers outside the European Economic 
Area.  I understand that some countries outside Europe may not have laws which 
protect my privacy to the same extent as the Data Protection Act in the UK or European 
Law. However, as stated in the patient information leaflet they have undertaken to treat ⁭ 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 52 of 66
 
 
 
my information as confidential 
I agree to take part in the NAXIVA study. 
⁭ 
 
 
 
 
______________________________________ 
__________________________ 
Signature of subject 
Date of Signature 
 
 
_______________________________________ 
Printed name of subject (BLOCK CAPITALS) 
 
 
 
I confirm that I have explained the nature of this trial to the above named patient and that they have understood 
the explanation given to them. 
 
 
 
_______________________________________ 
__________________________ 
Signature of person taking informed consent  
Date of Signature 
 
 
 
______________________________________ 
Printed name of person taking informed consent (BLOCK CAPITALS) 
 
 
 
 
1 copy for patient; 1 for researcher (original); 1 to be kept with hospital notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 53 of 66
 
 
 
 
Appendix 5 –Translational Patient Information Sheet and Informed Consent 
 
[To be printed on hospital headed paper] 
 
PATIENT INFORMATION SHEET – Translational Research 
 
‘NAXIVA’ 
 
Phase II neoadjuvant study of Axitinib for reducing extent of venous tumour thrombus 
in clear cell renal cell cancer with venous invasion 
 
EudraCT No: 2017-000619-17 
 
 
 
 
 
ISRCTN96273644 
IRAS ID: 223309 
 
PIS Version: 1.1 
Version Date: 30th June  2017 
 
 
 
Invitation Paragraph 
You are being invited to take part in a research study.  Before you decide if you want to take 
part it is important for you to understand why the research is being done, how your 
information will be used, what the research will involve and the possible benefits, risks and 
discomforts.  Please take time to read the following information carefully and discuss it with 
your relatives, friends or GP if you wish.   
 
Please ask if there is anything that is not clear or if you would like further information. 
 
Further Research 
 
1. What is translational research? 
Translational research is where findings that have been made in the basic science research 
laboratory are further developed with the aim of making a change in the treatment of a 
disease. Translational research is often called ‘bench to bedside research’. Translational 
research often makes use of the samples donated by a patient to better understand and 
treat the disease.  
 
2. What is the purpose of the translational research in NAXIVA? 
Within the NAXIVA trial we aim to use translational research to gain a better understanding 
of kidney cancer and its treatments with the class of medication (tyrosine kinase inhibitors) 
you will be taking in the study. We aim to identify ‘biomarkers’ that might allow identification 
of patients most likely to benefit from the drug given in NAXIVA. We also hope to gain 
insights into the development of resistance of some cancers to tyrosine kinase inhibitors.  
This extra research that may be done with your samples is not designed to specially benefit 
you. It may have an impact on the choice of specific treatment for this type of kidney cancer 
for others. By broadening the knowledge about kidney cancer, it may help other patients in 
your situation. 
 
3. Why have I been invited to take part? 
Your Oncologist feels that taking extra samples of blood, urine and your tumour would be 
safe and may help with our understanding of treatment of kidney cancer such as your own. 
 
 


 
 
 
 
 
 
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4. Do I have to take part? 
No, it is up to you to decide whether or not to take part.  If you do choose to take part you will 
be asked to sign an informed consent form and you will be given a copy to keep together 
with this information sheet.  For your safety your GP will be informed of your participation in 
this research.   
 
If you do not wish to take part in the translational research you do not have to give a reason. 
You will not be disadvantaged in any way, and it will not affect the standard of care you 
receive. This also applies if you initially decide to take part and then change your mind at a 
later date. 
 
5. What will happen to me if I decide to take part? 
You will have a biopsy taken of your kidney cancer along with a series of scans, tests and 
examinations to confirm you are eligible to take part in the NAXIVA study. At the time of 
biopsy, 4 extra tissue samples will be taken for research use within the NAXIVA trial. These 
will be done approximately 1 to 4 weeks before you start taking any study medication.  
In addition, at the time you have your surgery to remove your cancer (week 9); a tissue 
sample will be taken from the removed cancer for further analysis. 
The extra tissue will be sent and stored at the University of Cambridge Laboratory.  
 
You will have routine blood and urine samples taken throughout the NAXIVA study to 
monitor your progress. At each follow up prior to your surgery and at your final clinic visit (12 
weeks post surgery) you will have 2 extra blood samples taken and be asked to provide 1 
extra urine sample. These further tests will be used for side research to the NAXIVA study. If 
you agree to provide extra blood and urine samples, they will be sent and stored at the 
University of Cambridge Laboratory. One of your blood samples will be sent outside the 
European Union to Eve Technologies in Canada. Eve Technologies specialise in a specific 
analysis of blood and are currently the only institution in the world that can carry out this 
analysis. Your blood sample will be fully anonymised and will not be linked to you in anyway. 
 
This research will not have an effect on the standard of your medical care. 
 
Trial Visit Schedule 
 
 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5  
Visit 6 
Visit 7 
Visit 9 
 
1-4 weeks 
prior to 
study 
enrolment 
Week 1 Week 3 
Week 5 Week 7 Week 9 Week 9 6 
weeks 
post 
surgery 
12 
weeks 
post 
surgery 
Biopsy 
X 
 
 
 
 
 
 
 
 
Blood & Urine 
samples 
 
X 
X 
X 
X 
X 
 
 
X 
Surgery 
 
 
 
 
 
 
X 
 
 
 
6. What will I be asked to do? 
If you agree to take part in this sub-study, the tissue and blood samples will be taken and the 
urine sample collected at standard NAXIVA trial clinic visits.  
 
7. What will happen to any samples that I give? 
If you agree to take part in this translational research, and with your permission, we will ask 
the pathologist at the laboratory in your hospital to send the extra tissue, blood and urine 
samples to the University of Cambridge laboratory to carry out the research.  


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 55 of 66
 
 
 
In addition, 1 of the blood samples you supply during the trial will be sent outside the 
European Union for processing and analysis. This sample will be fully anonymised and will 
not be linked to you in anyway.  
 
At the end of the research your samples will be sent to a central tissue bank for continued 
storage. These samples may be used in future research which may be able to give us a 
better understanding of which treatments are best for which patients. 
 
8. What are the possible disadvantages and risks of taking part? 
The tissue and blood samples for research will be taken at the time of routine samples 
needed for your clinical care, i.e. with no extra passes of the biopsy or blood taking needle. 
However, there can be some discomfort from the needle used for biopsy of the kidney lump 
or blood taking and bruising or bleeding afterwards.  There is a small chance of infection 
which is minimised by taking the samples under sterile conditions. 
 
9. What if there is a problem or something goes wrong? 
In the unlikely event that you are harmed during the taking of the extra samples indemnity for 
your hospital is provided by the usual NHS indemnity arrangements. 
 
If you are harmed due to someone’s negligence, the hospital in which you were treated 
would be liable on the part of hospital staff. Your legal rights are not affected by giving your 
consent to take part in this research.  
 
If you wish to complain, or have any concerns about any aspect of the way you have been 
approached or treated during the course of the translational research, the normal National 
Health Service complaints mechanisms will be available to you.  
 
10. Will my participation in the translational research be kept confidential? 
Yes. Your medical notes (paper or computerised) will, however, need to be seen by 
authorised members of the research team at your hospital and the Scottish Clinical Trials 
Research Unit (SCTRU), which is coordinating the study. There is also a possibility that your 
medical notes will be reviewed by regulatory authorities in the UK. 
 
Medical records of patients are maintained under strict confidentiality as required by law. 
Confidentiality will be maintained during and after your participation in the study in 
accordance with the Data Protection Act 1998. Data collected during the study will be stored 
and analysed by computer. It will be stored for a prolonged period (over 15 years).  
 
If you consent to take part in the translational research, only limited identifying information 
will be recorded, including your initials and date of birth.  You will be given a unique ‘code’ or 
study number when you enrol, which will be written on all specimens relating to your 
participation in the study.   
 
One of your blood samples will be sent outside the European Union to Canada for analysis.  
Some countries outside the European Union may not have laws which protect your privacy 
to the same extent as the Data Protection Act in the UK or European Law. 
In this instance your sample would be fully anonymised (labelled 1-100) and will have no link 
to you in anyway. 
 
Once the study is complete the data collected will be processed and analysed by qualified 
personnel who will also respect the confidentiality and sensitivity of the data. Data obtained 
from the study may be archived, published in medical journals and presented at international 
meetings, even if you are excluded and do not participate in the study. In such cases your 
name will not be used so that confidentiality can be maintained.  
 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 56 of 66
 
 
 
By consenting to participate in the translational research you understand that all data derived 
from the specimens or samples obtained from you is the property of the study sponsor. 
However, you have the right of access to information relating to yourself and if needed, 
correction of such information. You have certain rights, which may allow you to have access 
to information held about you, and to object or prevent certain processing of your information 
if it will cause you damage or distress. You understand that you may obtain access to such 
information through your study doctor. For further details on your rights and how you can 
enforce them, you should contact the study doctors at the study centre. 
 
11. Involvement of GP/family doctor  
We will inform your GP that you are taking part in this study. 
 
12. Expenses and Payments 
You will not receive payment if you agree to take part in this study.  
 
13. What will happen to the results of the translational research? 
The results will be published in a respected medical journal and may help to decide how to 
treat kidney cancer in the future. You will not be identified in any report or publication about 
the study. Following the open access ethos, we will make the ‘raw data’ from experiments 
available to other researchers. This data will not identify you in anyway. 
 
Your hospital will inform you when the results are known to ask if you would like to see them. 
 
14. Will any genetic tests be done? 
Genetic analysis of your tumour tissue or blood may be undertaken. This will be to evaluate 
potential biomarkers (measurable indicators of the severity or presence of some disease 
state) in kidney cancer. 
 
15. Further information and contact details 
Your study doctor or research nurse will be happy to answer any questions you have about 
any aspect of the study.  You can telephone them on the numbers shown below, or speak to 
them again when you come to the clinic.  
 
The Patient Advice and Liaison Service (PALS) is also avaliable to you. PALS offers 
confidential advice, support and information on health-related matters. They provide 
information on the NHS, the NHS complaints procedure and support groups outside of the 
NHS. You can ask your doctor/nurse for details of your nearest PALS alternatively search 
online at www.nhs.uk  
 
 
You will also be given a card with contact numbers on – please keep this card on you at all 
times in case of emergency.  
 
Your Study Doctor is:  
 
Contact Number: 
 
Your Research Nurse is: 
 
Contact Number: 
 
 
Thank you for reading this information sheet and for considering participating in this research 
study. 
 
 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 57 of 66
 
 
 
[To be printed on hospital headed paper] 
 
 
INFORMED CONSENT FORM – Translational Research 
 
‘NAXIVA’ 
 
Phase II neoadjuvant study of Axitinib for reducing extent of venous tumour thrombus 
in clear cell renal cell cancer with venous invasion 
 
EudraCT No: 2017-000619-17 
 
               
ISRCTN96273644   
IRAS ID: 223309           
 
Principal Investigator Name:  
Centre Number:  
 
Patient Trial Identification Number:  N 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
                                                                                                                                                                   Please Initial 
I confirm that I have read and understood the information sheet dated 30th June 2017 
version 1.1 for the NAXIVA translational research and I have been given the 
opportunity to consider the information, discuss the research, ask questions and have 
had these answered satisfactorily.  
 
I understand that my participation in the translational studies is entirely voluntary and 
that I am free to withdraw at any time, without giving reason, and without my medical 
care or legal rights being affected. 
 
I understand that extra biopsy samples of my kidney tumour tissue will be taken during 
tumour biopsy. In addition I understand that excess tissue, will be taken from my 
kidney tumour removed at surgery. The results of these analyses will not be made 
available to me or the team looking after me as they are purely for research purposes. 
 
I understand that extra blood samples will be taken from me at every clinic visit before 
and after surgery.  The results of these analyses will not be made available to me or 
the team looking after me as they are purely for research purposes.  
 
I understand that extra urine samples will be taken from me at every clinic visit before 
and after surgery.  The results of these analyses will not be made available to me or 
the team looking after me as they are purely for research purposes.  
 
I give permission for samples collected during the study to be transferred for the 
purpose of analysis to associated researchers outside the European Economic Area.  I 
understand that some countries outside Europe may not have laws which protect my 
privacy to the same extent as the Data Protection Act in the UK or European Law 
However, as stated in the patient information leaflet they have undertaken to treat my 
information as confidential 
 
I consent to take part in the translational research within the NAXIVA study. 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 58 of 66
 
 
 
 
 
 
 
 
______________________________________ 
__________________________ 
Signature of subject 
Date of Signature 
 
_______________________________________ 
Printed name of subject (BLOCK CAPITALS) 
 
 
 
I confirm that I have explained the nature of this trial to the above named patient and that they have understood 
the explanation given to them. 
 
_______________________________________ 
__________________________ 
Signature of person taking informed consent  
Date of Signature 
 
 
______________________________________ 
Printed name of person taking informed consent (BLOCK CAPITALS) 
 
 
 
 
1 copy for patient; 1 for researcher (original); 1 to be kept with hospital notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 59 of 66
 
 
 
Appendix 6 – Translational Research Studies 
1. Introduction 
A key aim of this study is to evaluate changes in multiple molecular factors in relation to 
tumour response.  
The expression of these putative biomarkers of renal cancer response will be evaluated in 
tissue donated before and following treatment to define therapeutic response to treatment.  
In addition, novel techniques (including immunophenotyping and metabolomics analysis) will 
be applied to samples to gain a better fundamental understanding of the effect of TKIs on 
metabolites, immune function, proteomics and also to assess the potential for these and 
other markers (such as ctDNA) for predicting or tracking response to drugs. 
Analysis of tissue for such studies will be performed at the Stewart Lab, Academic Urology 
Group, Department of Surgery, University of Cambridge and collaborators within the 
Cambridge Renal Cancer (CamRenCan) collaborative.   
2. NAXIVA laboratory manual 
Detailed instructions for sample collection, processing, labelling, storage and transportation 
will be provided in the NAXIVA laboratory manual which is available from the Scottish 
Clinical Trials Research Unit (SCTRU) and should be referred to in conjunction with this 
protocol.  It is essential that these protocols are followed to enable reproducible high quality 
translational analyses. 
3. Tissue Acquisition and Processing at site 
  3.1. Baseline Primary tumour tissue sample 
Image guided percutaneous biopsy of the primary tumour should be performed prior to 
starting treatment.   Five tissue cores from one needle puncture should be obtained: two 
cores should be formalin-fixed and sent for paraffin-embedding by the local pathologist; one 
being retained by the site and used to establish a histological diagnosis whilst the other 
should be transferred to The University of Cambridge (this can be repatriated if a histological 
diagnosis cannot be obtained for whatever reason).  One of the remaining cores should be 
snap frozen in liquid nitrogen within 30 minutes after biopsy and stored at -80°C. The 
remaining 2 biopsies should be placed in 5ml media (as provided to the sites by The 
University of Cambridge) immediately after biopsy, stored at 4°C, and couriered to The 
University of Cambridge as soon as possible after biopsy (maximum within 24 hours of 
biopsy).  These samples will be processed for immunophenotyping.  Remaining biopsies 
should be transferred to the University of Cambridge on dry ice (or room temperature for 
formalin-fixed paraffin-embedded (FFPE) blocks).   
In the event of less than 5 biopsy cores being available please refer to the NAXIVA 
laboratory manual which is available on request from SCTRU for prioritisation of 
tissue processing.   
3.2. Nephrectomy specimen 
Nephrectomy specimens should be dissected by the local pathologist to obtain sufficient 
material for routine diagnostic purposes. Following this, multiregion sampling of tumour 
tissue, venous tumour thrombus and normal kidney should be undertaken with an 
accompanying photo or diagram. These tissues should be snap frozen in liquid nitrogen 
within 1 hour after the blood supply to the kidney has been interrupted and stored at -80°C at 
the local trial centre until transferred to the University of Cambridge on dry ice.  At the same 
time, samples should be taken from immediately adjacent to the above samples and should 
be immediately formalin-fixed and paraffin-embedded and stored at room temperature at the 
local trial centre until transferred to the University of Cambridge at room temperature. 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 60 of 66
 
 
 
Additionally, approximately 1cm3 of tumour, venous thrombus, and normal kidney should be 
placed in 5ml media (as provided to the sites by The University of Cambridge) within 1 hour 
after the blood supply to the kidney has been interrupted, stored at 4°C, and couriered to 
The University of Cambridge as soon as possible after biopsy (maximum within 24 hours of 
biopsy).  These samples will be processed for immunophenotyping, and primary culture of 
malignant and stromal cells.  Samples should also be taken from immediately adjacent to the 
above samples and should be immediately formalin-fixed and paraffin-embedded and stored 
at room temperature at the local trial centre until transferred to the University of Cambridge 
at room temperature. 
Trial centres should notify SCTRU one week in advance of any planned surgery. 
3.3. Paraffin Embedded Tissue Sections 
Paraffin embedded core biopsies that are no longer needed by the local pathologist for 
diagnostic purposes may be requested for use in translational work, following discussion 
with the local site consultant pathologist.  
3.4. Blood and Urine Processing 
Patients should be fasted for 6 hours prior to urine sampling.  Therefore, it is suggested that 
blood and urine sampling is performed as early in the morning as clinically feasible, and the 
times of the patient’s last meal and last axitinib should be recorded.   
 
3.4.1. Blood Samples 
Blood - Venous blood for biomarker analysis will be collected in ethylenediaminetetraacetic 
acid (EDTA) tubes. Two 10ml tubes will be collected on day 1 week 1 prior to starting 
axitinib treatment, two tubes at the week 3 clinic visit, two tubes at the week 5 clinic visit, 
two tubes at the week 7 clinic visit, two at time of nephrectomy and two tubes at 12 weeks 
post surgery follow up.  All blood samples must be processed locally.  Blood samples must 
be centrifuged and processed for whole blood and plasma within 1 hour of blood sampling, 
and within 4 hours of blood sampling for collection of buffy coat and peripheral blood 
mononuclear cells (PBMCs) from the remaining blood. Detailed instructions for blood 
processing are contained in the NAXIVA laboratory manual. From these two EDTA tubes the 
following samples must be collected: 
 
Whole blood (WB) – all centres:  Immediately after blood sampling gently invert the tubes 
8-10 times to mix and leave tubes upright prior to further processing.  From one of EDTA 
tubes, remove 1ml whole blood and place into a screw cap cryovial (labelled with ‘WB, 
patient’s trial number and the date).  Snap freeze the tube in liquid nitrogen and store at -
80°C at the trial centre until transfer to University of Cambridge on dry ice. 
 
Plasma (P) – all centres:  This step must be completed within 1 hour of blood sampling.  
Following transfer of whole blood from one vacutainer, spin both vacutainer tubes at 1600g 
for 10 min at room temperature using a “swing-out” rotor.  Transfer 1ml aliquots of plasma to 
sterile 2ml micro-tubes (non-screw capped RNase-free tubes can be used at this stage).  
Take care to avoid any buffy coat layer in this step. Centrifuge the plasma aliquots in a 
bench top centrifuge at 14,000rpm for 10 minutes at 4°C to pellet any remaining cellular 
debris. Carefully transfer 1ml aliquots of supernatant to labelled (P/patient’s trial 
number/date) sterile 1.8ml screw-capped cyrovials, and discard the pellet.  Store the original 
vacutainers with remaining blood at 4° C for collection of buffy coat or Peripheral Blood 
Mononuclear Cells (PBMCs). Aim to collect 4 cryovials with roughly even amounts of plasma 
in each.  Store at -80°C at the trial centre until transfer to University of Cambridge on dry ice.  
All plasma samples MUST be double-spun using the NAXIVA protocol above to allow 
down-stream translational assays to be performed. 
 


 
 
 
 
 
 
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Buffy coat (BC) 
For collection ONLY by sites NOT processing samples for PBMCs (as this step 
removes the PBMCs):  Following removal of whole blood and plasma from the vacutainers, 
remove the buffy coat with about 100ul of plasma taking care not to lift the red cells.  
Optional: If it is difficult to cleanly separate the buffy coat layer, combine the buffy coats from 
both vacutainers in a small Eppendorf tube/micro centrifuge tube and centrifuge at 10,600g 
for 2 minutes.  Then aliquot into 1 x labelled cryovial (BC/patient’s trial number/date).  Store 
at -80°C at the trial centre until transfer to University of Cambridge on dry ice. 
 
Peripheral blood mononuclear cells (PBMCs)  
Do NOT collect buffy coat if processing blood for PBMCs as buffy coat contains 
PBMCs resulting in very low yield using this protocol.   
This method requires the use of SepMate tubes, ficoll, and ‘freezing mix’ which will be 
provided to selected sites by the SCTRU as part of the sample collection kits.  All processing 
steps (including removal of plasma from vacutainers) MUST be carried out under sterile 
conditions eg. HEPA filtered CL2-certified tissue culture facilities, if blood samples are being 
used to isolate PBMCs. 
 
1. Ideally this step must be completed within 4 hours of blood sampling, but certainly 
completed same day.  If unable to process samples immediately after plasma 
extraction, store samples at 4°C.  
2. After removing plasma dilute the remaining blood in the tube 1:1 with pre-warmed 
(room temperature) sterile phosphate buffered saline (PBS) (if a full 10ml EDTA tube 
was taken from the patient the volume of PBS to add will be approximately 4ml).  
3. Mix tube well by inverting 3 times.   
4. Keeping the SepMate tube upright, pipette 15ml Ficoll through the central hole of the 
insert in the SepMate tube.  The top of the Ficoll will come to ABOVE the level of the 
insert.  Air bubbles may be seen under the insert and are reduced by pipetting the 
Ficoll more slowly through the insert, but don’t affect the cell separation. 
5. Quickly pipette the blood/PBS mix down the side of the SepMate tube. 
6. Centrifuge tubes at 1200g (2800 rpm) for 10 minutes at room temperature (using 
normal brake settings ie brake on).  
7. Remove tubes from centrifuge and collect the mononuclear cells by inverting the 
SepMate tube into a 50ml Falcon tube in one smooth movement.  Do not hold the 
SepMate tube inverted for >2 seconds or the red cells (which may be seen on the 
surface of the SepMate insert before inversion in addition to the bottom of the tube) 
start to dribble through the insert and will contaminate the mononuclear cells. 
8. Dilute mononuclear cells to 45ml with pre-warmed PBS. 
9. Centrifuge tubes at 1200g (2800 rpm) for 10 minutes at room temperature (normal 
brake settings) to wash the cells. 
10. Discard supernatant (carefully as cell pellet may be slimy). 
11. Resuspend cell pellet in 2ml 10% dimethylsulfoxide in fetal calf serum (‘freezing mix’) 
and freeze 4 labelled (PBMC/patient’s trial number/date) cryovials of PBMCs (aliquot 
equal volumes into each cryovial and record volumes). 
12. Immediately place at -80°C (in a pre-cooled (4°C) Mr Frosty/ similar container). NB 
check isopropanol level beforehand. Store at -80°C for up to a week, and then 
transfer to liquid nitrogen until transfer on dry ice to University of Cambridge. 
 
3.4.2. Urine Samples– all centres  
Urine samples will be collected on day 1 week 1, week 3, week 5, week 7 at nephrectomy 
and 12 week post surgery follow-up.  
15ml of urine (ideally after patient fasted for 6 hours, fasting time to be noted) should 
immediately be stored at -80°C at trial centres until transfer to University of Cambridge on 
dry ice.   


 
 
 
 
 
 
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In addition, 30ml urine in a falcon tube should have EDTA added immediately to prevent 
nuclease degradation (for cfDNA analysis). Add 600ul of 0.5M EDTA and gently invert 8-10 
times. Centrifuge at 3000g for 10 minutes within 1 hour of collection to remove cellular 
debris. Transfer 3.6ml aliquots of supernatant to fresh sterile 4ml cryotubes. Retain cell 
pellet, suspended in 1ml urine.  
Each specimen container should be labelled as specified in the NAXIVA laboratory manual. 
Labels will be supplied by the SCTRU as part of the sample collection kits. 
4. Storage and Collection of Samples  
Blood, urine and tissue samples should be stored at local trial centres in a -80°C freezer and 
transferred in batches as detailed in the NAXIVA laboratory manual to the University of 
Cambridge on dry ice unless part of the fresh tissue for immunophenotyping/ cell culture 
study.  Samples which are part of the fresh tissue for immunophenotyping/ cell culture study 
MUST be stored at 4°C and couriered to University of Cambridge in insulated polystyrene 
containers with ice packs in situ as soon as possible after collection (certainly within 24 
hours of collection but ideally same day).  Further details for transfer of these samples can 
be found in the NAXIVA laboratory manual. 
 
 4.1. Translational sample Schedule  
 
Visit/Assessment 
Within 28 days 
prior to registration 
Week 1 
Week 3 
 
Week 5 
 
Week 7 
Nephrectomy 
12 weeks post 
surgery follow up 
Percutaneous image guided biopsy of non-
necrotic region of primary renal tumour 
(5 cores, 2 to be sent to pathology for 
formalin-fixation and paraffin embedding of 
which 1 to be transferred to University 
Cambridge; 1 core to be snap frozen in 
liquid nitrogen and stored at -80°C; 2 to be 
placed in tubes containing media and 
couriered within 24 hours to University of 
Cambridge) 
X 
 
 
 
 
 
 
Nephrectomy tissue 
 
 
 
 
 
X 
 
2 EDTA tube blood samples for whole 
blood, double-spun to obtain plasma, buffy 
coat and PBMCs at selected sites 
(samples to be stored at -80°C) 
 
 
X 
X 
X 
X 
X 
X 
Urine sample (1 container to be stored at -
80°C, 1 sample EDTA treated and spun 
sample at -80°C) 
 
 
X 
X 
X 
X 
X 
X 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 63 of 66
 
 
 
           4.2. Sample Tracking 
Sites will be required to record the collection of participants’ samples by emailing a sample 
reporting form to the central lab at the University of Cambridge and SCTRU. SCTRU will 
provide courier account details for sites to organise transport of the samples. 
4.2.1. Tracking of baseline samples for ineligible patients 
In order to minimise invasive procedures, patients will be consented for the trial prior to 
obtaining both the standard diagnostic biopsy sample and baseline translational study 
research biopsies.  Patients will be asked to provide consent for the research samples to be 
sent to the University of Cambridge should histological examination of the diagnostic sample 
show that the patient is ineligible for NAXIVA.  Collection of these samples should be notified 
to the SCTRU by emailing: NSS.NAXIVA@nhs.net 
 
The following information will be required: 
 
Centre name 
 
Confirmation of written informed consent 
 
Trial ID 
 
Patient’s date of birth 
 
This notification will allow these samples to be tracked by the University of Cambridge and 
SCTRU. 
4.3 Expedited reporting of fresh tumour collection at biopsy and planned 
nephrectomy  
All participating sites must notify SCTRU in advance of the date of planned biopsy or 
nephrectomy.  
Centres should notify SCTRU of the biopsy or nephrectomy, by completing the NAXIVA 
expedited notification of tissue collection form (included within the NAXIVA laboratory 
manual) and emailing it to: NSS.NAXIVA@nhs.net 
 
SCTRU will then notify University of Cambridge (Mr Grant Stewart and Dr Sarah Welsh) to 
expect samples. 
4.4 Tissue Sample processing at the University of Cambridge  
All samples will be catalogued in an electronic database at the University of Cambridge. The 
time from core biopsy collection to snap freezing and from ischaemia to snap freezing for 
nephrectomy specimens will be recorded on a database. All tissues will be stored in an 
alarmed and locked -80°C freezer (or liquid nitrogen tank for PBMCs and dissociated tumour 
samples) which are dedicated to the storage of clinical trial patient samples. 
 4.4.1 Blood Specimens (Whole blood, Plasma, Buffy coat, PBMC) 
Analysis of whole blood, plasma, buffy coat, and PBMCs for translational studies will be 
conducted at the University of Cambridge.  Plasma will be analysed for biomarkers 
(including metabolites, circulating tumour (ct) DNA, and cytokines).  DNA will be extracted 
from whole blood/ or buffy coat and PBMCs for sequencing of host DNA.  PBMCs will be 
immunophenotyped using CyTOF. 
4.4.2. Urine Specimens 
Analysis of urine samples will be conducted at University of Cambridge.  Urine will be 
analysed for biomarkers (including metabolites, circulating tumour (ct) DNA, and cytokines). 
4.4.3 Core Biopsy and Nephrectomy Specimens 
Processing and analysis of core biopsy, nephrectomy and surgical specimens will be 
conducted at the University of Cambridge. Dissociation of fresh tumour, venous thrombus 
and normal kidney samples will be performed to separate malignant cells from associated 


 
 
 
 
 
 
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stromal and immune components, and immunophenotyping will be performed using CyTOF.  
Cell lines (tumour, stomal, lymphocyte) will be generated if sufficient tissue allows.  RNA and 
DNA from each will be extracted from fresh-frozen samples according to Good Laboratory 
Practice standards.  Immunohistochemistry and immunofluorescence staining will be 
performed on FFPE samples.  
5. 
Analysis of Biosamples 
Biosample analysis aims to correlate changes in biomarkers with toxicity and response to 
axitinib treatment. 
The techniques below may be used to explore this endpoint and are based on the current 
literature. Equivalent novel methods and technologies might be used at the time of analysis.   
5.1.    Metabolomics 
It is well established that there is a strong metabolic basis to ccRCC. The presence of the 
Warburg effect has revealed several novel targets for treatment or tumour surveillance. Dr 
Frezza is an expert in metabolomics, working mainly on inherited forms of kidney cancer. 
Using LC-MS, metabolites will be assayed in urine, blood and tissue across the various time 
points of the NAXIVA study to assess the use of these molecules in patients with IVC VTT 
and with Axitinib therapy. This work will be discovery in nature assessing alterations in 
metabolic profile within protein from tumour, plasma and urine at sequential time points 
within the NAXIVA study. 
5.2. Circulating Tumour DNA 
In view of intratumoural heterogeneity, the use of tumour tissue for the development of 
prognostic and predictive biomarkers in ccRCC is challenging. Circulating tumour DNA 
(ctDNA) has been established to represent the tumour biology and may be superior to tissue 
as heterogeneity will be negated. Variant analysis will be undertaken on multi-region 
sampled issue using exome and shallow whole genome sequencing. A custom capture 
panel for targeted higher-depth (and higher sensitivity) sequencing of plasma and urine 
samples will be developed for each patient to assess the feasibility of tracking circulating 
DNA molecules that harbour somatic mutations. The end-point of this analysis will be to 
determine the ability to identify variants in both tissue and plasma and the change in ctDNA 
profiles from baseline to treatment phase to posttreatment phase which may be informative 
regarding markers of tumour response and minimal residual disease. Further validation 
studies of any positive findings will be undertaken separately. 
5.3. 
Proteomics 
Formalin fixed paraffin embedded biopsy and nephrectomy tissue will be utilised in an 
automated quantified immunohistochemical based analysis of putative markers of response 
to tyrosine kinase inhibitors. In addition to Ki67 measurement of effect of Axitinib on 
proliferation, other markers of response to tyrosine kinase inhibitors will be evaluated. In 
recent work, it has been established that modulation of CA9 protein levels occurs following 
sunitinib therapy in metastatic clear cell RCC (ccRCC); this effect will be validated using 
patient samples from NAXIVA. The outcome of this work will be to establish a link between 
expression of these proteins and reduction in height of the VTT with axitinib. If a correlation 
is established these proteins will be helpful as surrogate translational endpoints in future 
ccRCC neoadjuvant studies. 
5.4. 
Immune studies 
It is known that RCC is a typical immunogenic tumour with immune mechanisms known to 
play an important role in its natural history.  Recent studies have also shown that TKI 
treatment can influence the immune system and, importantly, changes in the immune 
response may affect response and survival.  The immune studies aim to identify immune- 
and cytokine-based signatures in PBMCs, plasma and urine which predict response to 


 
 
 
 
 
 
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Version 1.2, 22nd September 2017                                                                     Page 65 of 66
 
 
 
axitinib treatment in RCC patients using CyTOF and luminex-based cytokine assays.  These 
studies will also provide important information about the effect of axitinib on the immune 
system in RCC, and vice versa, including providing comprehensive analysis of how 
peripheral immune cell populations and cytokines vary during treatment with axitinib, and 
whether they correlate with other markers of response and resistance in RCC patients.  
Importantly, it will also provide essential immunological information to inform biologically 
driven, rational, scheduling of future studies examining combinations of axitinib and 
immunotherapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
NAXIVA 
Version 1.2, 22nd September 2017                                                                     Page 66 of 66
 
 
 
Appendix 7– The Principles of ICH Good Clinical Practice 
 
1. Clinical trials should be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki, and that are consistent with GCP and the 
applicable regulatory requirement(s). 
2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed 
against the anticipated benefit for the individual trial subject and society. A trial 
should be initiated and continued only if the anticipated benefits justify the risks. 
3. The rights, safety, and well-being of the trial subjects are the most important 
considerations and should prevail over interests of science and society. 
4. The available nonclinical and clinical information on an investigational product should 
be adequate to support the proposed clinical trial. 
5. Clinical trials should be scientifically sound, and described in a clear, detailed 
protocol. 
6. A trial should be conducted in compliance with the protocol that has received prior 
institutional review board (IRB)/independent ethics committee (IEC) approval/ 
favourable opinion. 
7. The medical care given to, and medical decisions made on behalf of, subjects should 
always be the responsibility of a qualified physician or, when appropriate, of a 
qualified dentist. 
8. Each individual involved in conducting a trial should be qualified by education, 
training, and experience to perform his or her respective task(s). 
9. Freely given informed consent should be obtained from every subject prior to clinical 
trial participation. 
10. All clinical trial information should be recorded, handled, and stored in a way that 
allows its accurate reporting, interpretation and verification. 
11. The confidentiality of records that could identify subjects should be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable 
regulatory requirement(s). 
12. Investigational products should be manufactured, handled, and stored in accordance 
with applicable good manufacturing practice (GMP). They should be used in 
accordance with the approved protocol. 
13. Systems with procedures that assure the quality of every aspect of the trial should be 
implemented. 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
PUBLIC HEALTH SCOTLAND - SCTRU 
Page 1 of 16 
 
 
NAXIVA 
 
Phase II Neoadjuvant study of AXItinib for reducing extent of 
venous tumour thrombus in clear cell renal cell cancer with 
Venous invAsion. 
 
Statistical Analysis Plan 
 
Version 2.0, 20th August 2020 
 
 
Previously 
Author 
Lisa Hopcroft 
Scottish Cancer Trials Research Unit 
Public Health Scotland 
Edinburgh EH12 9EB 
Robert Hill  
Scottish Cancer Trials Research Unit 
NHS National Services Scotland 
Edinburgh EH12 9EB 
 
Reviewer 
Richard Dobbie 
Public Health Scotland 
Edinburgh EH12 9EB 
 
James Paul 
Head of Biostatistics 
Cancer Research UK Clinical Trials Unit 
The Beatson West of Scotland Cancer Centre 
Level 0 
1053 Great Western Road 
Glasgow, G12 0YN 
 
Trial Coordinating Centre: Scottish Clinical Trials Research Unit, Edinburgh. 
Cancer Clinical Trials Unit, Scotland (CaCTUS). 
 
ISRCTN: 
ISRCTN96273644 
EudraCT Number: 
2017-000619-17 
REC reference: 
17/EE/0240 
 
 
SAP authorised by 
Name: Grant D Stewart 
Role in Trial: Chief Investigator 
Signature: 
Date: 20/8/2020 
 


 
 
 
 
PUBLIC HEALTH SCOTLAND - SCTRU 
Page 2 of 16 
 
 
 
DOCUMENT CONTROL 
 
Document Control 
Version 
v2.0 
Date Issued 
20/08/2020 
Author(s) 
Lisa Hopcroft 
Other Related Documents 
Protocol (version 2.0); CRF (version 1.0); 
Comments to 
Lisa.Hopcroft1@nhs.net 
 
Document History 
 
Version 
Date 
Author 
Reviewer 
Amendments 
0.1 
18/1/2018 
Jack Vize 
Robert Hill 
New document started 
0.2 
22/1/2018 
Robert Hill 
Jack Vize 
Updating missing sections 
0.3 
10/12/2018 
Robert Hill 
 
Updating the statistical methods 
0.4 
26/02/2019 
Robert Hill 
 
Updating following comments by the DMC 
0.5 
26/03/2019 
Robert Hill 
 
Updated following comments from Elaine 
McCartney and Grant Stewart 
0.6 
10/04/2019 
Robert Hill 
Jim Paul 
Updated to incorporate comments from Grant 
Stewart 
0.7 
22/4/2019 
Robert Hill 
Jim Paul 
Updated to incorporate comments from Jim 
Paul 
1.0 
23/4/2019 
Robert Hill 
Jim Paul 
Updated following additional comments from 
Jim Paul 
2.0 
20/8/2020 
Lisa Hopcroft 
Richard Dobbie 
Extensive update following identification of 
inconsistencies with previous, draft versions 
(specifically 0.5, 0.7); in consistencies 
between the SAP and protocol; and 
comments from DMC, notably: 
 Additional endpoint for RV-only patients is 
defined, following discussion and 
agreement with the DMC. 
 Addition of sensitivity analysis using the 
ITT population for assessments of 
endpoints, in addition to the evaluable 
population. 
Also updated Sponsor information. 
 
 
 


 
 
 
 
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TABLE OF CONTENTS 
1 
Study Objectives ..................................................................................................... 4 
1.1 
Primary endpoint ....................................................................................................... 4 
1.2 
Secondary endpoints ................................................................................................ 4 
2 
Study design ........................................................................................................... 4 
3 
Reporting outline .................................................................................................... 5 
3.1 
Interim Analysis ......................................................................................................... 5 
3.2 
Final Analysis ............................................................................................................ 6 
4 
Populations and sample size ................................................................................. 7 
4.1 
Sample Size Calculations ......................................................................................... 7 
4.2 
Intention-to-treat (ITT) Population ............................................................................. 7 
4.3 
Evaluable Population ................................................................................................ 7 
5 
Safety Evaluations .................................................................................................. 7 
6 
Efficacy evaluations ................................................................................................ 8 
7 
Tabulations, Figures and Listings ....................................................................... 10 
7.1 
Study Recruitment .................................................................................................. 10 
7.2 
Eligibility/Population membership ............................................................................ 10 
7.3 
Baseline data and demographic characteristics ...................................................... 10 
7.4 
Delivery of study therapy ......................................................................................... 11 
7.5 
Safety Analysis ....................................................................................................... 12 
7.6 
Efficacy analysis ..................................................................................................... 13 
7.7 
Additional analyses ................................................................................................. 15 
8 
Statistical Methods for the Analysis of the Study Data ...................................... 15 
8.1 
Methods for handling missing values ...................................................................... 15 
9 
Reference list ........................................................................................................ 16 
 
 


 
 
 
 
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1 
Study Objectives 
1.1 Primary endpoint 
The primary end-point for this study is the percentage of evaluable patients with an improvement in 
disease as a result of taking the study drug.  The definition of an improvement will vary according to 
the patient’s Mayo Level as captured at screening: 
 For patients presenting at screening with a Mayo Classification of Level 1 or above, an 
improvement in disease will be represented by a reduction in their Mayo Classification at week 9. 
 For patients presenting at screening with a Mayo Classification of Level 0, an improvement 
in disease will be represented by either: 
 
a change of tumor thrombus from main renal vein to branches of the renal vein (on the right); 
or 
 
a change of tumor thrombus from main renal vein to the renal vein lateral to the gonadal vein 
(on the left). 
See Section 6.1 for further details regarding the definition of improvement in relation to the Mayo 
classification and the surgical approach classification. 
1.2 Secondary endpoints 
Secondary endpoints are: 
 % change in surgical approach 
 % change in VTT length 
 Response rate (RECIST) 
 Evaluation of surgical morbidity assessed by Clavian-Dindo classification 
2 
Study design 
NAXIVA is a single arm, single agent, open label, phase II feasibility study of axitinib in patients with both 
metastatic and non-metastatic renal cell carcinoma of clear cell histology. 20 evaluable patients will be 
recruited from multiple centres within the United Kingdom. 
Patients who have signed informed consent and who have met all eligibility criteria will be registered into the 
trial.  
The starting dose of axitinib will be 5mg BID, escalated to 7mg BID and then 10mg BID. A dose modification 
assessment will take place every 2 weeks in clinic during the 8 week pre-surgical treatment period and will 
be dependent on tolerability of treatment. Patients will follow an aggressive axitinib dose escalation process 


 
 
 
 
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within the 8 week period to a maximum of 10mg BID. Patients should stop axitinib a minimum of 36 hours 
and a maximum of 7 days prior to surgery in week 9. 
Blood, urine and tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment 
response. Nephrectomy and IVC tumour thrombectomy will be planned for all patients on the trial.  
Where there is diagnostic doubt at site, a central review of week 0, 3 and 9 MRI and CT scans will be 
conducted to determine if a patient has progressed as per RECIST 1.1 criteria. In addition, those particular 
patient cases will be discussed on an individual basis by the trial steering committee (TSC).  In addition, a 
central review of scans will be carried out once all scans have been carried out to ensure that all 
measurements are compliant with the NAXIVA MRI SOP (v2.1). 
Patients will be assessed at weeks 1, 3, 5, 7, and 9 before surgery and followed up in clinic at 6 & 12 weeks 
post-surgery.  
3 
Reporting outline 
This section outlines the planned content of interim, final analyses and, if relevant, additional statistical study 
reports. 
3.1 Interim Analysis  
An interim analysis will be performed after thirteen patients have been recruited (recruitment will only 
be suspended for the purposes of conducting the interim analysis if no improvement in the Mayo 
Classification has been seen in any patients at the point where the thirteenth patient is recruited). The 
contents of this report are outlined in this section.  Further details regarding the composition of the 
relevant patient populations are provided in Section 4. 
3.1.1 Recruitment/accrual 
Data describing patient accrual, including comparison to desired targets, will be presented here 
(Section 7.1). 
3.1.2 Early stopping rules 
Stopping for reasons of futility: if zero evaluable patients have shown an improvement in 
disease, from screening to week 9, the trial will be stopped for futility. The rule for futility is 
specified in (Section 1.1) with further details set out in the efficiency analysis section (Section 
7.6.1). 


 
 
 
 
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Stopping for reasons of patient safety: completion rates for patient safety data in the ITT 
population (see Section 4.2 for population definition) to assess whether the early stopping rules 
have been violated will be prioritised for review by the DMC.  Should data completion be adequate 
to assess the early stopping rules (i.e., complete data for thirteen patients), each rule will be 
assessed. If any rules are violated the trial will be stopped for reasons of patient safety.  These 
rules are specified in Section 5.2 with further details set out in the safety analysis section 
(Sections 7.5.1, 7.5.2 and 7.5.3). 
3.1.3 Safety 
Data regarding toxicities, adverse events/reactions, serious adverse events (SAEs) and 
suspected unexpected serious adverse reaction (SUSARs) will be provided here. These analyses 
will be specified further in Section 5.1, with further details set out in the Toxicities (Sections 7.5.4) 
and Serious Adverse Events sections (Section Error! Reference source not found.). 
3.1.4 Efficacy 
Analyses relating to efficacy endpoints will be carried out on the evaluable population (see 
Section 4.3 for population definition); these analyses will be further specified in Section 6Error! 
Reference source not found. with further details set out in the Efficacy analysis section (Section 
7.67.6.1).  All endpoints will also be calculated for the ITT population to ensure that the 
conclusions drawn are the same in the context of patient discontinuation/compliance; this will 
require a change in denominator where percentages are calculated (Section 6.1Error! Reference 
source not found.). 
3.1.5 Baseline demographics 
Baseline demographics will be presented for the ITT population (see Section 7.3 for details). 
 
3.2 Final Analysis  
The final analysis will be performed after all data for 20 evaluable patients has been obtained.  The 
analyses performed and the data presented is as described in Section 3.1 for the interim report. 
If analysis findings with regards to efficacy endpoints for the evaluable population and the ITT 
population conflict (see Section 3.1.4), the DMC will discuss and advise with regards to the 
interpretation of these results. 


 
 
 
 
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In addition, 80% two-sided confidence intervals (to correspond to the 10% 1-sided sample size 
calculation) for the proportions relevant to the efficacy endpoints will be calculated using the approach 
in Koyama and Chen5 (again using both the evaluable and ITT populations as alternative contexts). 
4 
Populations and sample size  
4.1 Sample Size Calculations and recruitment schedule 
The aim is to recruit 20 patients over a 24 month period. A Simon two stage minimax design to 
distinguish a <5% from a >25% improvement in the Mayo classification requires 20 evaluable patients 
(90% power, 10% 1-sided). 
Thirteen patients would be recruited in the first stage.  If no patients demonstrate an improvement in 
their Mayo classification between screening and week 9, accrual to the clinical trial would stop (see 
Section 3.1.2).  If one or more patients demonstrate an improvement in the Mayo classification 
between screening and week 9, a further seven patients would be recruited (to the final total of 20 
evaluable patients).  In order for the clinical trial to be considered a success, at least three evaluable 
patients should demonstrate an improvement in disease or treatment between screening and week 9 
(see Section 7.6.1). 
4.2 Intention-to-treat (ITT) Population 
The Intention-to-treat (ITT) population includes all patients registered onto the study. 
4.3 Evaluable Population 
The evaluable population includes all patients in the ITT population who have received at least one 
dose of the study drug (including any patients who were enrolled in error, received study drug and 
were subsequently found to be ineligible). 
4.4 Safety Population 
The safety population includes all patients in the ITT population who have received at least one dose 
of the study drug (including any patients who were enrolled in error, received study drug and were 
subsequently found to be ineligible).  In this study, this population is equivalent to the evaluable 
population. 
5 
Safety Evaluations 
The study will use the following safety parameters. 


 
 
 
 
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5.1 Adverse events, SAEs and SUSARs 
All reported adverse events (including adverse reactions, SAEs and SUSARs) will be presented, 
with events categorised against the National Cancer Institute Common Terminology Criteria for 
Adverse Events v4.0. 
5.2 Early stopping rules 
Patient safety will be ensured by applying the following early stopping rules: 
(1) If a single M0 (staging data: cancer has not spread to other parts of the body) patient 
progresses to the point where surgery is no longer possible, then recruitment of new 
patients will be suspended following a review by the data monitoring committee (DMC) 
(2) If a single M0 (staging data: cancer has not spread to other parts of the body) patient 
becomes a M1 (staging data: cancer has spread to other parts of the body) patient, 
recruitment of new patients will be suspended following a review by the DMC. 
(3) If in 3 patients the VTT extends (as indicated by an increase in Mayo classification) but 
patients remain surgically resectable the trial will close. If the VTT has extended the patient 
will be expedited and operated on as soon as possible. 
6 
Efficacy evaluations 
Note that these evaluations will be made for both the evaluable and ITT populations.  This represents a 
sensitivity analysis that assesses whether results are robust in the ITT population. 
This study will use the following efficacy parameters: 
 
At least 3 evaluable patients showing improvement in disease extent between screening and week 9 
are required for a positive trial. 
 
The change in Mayo classification between screening and week 9 in evaluable patients will be 
presented with the percentage of patients with an improvement, no change and a deterioration in 
Mayo classification shown.  Percentages will be calculated using both the evaluable population and 
the ITT population. 
 
The VTT length measurement will be calculated as the sum of: (1) length of IVC tumour thrombus 
ABOVE renal vein (measured from ostium of RV+IVC to tip of tumour thrombus); (2) length of IVC 
tumour thrombus BELOW renal vein (measured from ostium of RV+IVC to tip of tumour thrombus) 
and (3) length of RV thrombus.  Those patients who are identified as “main renal vein” will only have 
the third value populated.  Any values that are missing cannot be assumed to represent 0 and must 
be clarified either via contact with sites or by manual checking of the paper CRF. 


 
 
 
 
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 
The percentage of patients who have had a change in the surgical approach will be calculated with 
the percentage with a less invasive and the percentage with a more invasive approach shown 
separately. Two pieces of data are relevant here: (1) a change from “Open Surgery” to “Minimally 
invasive surgery”; and (2) a change from a more invasive open to a less invasive open surgical 
approach (see Section 6.1 for a definition of surgical approach in this respect).  Percentages will be 
calculated using both the evaluable population and the ITT population. 
 
The response rate, as determined by RECIST criteria v1.1 and provided by sites will be presented 
and the percentage of outcomes categorised as complete response, partial response and progressive 
disease shown; only pre-surgical timepoints (i.e., weeks 3 and 9) will be considered. To provide further 
quality assurance that these RECIST evaluations are correct, the RECIST response will be 
recalculated from source data by the study statistician and compared to the evaluations provided 
provided by sites.  Should the evaluations not correspond with each other, a data query will be raised 
with the sites. 
 
Morbidity, in terms of the Clavien-Dindo classification system will be presented and percentage of 
patients with complications of grade I to V will be presented.  Percentages will be calculated using 
both the evaluable population and the ITT population. 
6.1 Additional definitions 
Definitions of the Mayo classification and surgical approach classification systems that should be used 
to define improvement are shown below: 
Mayo classification (levels are ordered by increasing extensiveness): 
 
Level 0: thrombus limited to the renal vein 
 
Level 1: into IVC <2cm from renal vein ostium level 
 
Level 2: IVC extension >2cm from renal vein ostium and below hepatic vein 
 
Level 3: thrombus at the level of or above the hepatic veins but below the diaphragm 
 
Level 4: thrombus extending above the diaphragm. 
Tumour thrombus surgical management approach classification (approaches are ordered by 
increasing invasiveness): 
1. Thrombus - Milked back into renal vein and side clamped 
2. Infra-hepatic (IVC clamping with no liver mobilisation) 
3. Retro-hepatic (liver mobilisation and clamping below hepatic veins) 
4. Retro-hepatic (liver mobilisation and clamping above hepatic veins) 
5. Supra-hepatic (infradiaphragmatic) 


 
 
 
 
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6. Supra-hepatic (supradiaphragmatic) 
Note that efficacy outcomes can be expressed as a percentage of the ITT population or the evaluable 
population (meaning that the denominator should change to be either the size of the relevant 
population). 
7 
Tabulations, Figures and Listings 
This section is the complete operational specification for the statistical analysis and subsequent presentation 
of that analysis for the lifetime of this trial. Throughout this section, tabulations consist of counts and 
percentages per category unless stated otherwise.  Listings will include the patient identifier and the specific 
data for that listing. 
7.1 Study Recruitment (ITT population) 
- 
Plot of actual cumulative recruitment against time since study opened will be provided; target 
recruitment rate line will be superimposed on this plot. 
- 
Table of recruitment by centre showing the date the centre opened, the date the first and last 
patients were recruited and the number recruited. Centres that have opened but not recruited 
patients will be included in this table. 
7.2 Eligibility/Population membership (ITT population) 
- 
Numbers of patients in each population (Sections 4.2 and 4.3) will be presented. 
- 
Ineligible patients will be listed along with the reason for their ineligibility. 
- 
Patients who are recruited but do not receive any treatment will be listed with reasons for not 
treating. 
7.3 Baseline data and demographic characteristics (ITT population) 
Discrete variables will be summarised by frequencies and percentages. For continuous variables 
medians, inter-quartile ranges and ranges will be presented and where appropriate, the results will be 
presented in suitable categories: 
- 
Registering centre 
- 
Age at registration 
- 
Karnofsky Performance status (ECOG) 
- 
Other medical conditions (frequency and list), with specific reference to cardiovascular, 
cerebrovascular, 
thromboembolic, 
respiratory, 
gastrointenstinal, 
endocrine/metabolic, 


 
 
 
 
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neurological conditions (further specification of “Other” reasons will be listed).  Existing 
allergies should also be included and specified. 
- 
Heart rate, respiratory rate, systolic and diastolic blood pressure 
- 
Height, Weight, BMI 
- 
Pregnancy test (conducted and result) 
- 
Existing signs and symptoms (with CTCAE gradings) 
- 
Laboratory investigations, including full blood count; white blood cell count; serum 
biochemistry; thyroid function; urinalysis 
- 
Previous diagnosis of other cancer 
- 
Renal Cell Carcinoma histological type (including whether predominantly clear cell) 
- 
Tumour data, including staging (TNM status); grading (ISUP/Furman); MSKCC model and 
risk; IMDC model and prognosis 
- 
Surgical assessment data, including whether patient is surgically resectable; whether 
radiotherapy has been given 
- 
Lesion data: number of target and non-target lesions; sums of longest target lesions diameters 
- 
Thrombus data: IVC and/or MRV involvement; relevant measurements (see Section 6) 
- 
Mayo classification  
7.4  Delivery of study therapy (evaluable population) 
- 
Total dose (mg) taken per patient separately for axitinib (median, IQ range and range) 
- 
Total dose (mg) missed per patient separately for axitinib (median, IQ range and range) 
- 
Percentage of intended dose taken per patient (taken/(taken+missed)) separately for axitinib 
(median, IQ range and range) 
- 
Reasons for missed doses will be tabulated; further specification of “other” reasons will be 
listed. 
- 
The number of dose reductions per patient 
- 
The number of dose escalations per patient 
- 
Reasons why axitinib was reduced to 3mg BID 
- 
Reasons why axitinib was reduced to 2mg BID 
- 
Reasons for stopping trial drug will be tabulated; “other” reasons and “Adverse event/toxicity” 
reasons will be listed 


 
 
 
 
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7.5 Safety Analysis 
7.5.1 To inform early stopping rule (1) (Section (1)5) (ITT population) 
A listing of: 
- 
Patient label 
- 
Staging (M) data at screening  
- 
Date of Surgery 
- 
Flag indicating whether surgery took place 
- 
Whether the patient belongs to the evaluable population 
- 
Relevant patient notes including any reasons that surgery was not performed or staging has 
not been provided 
7.5.2 To inform early stopping rule (2) (Section 5) (ITT population) 
A listing of: 
- 
Patient label 
- 
Staging (M) data at screening 
- 
Flag indicating whether surgery took place 
- 
Staging (M) data at surgery  
- 
Whether the patient belongs to the evaluable population 
- 
Relevant patient notes including any reasons that surgery was not performed or staging has 
not been provided 
7.5.3 To inform early stopping rule (3) (Section 5) (ITT population) 
A listing of: 
- 
Patient label 
- 
Mayo classification at screening 
- 
Mayo classification at week 3 
- 
Mayo classification at week 9 
- 
Flag indicating whether surgery took place 
- 
Details of all patients with extension of their VTT will be presented including the planned 
surgery and procedure performed. 


 
 
 
 
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7.5.4 Toxicities (including adverse events and laboratory values) (Safety population) 
- 
All adverse events will be coded according to the CTC toxicity criteria and the worst value over 
the study drug periods determined for each patient. 
- 
Laboratory values will be coded according to the CTC toxicity criteria and the worst value over 
the study period determined for each patient. 
- 
Any adverse events or laboratory anomalies which are graded ≥ grade 1 by at least 10% of 
patients will be tabulated. 
- 
Details of toxicities will be summarised to show (i) grade at trial entry; (ii) the highest grade 
over the course of treatment; and (iii) the highest grade in follow up.  For any toxicity graded 
≥ grade 2 at any timepoint, the toxicity grading will be tracked over the course of the trial in a 
graphical form. 
7.5.5 Serious Adverse Events/Reactions and SUSARs (ITT population) 
- 
Details of serious adverse events/reactions and SUSARs will be provided in a separate 
document output from the SCTRU’s pharmacovigilance database. 
7.6 Efficacy analysis (evaluable and ITT populations) 
Note that these analyses will be carried out for both the evaluable and ITT populations.  This 
represents a sensitivity analysis that assesses whether results are robust in the ITT population. 
7.6.1 Primary endpoints 
NB. For all primary endpoint assessments, if a patient does not have a week 9 scan, then their 
week 3 scan (if available) should be used instead. 
7.6.1.1 For patients presenting at screening with a Mayo Classification of Level 1 or above 
- 
The number and percentage of patients with an improvement in the Mayo Classification 
between screening and week 9 (see Section 6.1 for Mayo classification system). 
- 
The number and percentage of patients with no change in the Mayo Classification between 
screening and week 9 (see Section 6.1 for Mayo classification system). 
- 
The number and percentage of patients with deterioration in the Mayo Classification between 
screening and week 9 (see Section 6.1 for Mayo classification system). 
7.6.1.2 For patients presenting at screening with a Mayo Classification of Level 0 
- 
The number and percentage of patients demonstrating improvement in status, i.e.: 


 
 
 
 
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o For patients presenting with right renal vein tumour thrombus: a change of tumour 
thrombus from main renal vein to branches of the renal vein between screening and 
week 9. 
o For patients presenting with left renal vein tumour thrombus: a change of tumour 
thrombus from the main renal vein between screening and week 9 as follows: 
 
If the patient is lateral to the gonadal vein at screening, a change from the main 
renal vein into the segmental veins 
 
If the patient is medial to the gonadal vein at screening, a change from the main 
renal vein medial to the gonadal vein to the renal vein lateral to the gonadal 
vein 
- 
The number and percentage of patients with no change in tumour thrombus status (i.e., tumour 
still present in the main renal vein and medial to the gonadal vein (on left side)) between 
screening and week 9. 
- 
The number and percentage of patients demonstrating an extension of the thrombus into the 
inferior vena cava between screening and week 9. 
7.6.2 Secondary endpoints 
- 
% change in surgical approach for all patients comprising: 
 
% with less invasive approach 
 
% with no change in surgical approach 
 
% with more invasive approach 
- 
% change in VTT length across all timepoints for each patient (see Section 6) 
- 
% change in VTT length, stratified by pre-surgical RECIST response (as provided by site) 
- 
Waterfall plot of % change in VTT length, coloured by pre-surgical RECIST response (as 
provide by site) 
- 
Radiological response (RECIST) data (pre-surgical timepoints only), comprising: 
 
% with complete response 
 
% with partial response 
 
% with stable disease 
 
% with progressive disease 
 
comparison with RECIST values calculated in-house where possible 
- 
Evaluation of morbidity assessed by Clavian-Dindo classification 
 
% with grade I to V complications 


 
 
 
 
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7.7 Additional analyses 
The correlation of the drug exposure with the response of the VTT will be examined by presenting the 
Pearson’s correlation coefficient between the total dose of drug received and the percent reduction in 
VTT. 
8 
Statistical Methods for the Analysis of the Study Data 
As this is a single arm feasibility study results will be presented as counts, frequencies and percentages. 80% 
confidence intervals will be provided for the percentage of evaluable patients with an improvement in their 
Mayo Classification between screening and week 9, percentage change in surgical approach and percentage 
change in VTT height. 
8.1 Methods for handling missing values 
As part of the trial management process missing data is closely managed with the intention of 
minimising the amount of missing data to the lowest level possible. Particular attention will be placed 
upon primary and secondary end point data.  
SCTRU will regularly review the data for compliance with the protocol, and for inconsistent or missing 
data. Should any missing data or data anomalies be found, queries will be sent to the site for resolution. 
Sites are expected to respond to queries within a timeous manner. 
All missing data is queried with sites and where the data cannot be sources an explanation is required 
and quality assurance procedures are applied to validate the quality and completeness of the data 
before any analysis is carried out. 
Once the data has been declared as ready for analysis a missing value analysis will be carried out. 
This will describe the pattern of missing data, identify where the missing data are located and how 
extensive it is, identify pairs of variables which have missing values in multiple cases and assess if 
data is missing randomly. 
Means, standard deviations, covariates and correlations for different missing value methods (listwise, 
pairwise, regression and expectation-maximisation) will be produced. 
Where missing data is above an acceptable level of 10% for any primary or secondary outcome data 
or explanatory covariates multiple imputation will be considered. 


 
 
 
 
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9 
Reference list 
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(version 1.1). Eur J Cancer 2009;45:228-47.  
2. National Cancer Institute. Cancer Therapy Evaluation Programme. Common Terminology Criteria 
for Adverse Events v4.0. Available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
3. Mander A.P., Thompson S.G. Two-stage designs optimal under the alternative hypothesis for phase 
II cancer clinical trials. Contemp Clin Trials. 2010 Nov; 31(6): 572–578. Available at 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049867/ 
4. Vollset, S. E. ‘Confidence intervals for a binomial proportion’, Statistics in Medicine, 12, 809–824 
(1993). 
5. Koyama, Tatsuki, and Heidi Chen. “Proper inference from Simon's two-stage designs.” Statistics in 
medicine vol. 27,16 (2008): 3145-54. Available at 
https://onlinelibrary.wiley.com/doi/10.1002/sim.3123.