A study to see how effective the drug Axitinib is at preventing cancer cells from growing and to see if this means that patients with kidney cancer require less extensive surgery

ISRCTN	ISRCTN96273644
DOI	https://doi.org/10.1186/ISRCTN96273644
EudraCT/CTIS number	2017-000619-17
ClinicalTrials.gov number	NCT03494816
Secondary identifying numbers	NAXIVA 2.0 (06/06/2018)

Submission date: 13/02/2017
Registration date: 01/03/2017
Last edited: 10/10/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-of-axitinib-for-kidney-cancer-naxiva

Contact information

Mrs Kathleen Riddle
Public

Scottish Clinical Trials Research Unit
Information Services Division
NHS National Services Scotland
Gyle Square
1 South Gyle Crescent
Edinburgh
EH12 9EB
United Kingdom

Dr Grant Stewart
Scientific

Academic Urology Group
University of Cambridge
Box 43, Addenbrooke's Hospital
Cambridge Biomedical Campus
Hill's Road
Cambridge
CB2 0QQ
United Kingdom

ORCID ID	0000-0003-3188-9140

Study information

Study design	Single-arm single-agent open label phase II feasibility study
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet.
Scientific title	Phase II neoadjuvant study of Axitinib for reducing extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion
Study acronym	NAXIVA
Study objectives	A reduction in the extent of the venous tumour thrombus, 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.
Ethics approval(s)	East of England – Cambridgeshire and Hertfordshire Ethics Committee, 02/08/2017
Health condition(s) or problem(s) studied	Clear cell renal cell cancer with venous thrombus invasion
Intervention	All participants will receive an 8 week course of Axitinib. Patients will be followed up every 2 weeks from day 1, week 1 of receiving Inlyta. All patients will start at 5mg BID with possible escalation to 7mg BID and the max 10mg BID. Only if no adverse events related to study drug above CTCAE grade 2 for a consecutive 2-week period the patient may have their dose increased by one dose level to a maximum of 10 mg BID. Patients will be given a 2 week supply at each follow up visit of Inlyta (oral tablet) to be taken twice daily as per instructed.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Axitinib
Primary outcome measure	Thrombus invasion will be measured using MRI scanning according to the Mayo classification at baseline and pre-surgery (week 9).
Secondary outcome measures	Current secondary outcome measures as of 23/04/2018: 1. Percentage change in surgical approach (to a less invasive surgical approach) as assessed by review of MRI scans by surgeons at baseline and week 9 (i.e after axitinib therapy has been completed) 2. Percentage change in height of the cancer invasion into the large blood vessels draining the kidney (venous tumour thrombus). This will be evaluated by comparing baseline and week 9 scans. Local radiologists will conduct the evaluation and a central radiology review will be conducted. 3. Objective tumour response rate measured by MRI/CT scans at baseline and week 9. 4. Complications of surgery (i.e. blood loss and need for a blood transfusion) assessed according to the Clavien-Dindo classification of surgical complications at baseline and week 9 Previous secondary outcome measures 1. Percentage change in surgical approach is assessed by review of MRI scans by surgeons at baseline and 9 weeks 2. Percentage change in height of the venous tumour thrombus will be evaluated by comparing baseline and week 9 scans. Local Radiologists will conduct the evaluation and a central radiology review will be conducted. 3. The response rate (RECIST) will be measured by MRI/CT at baseline and week 9 4. Change in Inferior vena cava- tumour thrombus volume will be assessed by radiologists comparing CT/MRI scans taken at baseline and week 9 5. Morbidity will be measured using MRI/CT scanning according to the Clavien-Dindo classification at baseline and week 9
Overall study start date	01/03/2017
Completion date	10/06/2020

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	20 patients will be recruited over a 24 month period in 6-8 sites across the UK.
Total final enrolment	21
Key inclusion criteria	Current inclusion criteria as of 11/02/2019: 1. Aged 18 years and over 2. Biopsy-proven clear cell RCC 3. Immediate resection of the primary tumour considered technically possible 4. The patient must be suitable for and willing to undergo nephrectomy surgery 5. The clinical (radiologically determined) stage of the tumour must be into the main renal vein (cT3a, but seen in the main branch of the renal vein leading to but not beyond the vein ostium with the inferior vena cava (IVC)), or the IVC itself either below of above the diaphragm (cT3b or cT3c respectively) 6. Nodal status may be clinically node negative (cN0) on CT, indeterminate (cNx) or clinically node positive on CT (cN1) 7. Non-metastatic (M0) and metastatic (M1) clear cell renal cell patients 8. The patient must have an ECOG performance status of either 0 or 1 9. Urine must contain less than 2 g protein. If urine contains ≥2 g then a 24-h urine collection or urinary protein creatinine ratio (PCR) should be performed and the patient may enter NAXIVA only if urinary protein is <2g per 24 hours or PCR <200mg/mmol. 10. Serum Creatinine ≤1.5xULN or estimated Creatinine clearance ≥30mL/min as calculated using the Cockcroft- Gault (CG) equation. 11. 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. Previous inclusion criteria as of 23/04/2018: 1. Aged 18 years and over 2. Biopsy-proven clear cell RCC 3. Immediate resection of the primary tumour considered technically possible 4. The patient must be suitable for and willing to undergo nephrectomy surgery 5. The clinical (radiologically determined) stage of the tumour must be into the main renal vein (cT3a, but seen in the main branch of the renal vein leading to but not beyond the vein ostium with the inferior vena cava (IVC)), or the IVC itself either below of above the diaphragm (cT3b or cT3c respectively) 6. Nodal status may be clinically node negative (cN0) on CT, indeterminate (cNx) or clinically node positive on CT (cN1) 7. Non-metastatic (M0) and metastatic (M1) clear cell renal cell patients 8. The patient must have an ECOG performance status of either 0 or 1 9. Urine must contain less than 2 g protein. If urine contains ≥2 g then a 24-h urine collection should be performed and the patient may enter if urinary protein is <2 g 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. Previous inclusion criteria: 1. Aged 18 years and over 2. Biopsy proven clear cell RCC 3. Resectable Tumour 4. The clinical (radiologically determined) stage of the tumour must be into the main renal vein (cT3a, but seen in the main branch of the renal vein leading to but not beyond the vein ostium with the inferior vena cava (IVC)), or the IVC itself either below of above the diaphragm (cT3b or cT3c respectively) 5. Nodal status may be clinically node negative (cN0) on CT, indeterminate (cNx) or clinically node positive on CT (cN1) 6. Non-metastatic (M0) and Metastatic (M1) clear cell renal cell patients 7. Stratification by the Mayo classification
Key exclusion criteria	Current exclusion criteria as of 11/02/2019: 1. Metastatic patients with poor risk on the Memorial Sloan Kettering Cancer Centre (MSKCC) score and deemed suitable for cytoreductive nephrectomy at time of enrolment 2. Other invasive malignancy within the last 2 years. Patients with previous history of malignancies with a negligible risk of metastasis or death and treated with expected curative intent are eligible, for example but not exclusively: 2.1. Carcinoma in situ of the cervix. 2.2 Basal or squamous cell skin cancer. 2.3 Localized low to intermediate risk prostate cancer treated with curative intent and absence of prostate specific antigen (PSA) relapse; or prostate cancer (Stage T1/T2a, Gleason ≤6 and PSA 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. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrolment. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. 4. Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine, pulmonary disease other than directly related to RCC 5. Gastrointestinal abnormalities including: 5.1. Inability to take oral medication 5.2. Requirement for intravenous alimentation 5.3. Prior surgical procedures affecting absorption including total gastric resection 5.4. Treatment for active peptic ulcer disease in the past 6 months 5.5. 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 5.6. Malabsorption syndromes 6. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (see section 8.12, concomitant therapy) 7. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (see section 8.12, 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: 10.1 myocardial infarction 10.2 uncontrolled angina 10.3 coronary/peripheral artery bypass graft 10.4 symptomatic congestive heart failure 10.5 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 upper limit of normal; Bilirubin ≥1.5 x upper limit of normal 14. Serum creatinine ≥1.5 x upper limit of normal 15. Neutrophil count <1.0 x 10(9)/l; platelet count <100 x 10(9)/l; Hb ≤90 g/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. Previous exclusion criteria as of 23/04/2018: 1. Metastatic patients with poor risk on the Memorial Sloan Kettering Cancer Centre (MSKCC) score and deemed suitable for cytoreductive nephrectomy at time of enrolment 2. 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. 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. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrolment. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. 4. Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine, pulmonary disease other than directly related to RCC 5. Gastrointestinal abnormalities including: 5.1. Inability to take oral medication 5.2. Requirement for intravenous alimentation 5.3. Prior surgical procedures affecting absorption including total gastric resection 5.4. Treatment for active peptic ulcer disease in the past 6 months 5.5. 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 5.6. Malabsorption syndromes 6. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (see section 8.12, concomitant therapy) 7. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (see section 8.12, 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: 10.1 myocardial infarction 10.2 uncontrolled angina 10.3 coronary/peripheral artery bypass graft 10.4 symptomatic congestive heart failure 10.5 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 upper limit of normal; Bilirubin ≥1.5 x upper limit of normal 14. Serum creatinine ≥1.5 x upper limit of normal 15. Neutrophil count <1.0 x 10(9)/l; platelet count <100 x 10(9)/l; Hb ≤90 g/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. Previous exclusion criteria 1. 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. 2. 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. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment. 3. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy 4. Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine, pulmonary disease other than directly related to RCC. 5. Gastrointestinal abnormalities including: 5.1. Inability to take oral medication 5.2. Requirement for intravenous alimentation 5.3. Prior surgical procedures affecting absorption including total gastric resection 5.4. Treatment for active peptic ulcer disease in the past 6 months 5.5. 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 5.6. Malabsorption syndromes 6. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (see section 8.12, concomitant therapy) 7. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (see section 8.12, 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. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness
Date of first enrolment	01/12/2017
Date of final enrolment	06/01/2020

Locations

Countries of recruitment

England
Scotland
United Kingdom

Study participating centres

Addenbrooke's Hospital

Cambridge Biomedical Campus
Hill's Road
Cambridge
CB2 0QQ
United Kingdom

Beatson West of Scotland Cancer Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Western General Hospital

Crewe Road South
Edinburgh
EH4 2XU
United Kingdom

Royal Marsden

Fulham Road
London
SW3 6JJ
United Kingdom

St George's Hospital

Blackshaw Road
London
SW17 0QT
United Kingdom

Broomfield Hospital

Court Road
Broomfield
Chelmsford
CM1 7ET
United Kingdom

The Royal Free Hospital

Pond St.
Hampstead
London
NW3 2QG
United Kingdom

Sponsor information

Common Services Agency
Government

Strategic Business Unit
Public Health and Intelligence (Information Services Division)
Gyle Square
South Gyle Crescent
Edinburgh
EH12 9EB
United Kingdom

"ROR"	https://ror.org/04za2st18

Funders

Funder type

Industry

Pfizer UK
Private sector organisation / For-profit companies (industry)

Alternative name(s): Pfizer Ltd, Pfizer Limited
Location: United Kingdom

Results and Publications

Intention to publish date	01/07/2022
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Other
Publication and dissemination plan	Planned publication in a high-impact peer-review journal.
IPD sharing plan	The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results	ClinicalTrials.gov	30/06/2021	23/05/2022	No	No
Basic results	EU-CTR	23/05/2021	16/06/2022	No	No
Results article		23/06/2022	29/07/2022	Yes	No
Protocol file	version 2.0	06/06/2018	10/10/2022	No	No

Additional files

ISRCTN96273644_Protocol_V2.0_06Jun2018.pdf

Editorial Notes

10/10/2022: Protocol file uploaded.
29/07/2022: Publication reference added.
16/06/2022: EU Clinical Trials Register results added.
23/05/2022: ClinicalTrials.gov results added.
10/03/2022: The intention to publish date has been changed from 01/03/2022 to 01/07/2022.
17/12/2021: The intention to publish date was changed from 10/12/2021 to 01/03/2022.
10/06/2021: The intention to publish date has been changed from 10/06/2021 to 10/12/2021.
07/10/2020: The contact details were updated.
17/08/2020: The following changes were made to the trial record:
1. The overall trial end date was changed from 10/08/2020 to 10/06/2020.
2. The intention to publish date was changed from 10/08/2021 to 10/06/2021.
3. IPD sharing statement added.
07/01/2020: The following changes have been made:
1. The total final enrolment number has been changed from 20 to 21.
2. The recruitment end date has been changed from 30/11/2019 to 06/01/2020.
20/12/2019: The following changes have been made:
1. The total final enrolment number has been added.
2. The overall trial end date has been changed from 01/01/2020 to 10/08/2020.
3. The intention to publish date has been changed from 31/07/2021 to 10/08/2021.
11/02/2019: The following changes were made:
1. The public contact was changed
2. A ClinicalTrials.gov number was added
3. The protocol /serial number was changed from NAXIVA 1.2 (22/09/2017) to NAXIVA 2.0 (06/06/2018)
4. The exclusion criteria have been changed
5. The trial participating centre "Christie Hospital, Manchester" has been removed, and "Broomfield Hospital,Chelmsford" and "The Royal Free Hospital, London" have been added.
6. The inclusion criteria have been changed.
14/05/2018: Cancer Research UK lay summary link added to plain English summary field
23/04/2018: The following changes have been made following changes to the trial design associated with REC and MHRA review:
1. The protocol number has been changed from NAXIVA 1.0 to NAXIVA 1.2 (22/09/2017)
2. Ethics approval information has been added.
3. The secondary outcome measures have been changed.
4. The participant inclusion criteria have been changed.
5. The participant exclusion criteria have been changed.
6. The recruitment start date has been changed from 30/09/2017 to 01/12/2017.
7. The recruitment end date has been changed from 01/10/2019 to 30/11/2019.
16/01/2018: Internal review.
16/10/2017: Internal review.