IN THE CLINIC
‘NAXIVA’ stands for Neoadjuvant study of AXItinib for reducing extent of venous tumour thrombus in clear cell renal cell cancer with Venous invAsion, a phase II feasibility study investigating the effectiveness of the drug axitinib at reducing the extent of cancer invasion into the large blood vessels draining the kidney.
While the current standard of care for patients with clear cell renal cell cancer (ccRCC) involves surgical excision within 4 weeks of confirmed diagnosis, 5-year survival rates after surgery remain poor and new approaches are urgently required. Already used as standard of care in metastatic renal cell cancer (mRCC), axitinib offers a promising candidate for novel neoadjuvant treatment. Previous findings suggest that pre-surgical treatment with axitinib is safe and effective in non-metastatic patients, with a 100% tumour response rate and a 28% average reduction of tumour size (Karam et al, 2017), but the effects on ccRCC patients with VTT have not yet been studied.
Specifically designed to address this need, NAXIVA is a multicentre, single arm, single agent, open label phase II feasibility study investigating the effectiveness of axitinib as a method of downstaging the extent of venous tumour thrombus (VTT) prior to extirpative surgery in patients with both metastatic and non-metastatic ccRCC. Since a reduction in VTT invasion could potentially minimise the extent and complexity of surgery required - lessening surgical risks and complications as a result of smaller incisions and less invasive operations – the results have the potential to reduce post-surgery morbidity and mortality and offer the possibility of longer disease-free survival in patients treated with axitinib prior to surgery.
NAXIVA aims to recruit 20 patients with both metastatic and non-metastatic ccRCC with VTT over a 24-month period, identifying potentially eligible patients from hospital clinics across 7 UK centers. Eligible participants will include patients either with RCC cancer invasion confined to the renal vein - where a reduction in the extent of the venous invasion would enable simpler laparoscopic surgery in place of more complicated open surgical approaches – or with more extensive cancer invasion into the inferior vena cava, where surgical complexity and associated morbidity could also potentially be reduced as a result of ameliorated venous invasion.
All participants will receive axitinib for 8 weeks prior to surgery according to a well-established dose regime shown to be effective in patients with mRCC (starting at 5mg twice a day, then to 7mg twice a day and then up to a maximum of 10mg twice a day, as rapidly as possible). Since this regime doubles the standard 4-week period between diagnosis and surgery, all participants will receive extra MRI scans at week 3 to counteract possible risk of tumour progression from operable to non-operable. Any participant whose tumour has grown by 20% or more will be removed from the trial and expedited for surgery as soon as possible. In addition, all non-metastatic patients will have an additional chest CT at this point to assess for disease progression and reduce the risk of withholding surgery.
Patients will be followed up 2 weeks after axitinib is first dispensed and then every 2 weeks until surgery in week 9. At each visit blood pressure, bloods and urine samples will be taken to test and monitor side effects and toxicities. At week 9 the patient will have completed their course of study drug and no further axitinib will be prescribed. Routine assessments will be carried out prior to surgery. As per standard care, patients will be seen at 6 and 12 weeks post surgery.
Trial Visit Schedule
The response of VTT to axitinib will be assessed according to the percentage of patients with reduction in the Mayo Classification. Secondary outcomes include the percentage change in surgical approach, the percentage change in height of the VTT, the objective tumour response rate (RECIST), and evaluation of surgical morbidity assessed by Clavian-Dindo classification. If the results of this trial are positive, therapeutic mechanisms and possibilities will be explored in a fully powered phase III randomised control trial.
Led by Professor Grant Stewart as Chief Investigator, NAXIVA is sponsored by the Common Services Agency and co-ordinated by the Scottish Clinical Trials Research Unit (SCTRU) in Edinburgh. The trial is funded by Pfizer Limited and endorsed by Cancer Research UK (CRUK).