Study of Axitinib for Reducing Extent of Venous Tumour Thrombus in Renal Cancer With Venous Invasion

Study Overview
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Brief Summary
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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
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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.

Official Title
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NAXIVA- Phase II Neoadjuvant Study of Axitinib for Reducing Extent of Venous Tumour Thrombus in Clear Cell Renal Cell Cancer With Venous Invasion

Conditions
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Renal Cell Carcinoma, Metastatic Renal Cell Carcinoma, Non-metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Axitinib Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Age ≥ 18. 2. Histologically proven clear cell RCC. 3. Immediate resection of the primary tumour considered technically possible. 4. Suitable for and willing to undergo nephrectomy (either cytoreductive or with curative intent) 4. cT3b, cT3c, cT3a (main renal vein) 5. N0, N1, or Nx 6. M0, or M1 7. ECOG performance status 0 - 1 8. 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. 9. 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. Exclusion Criteria: For M1 patients: poor risk on Memorial Sloan Kettering Cancer Centre (MSKCC) score and deemed suitable for cytoreductive nephrectomy at time of enrolment. 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. 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). Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine or pulmonary disease other than directly related to RCC. 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. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (see section 4.4, concomitant therapy). Current use, or anticipated need for treatment with, drugs that are known CYP3A4 inducers or substrates for CYP1A2 (see section 4.4, concomitant therapy). 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. Active seizure disorder, spinal cord compression, or carcinomatous meningitis. 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. Uncontrolled hypertension (>160/100 mmHg despite optimised antihypertensive treatment). Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. ALT or AST ≥ 1.5 x ULN; Bilirubin ≥ 1.5 x ULN. Serum creatinine ≥ 1.5 x ULN Neutrophil count < 1.0 x 109/L; platelet count < 100 x 109/L; Hb ≤ 90g/L. Known severe hepatic impairment (Child-Pugh class C) 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axitinib<br>Axitinib - oral tablet twice daily for 8 weeks prior to surgery. Starting dose 5mg. | Drug: Axitinib Oral Tablet<br>* 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.<br>* Other names: AG-013736;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With a Change in Mayo Classification | The number and percentage of evaluable patients with a change in the Mayo Classification. A patient is defined as a responder if their Mayo level is lower at 9 weeks as compared to baseline; all other patients are defined as non-responders. The Mayo Classification levels are defined as follows, ordered by increasing severity: 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 | Surgery and radiology assessment at week 9 in comparison to pre-axitinib assessment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| % Patients With Change in Surgical Management | The percentage of patients with a change in surgical management. Tumour thrombus surgical management approaches are provided below, ordered by increasing invasiveness: Thrombus - Milked back into renal vein and side clamped Infra-hepatic (IVC clamping with no liver mobilisation) Retro-hepatic (liver mobilisation and clamping below hepatic veins) Retro-hepatic (liver mobilisation and clamping above hepatic veins) Supra-hepatic (infradiaphragmatic) Supra-hepatic (supradiaphragmatic) | Surgical planning will be conducted at week 1 (prior to axitinib) and compared to the actual outcome at week 9. | 
| Change in Venous Tumour Thrombus (VTT) Height | The percentage change in VTT height. VTT height is measured as follows: if the size of the tumour is X at baseline and Y at the later timepoint, the reduction value is calculated as follows: 1-(Y/X). Therefore, positive values indicate a reduction and negative values indicate an increase. | Radiology assessment- The VTT height will be measured prior to axitinib and compared with the VTT height just before surgery (week 9). Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis. | 
| Number of Patients With RECIST Responses | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI. In summary, the RECIST v1.1 response categories are: Complete Response (CR): disappearance of all target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions Progressive Disease (PD): >=20% increase in the sum of diameters of target lesions AND an absolute increase of >5mm (or the appearence of 1+ new lesions) Stable Disease (SD): neither sufficient shrinkage to for PR nor sufficient increase for PD Eisenhauer et al., 2009. Eur J Cancer; 45(2): 228-47. | Radiology assessment- The response rate (RECIST) will be assessed at week 9 in comparison to pre-axitinib measurements.Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis. | 
| Surgical Complication Rates | Morbidity will be measured according to the Clavien-Dindo classification. A summary of the relevant categories is as follows: Grade I: Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention (inc. certain drugs, physiotherapy and wound infections that are opened at the bedside) Grade II: Complications requiring drug treatments other than those allowed for Grade I complications (inc. blood transfusion and total parenteral nutrition (TPN)) Grade III: Complications requiring surgical, endoscopic or radiological intervention (IIIa=not under general anaesthetic/IIIb=under general anaesthetic) Grade IV: Life-threatening complications (inc. CNS complications requiring intensive care, but excludes transient ischaemic attacks (TIAs)) (IVa=single-organ dysfunction (inc. dialysis)/IVb=multi-organ dysfunction) Grade V: Death of the patient Dindo et al., 2004. Ann Surg;240(2):205-13. | Morbidity rates will be assessed by radiology assessment using pre-axitinib and week 9 scans. Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant, Venous Tumour Thrombus, Axitinib, Mayo Classification, Nephrectomy, Thrombectomy