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

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.

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.

Eligibility Criteria:
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:

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
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.