A Phase II Study of Axitinib in Patients With Metastatic Renal Cell Cancer Unsuitable for Nephrectomy

A-PREDICT is a study of axitinib in patients with metastatic renal cell carcinoma unsuitable for nephrectomy (as judged by the treating clinician) to evaluate efficacy, safety, toxicity and changes in biomarkers during therapy. Axitinib will given twice daily by mouth according to tolerability of treatment, for as long as patients are deriving clinical benefit. Blood and tumour tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response. The primary clinical objective of this study is to define the activity of axitinib given to patients with metastatic renal cell carcinoma unsuitable for nephrectomy.

A-PREDICT is a single arm, single agent, open label, multicentre, phase II study of axitinib in patients with metastatic renal cell carcinoma of predominant clear cell histology and unsuitable for debulking nephrectomy (as judged by the treating clinician). Patients who have provided consent and have satisfied the eligibility criteria will be registered into the trial.

The starting dose of axitinib will be 5 mg twice daily by mouth, escalating to a maximum of 10mg twice daily by mouth according to tolerability of treatment, for as long as patients are deriving clinical benefit. Treatment will be paused for one week prior to percutaneous biopsy of the primary on day 1 week 9. Disease progression will be evaluated according to RECIST v1.1 criteria 8 weeks after commencing treatment, at 8 weekly intervals to 6 months and 3 monthly thereafter. Blood and tumour tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response. Nephrectomy will be carried out on any patient who becomes suitable in the opinion of the treating clinician during the course of the trial. Where possible, tissue samples will be taken from resected specimens. Response to axitinib in marker lesions will be correlated with changes in biomarkers.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically confirmed metastatic renal cell carcinoma of predominant clear cell histology
2. Unsuitable for nephrectomy
3. Unsuitable for 'watch and wait' policy
4. No prior systemic therapy for renal cell carcinoma
5. Measurable metastatic disease using RECIST v1.1
6. Life expectancy 12 weeks or greater
7. ECOG performance status 0 or 1
8. Adequate organ function as defined by serum aspartate transaminase (AST) or serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities are due to liver metastases; total serum bilirubin ≤1.5 x ULN
9. Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1500/μL, platelets ≥75,000/μL, haemoglobin ≥9.0 g/dL and prothrombin time (PT) ≤1.5 x ULN
10. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min;
11. Urinary protein \<2+ by urine dipstick.
12. No evidence of pre-existing uncontrolled hypertension
13. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.
14. Willingness and ability to comply with study procedures, including tumour biopsies.
15. Written informed consent

Exclusion Criteria:

1. The presence of intracranial disease, unless stable \>6 months. In the case of a solitary brain metastasis which has been resected, there must be evidence of a disease-free interval of at least 3 months post-surgery. All patients previously treated for brain metastases must be stable off corticosteroid therapy for at least 28 days.
2. The presence of active second malignancy.
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.
4. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy.
5. Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine, pulmonary disease other than directly related to RCC.
6. Gastrointestinal abnormalities including:

   1. inability to take oral medication;
   2. requirement for intravenous alimentation;
   3. prior surgical procedures affecting absorption including total gastric resection;
   4. treatment for active peptic ulcer disease in the past 6 months;
   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;
   6. malabsorption syndromes.
7. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (see section 8.12, concomitant therapy).
8. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (see section 8.12, concomitant therapy).
9. 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.
10. Active seizure disorder, spinal cord compression, or carcinomatous meningitis.
11. 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.
12. Deep vein thrombosis or pulmonary embolism within 6 months prior to study entry.
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
14. Known galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption