Axitinib Intensification Plus Nivolumab or Nivolumab Alone After Nivolumab Plus Ipilimumab in mRCC Patients

Inclusion Criteria:

1. Histologically or cytologically confirmed advanced RCC with predominantly clear-cellsubtype and candidate to receive nivolumab after nivolumab plus ipilimumab inductionas per standard clinical practice.
2. Completion of the induction of nivolumab and ipilimumab without toxicity ≥ G2 and nocomplete response or progressive disease.
3. Male or female subjects aged ≥ 18 years
4. Available tumor tissue sample.
5. At least one measurable lesion as defined by Response Evaluation Criteria In SolidTumors (RECIST) version 1.1.
6. Eastern Cooperative Oncology Group performance status 0 or 1.
7. Adequate organ and bone marrow function based upon meeting all of the followinglaboratory criteria within 10 days before the start of treatment:
8. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L)
9. Platelets ≥ 100,000/mm3 (≥ 100 GI/L).
10. Haemoglobin ≥ 9 g/dL (≥ 90 g/L).
11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upperlimit of normal.
12. Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert'sdisease ≤ 3 mg/dL (≤ 51.3 µmol/L).
13. Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockroft-Gault.
14. Capable of understanding and complying with the protocol requirements and must havesigned the informed consent document.
15. Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 5 months after the last dose of study treatment.
16. Female subjects of childbearing potential must not be pregnant at screening. Femalesof childbearing potential are defined as premenopausal females capable of becomingpregnant (i.e., females who have had any evidence of menses in the past 12 months,with the exception of those who had prior hysterectomy). However, women who have beenamenorrhoeic for 12 or more months are still considered to be of childbearingpotential if the amenorrhea is possibly due to prior chemotherapy, antioestrogens, lowbody weight, ovarian suppression or other reasons.

Exclusion Criteria:

1. Prior treatment with systemic therapy for advanced RCC with the exclusion of theinduction of nivolumab and ipilimumab.
2. Prior adjuvant or neoadjuvant therapy
3. Active seizure disorder or evidence of brain metastases, spinal cord compression, orcarcinomatous meningitis
4. Diagnosis of any non-RCC malignancy occurring within 2 years prior to the date of thestart of treatment except for adequately treated basal cell or squamous cell skincancer, or carcinoma in situ of the breast or of the cervix or low-grade prostatecancer with no plans for treatment intervention.
5. Radiation therapy for bone metastasis within 2 weeks, any other external radiationtherapy within 4 weeks before the start of treatment. Systemic treatment withradionuclides within 6 weeks before the start of treatment. Subjects with clinicallyrelevant ongoing complications from prior radiation therapy are not eligible.
6. Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 3 monthsbefore the start of treatment. Eligible subjects must be neurologically asymptomaticand without corticosteroid treatment at the time of the start of treatment.
7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (e.g.,warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g.,clopidogrel).
8. In past 6 months: myocardial infarction, uncontrolled angina, coronary/peripheralartery bypass graft, symptomatic congestive heart failure, cerebrovascular accident,or transient ischemic attack.
9. Chronic treatment with corticosteroids or other immunosuppressive agents (with theexception of inhaled or topical corticosteroids or corticosteroids with a daily dosageequivalent ≤ 10 mg prednisone if given for disorders other than renal cell cancer).Subjects with brain metastases requiring systemic corticosteroid are not eligible.
10. The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions: I. Cardiovascular disorders:
11. Symptomatic congestive heart failure, unstable angina pectoris, serious cardiacarrhythmias.
12. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100mm Hg diastolic despite optimal antihypertensive treatment.
13. Stroke (including TIA), myocardial infarction, or other ischemic event, orthromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6months before the start of treatment. II. Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation:
14. Tumors invading the GI-tract, active peptic ulcer disease, inflammatory boweldisease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,acute pancreatitis or acute obstruction of the pancreatic or biliary duct, orgastric outlet obstruction.
15. Abdominal fistula, gastrointestinal perforation, bowel obstruction, orintra-abdominal abscess within 6 months before the start of treatment. Note:Complete healing of an intra-abdominal abscess must be confirmed before the startof treatment. III. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonaryhemorrhage) within 3 months before the start of treatment. IV. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. V. Lesions invading major pulmonary blood vessels. VI. Other clinically significant disorders such as:
16. Active infection requiring systemic treatment, infection with humanimmunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or chronic hepatitis B or C infection.
17. Serious non-healing wound/ulcer/bone fracture.
18. Malabsorption syndrome.
19. Uncompensated/symptomatic hypothyroidism.
20. Moderate to severe hepatic impairment (Child-Pugh B or C).
21. Requirement for hemodialysis or peritoneal dialysis.
22. History of solid organ transplantation.
23. In past 6 months: deep vein thrombosis or pulmonary embolism.
24. History of aneurysms and/or artery dissections
25. Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 3months before the start of treatment. Complete wound healing from major surgery musthave occurred 1 month before the start of treatment and from minor surgery (e.g.,simple excision, tooth extraction) at least 10 days before the start of treatment.Subjects with clinically relevant ongoing complications from prior surgery are noteligible.
26. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec within 1month before the start of treatment (see Section 5.5.4 for Fridericia formula). ThreeECGs must be performed. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.
27. Vaccination within 4 weeks of the first dose of nivolumab and while on trials isprohibited except for administration of inactivated vaccines.
28. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatoryagent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroiddiseases not requiring immunosuppressive treatment are eligible.
29. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,inhaled, topical steroids, or local steroid injection (e.g., intra-articularinjection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisoneor equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CTscan premedication).
30. Has a history of substance abuse or medical, psychological, or social conditions thatmay interfere with the patient's participation in the study or evaluation of the studyresults.
31. Has illness or medical conditions that are unstable or could jeopardize the safety ofthe patient and his or her compliance in the study.
32. Pregnant or lactating females.
33. Inability to swallow tablets or capsules.
34. Previously identified allergy or hypersensitivity to components of the study treatmentformulations.
35. Rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption.