This is an open label single arm, multicenter, phase II study designet To assess the progression free survival (PFS) of cabozantinib in patients pretreated with one immunocheckpoint inhibitor (CPI) in monotherapy or in combination

Inclusion Criteria:

1. Signed written informed consent

2. One previous anticancer treatment with a PD1/PDL1 inhibitor, as monotherapy or in combination with an angiogenesis inhibitor or anti CTLA 4, in both setting first line or adjuvant ( in this case patient having recurrence during the adjuvant treatment or within 6 months after therapy with PD1-PD-L1 therapy)

3. Age ≥18 years

4. Patients with histological diagnosis of predominant clear cells renal cell carcinoma

5. Measurable disease (as per RECIST 1.1 criteria) with documented radiological progression

6. Fertile women (<2 years after last menstruation) and men of childbearing potential must use effective methods of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgical sterilisation) during the study and for 4 months after the last dose of study treatment

7. All sites of disease including brain metastases (non symptomatic)

8. Karnofsky performance status ≥ 70%

9. Life expectancy greater than 3 months

10. The required values at baseline are as follows:

    • Absolute neutrophil count >1.5 x 109 /L,
    • Platelet count > 100 x 109 /L,
    • Haemoglobin > 9g/dl,
    • Total bilirubin < 1.5 upper limit of normal (ULN);
    • AST, ALT<2.5 ULN in patients without liver metastases, <5 ULN in patients with liver metastases;
    • serum creatinine < 2.0 mg/dl, amylase and lipase <1.5 ULN 11- Female subjects of childbearing potential must not be pregnant at screening

Exclusion Criteria:

1. Major surgical procedure within 28 days prior to study treatment start
2. Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix, meningiomas)
3. Clinically significant cardiovascular disease, for example cerebrovascular accidents (<6 months), myocardial infarction (<6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure or serious cardiac arrhythmia requiring medication
4. Recent (within the 30 days prior to randomisation) treatment with another investigational drug or participation in another investigational study
5. Symptomatic brain metastasis
6. History of other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding giving reasonable suspicion of a disease condition that contraindicates use of an investigational drug or patient at high risk from treatment complications
7. PT or INR and PTT >1.5 times the Upper Normal Limit of the institution (patient who are being therapeutically anticoagulated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists).For patients on warfarin, close monitoring of at least weekly evaluations will be performed, until INR is stable based on a measurement at pre-dose, as defined by the local standard of care
8. Previous or concomitant radiotherapy in the lesion parameter of disease
9. Previous radiotherapy or other locoregional antitumoral treatment performed within 21 days before the study recruitment
10. Uncontrolled hypertension (>= 160 mmHg systolic and/or 90 mmHg diastolic) while receiving chronic medication
11. Inability to swallow tablets or capsules
12. Female subject who is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women
13. Known history of human immunodeficiency virus (HIV) infection, active hepatitis B, or active hepatitis C.
14. Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption