Study of Cabozantinib as 2nd Line Treatment in Subjects With Locally Advanced or Metastatic Renal Cell Carcinoma (RCC) With a Clear-Cell Component Who Progressed After 1st Line Treatment With Checkpoint Inhibitors

Exclusion Criteria

• •4. Subjects must have radiographic disease progression, according to Investigator's judgement following 1st line treatment with CPI (ipilimumab plus nivolumab) (Cohort A) or CPI in combination with VEGF-targeted therapy (Cohort B);
• •5. Subjects present ≥1 target lesion according to RECIST 1.1 per Investigator;
• •6. Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1;
• •Subjects will not be included in the study if the subject:
• •1. Inability to swallow tablets;
• •2. Was treated with any other investigational medicinal product (IMP) within the last 30 days before baseline;
• •3. Was previously treated with cabozantinib;
• •4. Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast medium used for Contrast Tomography (CT)-scan;
• •5. Presents untreated brain or leptomeningeal metastases, or current clinical or radiographic progression of known brain metastases;
• •6. Has a diagnosis of a serious cardiovascular disorder:
• •1. Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, or serious cardiac arrhythmias;
• •2. Uncontrolled hypertension, defined as sustained blood pressure (BP) (\>140 mm Hg systolic or \>90 mm Hg diastolic pressure) despite optimal antihypertensive treatment;
• •3. Stroke (including transient ischaemic attack (TIA)), myocardial infarction (MI) or other ischaemic event, or thromboembolic event (e.g. deep venous thrombosis, pulmonary embolism) within 6 months before screening;
• •4. History of risk factors for torsades de pointes (e.g., long QT syndrome);
• •7. Is receiving concomitant anticoagulation with coumarin agents (e.g. warfarin), direct thrombin inhibitor dabigatran, Direct Factor Xa inhibitors betrixaban or platelet inhibitors (e.g. clopidogrel); Note: The following are allowed anticoagulants: prophylactic use of low-dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparin (LMWH) are permitted. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in patients without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before baseline without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumour.
• •8. Has a gastrointestinal (GI) disorder including those associated with a high risk of perforation or fistula formation:
• •(a) Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction; b) Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before screening; Note: Complete healing of an intra-abdominal abscess must have been confirmed before screening
• •9. Presents a corrected QT (QTc) interval calculated by the Fridericia formula (QTcF) \> 500 msec within 1 month prior to baseline; Note: If a single ECG shows a QTcF with an absolute value \> 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility
• •10. Presents clinically significant haematuria, hematemesis, or haemoptysis of \>0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g.
• •pulmonary haemorrhage) within 3 months before screening;
• •11. Presents cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
• •12. Presents lesions invading major pulmonary blood vessels;
• •13. Has been diagnosed with other clinically significant disorders such as:
• •1. Serious nonhealing wound/ulcer/bone fracture;
• •2. Malabsorption syndrome;
• •3. Uncompensated/symptomatic hypothyroidism;
• •4. Moderate to severe hepatic impairment (Child-Pugh B or C);
• •5. Requirement for haemodialysis or peritoneal dialysis;
• •6. History of solid organ transplantation;
• •14. Has a predicted life expectancy of less than 3 months;
• •15. Has had prior surgery within 4 weeks prior to baseline. Note: If the subject has undergone major surgery, complete wound healing must have occurred 1 month prior to baseline
• •16. Has had palliative radiation therapy for bone within 2 weeks or for radiation fields including viscera within 4 weeks prior to baseline. Note: Resolution/healing of side effects must be complete prior to baseline;
• •17. Has a history of another active malignancy within 3 years from screening except for locally curable cancers that have been apparently cured, such as low-grade thyroid carcinoma, prostate cancer not requiring treatment (Gleason Grade ≤6), basal or squamous cell skin cancer, superficial bladder cancer, in situ melanoma, in situ prostate, cervix or breast carcinoma or other treated malignancies with \<5% chance of relapse according to the Investigator;
• •18. Has a history of allergy to study treatment components or agents with a similar chemical structure or any excipient used in the formulation as listed in the Summary of Product Characteristics (SmPC) document;
• •19. Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded;
• •20. Has a serious medical or psychiatric condition that renders the subject unable to understand the nature, scope and possible consequences of the study, and/or presents an uncooperative attitude;
• •21. Is pregnant or breastfeeding. A β-human chorionic gonadotrophin (HCG) serum pregnancy test will be performed up to 7 days prior to baseline for all female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and not surgically sterile);
• •22. Is likely to require treatment during the study with drugs that are not permitted by the study protocol;
• •23. Has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the subject's safety