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

Inclusion Criteria

All subjects must fulfil all the following criteria to be included in the study:

• Subjects must provide a signed informed consent prior to any study-related procedures;
• Male or female subjects must be aged ≥18 years on the day the informed consent is signed;
• Subjects must have histologically confirmed unresectable, locally advanced (defined as disease not eligible for curative surgery or radiation therapy) or metastatic RCC with a clear-cell carcinoma component;
• 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);
• Subjects present ≥1 target lesion according to RECIST 1.1 per Investigator;
• Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1;
• Subjects with treated brain metastases are eligible if metastases have been shown to be stable as per Investigator's judgement;
• Subjects must have adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 15 days before baseline:
• Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L).
• Platelets ≥ 100,000/mm3 (≥ 100 GI/L).
• Haemoglobin ≥ 9 g/dL (≥ 90 g/L).
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 140 mm Hg systolic or >90 mm Hg diastolic pressure) despite optimal antihypertensive treatment;
• 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;
• History of risk factors for torsades de pointes (e.g., long QT syndrome);
• 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.
• 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

• 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
• 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;

• Presents cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
• Presents lesions invading major pulmonary blood vessels;
• Has been diagnosed with other clinically significant disorders such as:
• Serious nonhealing