caBozantinib in Pre-treated pAtients With Metastatic COlorectal Cancer.

Inclusion Criteria:

Histologically proven diagnosis of colorectal adenocarcinoma. 2. Male or female patients ≥ 18 years of age. 3. Diagnosis of metastatic disease. 4. Known RAS status (NRAS and KRAS exon 2,3 and 4) per local laboratory assessment.

5\. Patients should have received at least two standard lines of treatment including all the following: fluoropyrimidines, irinotecan, oxaliplatin, anti-angiogenic drugs (eg. bevacizumab and or aflibercept) and, in case of patients harbouring RAS WT tumours, anti-Epidermal Growth Factor receptors monoclonal antibodies (cetuximab or panitumumab). Note: Prior treatment with trifluridine-tipiracil is allowed.

6\. Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.

7\. Measurable disease according to RECIST criteria v1.1. 8. ECOG Performance Status 0-1. 9. Life expectancy of at least 3 months. 10. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 10 days before study entry:

* Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L).
* Platelets ≥ 100,000/mm3 (≥ 100 GI/L).
* Hemoglobin ≥ 9 g/dL.
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3.0 × upper limit of normal.
* Total bilirubin ≤ 1.5 × the upper limit of normal. For subjects with Gilbert's disease ≤ 3 mg/dL.
* Fasting serum triglycerides ≤ 2.5 × upper limit of normal and total cholesterol ≤ 300 mg/dL.

Note: Lipid-lowering medication is allowed.

* HbA1c ≤ 8%.
* Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockroft-Gault equation.
* 24-hour urine protein \< 1 g. 11. In the investigator judgement, compliance with the protocol requirements and signed informed consent document. 12. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.

  13\. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (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 been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, low body weight, ovarian suppression or other reasons.

Exclusion Criteria:

Prior treatment with cabozantinib. 2. Prior treatment with VEGFR-targeting TKI (e.g. regorafenib). 3. Treatment with any anticancer drug within 4 weeks before study entry. 4. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before study entry. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.

5\. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before study entry. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of study entry.

6\. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (e.g., warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel).

Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (\<1 mg/day), and low dose, low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before study entry, and who have had no complications from a thromboembolic event or the anticoagulation regimen.

7\. Chronic treatment with corticosteroids or other immunosuppressive agents (with the exception of inhaled or topical corticosteroids or corticosteroids with a daily dosage equivalent ≤ 10 mg prednisone). Subjects with brain metastases requiring systemic corticosteroid are not eligible.

8\. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

* Cardiovascular disorders:

  * Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias.
  * Uncontrolled hypertension defined as sustained BP \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment.
  * Stroke (including TIA), myocardial infarction, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before study entry.
* Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:

  * 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.
  * Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before study entry. Note: Complete healing of an intra-abdominal abscess must be confirmed before study entry.
* Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of redblood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 3 months before study entry.
* Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
* Lesions invading major pulmonary blood vessels.
* Other clinically significant disorders such as:

  * Active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)- related illness, or chronic hepatitis B or C infection.
  * Serious non-healing wound/ulcer/bone fracture.
  * Malabsorption syndrome.
  * Uncompensated/symptomatic hypothyroidism.
  * Moderate to severe hepatic impairment (Child-Pugh B or C).
  * Requirement for hemodialysis or peritoneal dialysis.
  * History of solid organ transplantation. 9. Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 3 months before study entry. Complete wound healing from major surgery must have occurred 1 month before study entry and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before study entry. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.

    10\. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 msec within 1 month before study entry.

    11\. Pregnant or lactating females. 12. Inability to swallow tablets. 13.Previously identified allergy or hypersensitivity to components of the study treatment formulation.

    14\. Diagnosis of another malignancy within 2 years before study entry, except for superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic therapy.