This study seeks to use Cabozantinib to treat those with Metastatic Colorectal Cancer who have not previously responded to treatment.

This is a phase II clinical trial that seeks to use Cabozantinib to treat those with Metastatic Colorectal Cancer who have not previously responded to treatment. This study is a two stage study that will first measure (up to) 16 patients' progression free survival (PFS). Stage two will, again, measure PFS, but in a population (up to) 28 patients.

Inclusion Criteria:

1. The subject has a histologic or cytologic diagnosis of colorectal adenocarcinoma that is metastatic or unresectable and is refractory to or progressed (or relapsed) following a fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab; prior epidermal growth factor inhibitor therapy is required for patients with left-sided, RAS wild-type tumors; prior FDA-approved PD-1 inhibitor therapy is required for patients with MSI-H colorectal cancer. Prior regorafenib or TAS-102 treatment is not required.

2. Measurable disease per RECIST 1.1 as determined by the investigator.

3. The subject has had an assessment of all known disease sites e.g., by computerized tomography (CT) scan and/or magnetic resonance imaging (MRI) within 28 days before the first dose of cabozantinib.

4. The subject is ≥ 18 years old on the day of consent.

5. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

6. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.

7. Adequate archival frozen or fixed tissue available from primary or metastatic site for genotypic analysis (at least 15 unstained slides and/or tumor block).

8. The subject has organ and marrow function and laboratory values as follows within 7 days before the first dose of cabozantinib:

   1. ANC ≥ 1500/mm3 without colony stimulating factor support;

   2. Platelets ≥ 100,000/mm3;

   3. Hemoglobin ≥ 9 g/dL;

   4. Bilirubin ≤ 1.5 x ULN. For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL;

   5. Serum albumin ≥ 2.8 g/dl;

   6. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used:

      • Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72);
      • Female: Multiply above result by 0.85;

   7. ALT and AST ≤ 3.0 x ULN;

   8. Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis;

   9. UPCR ≤ 1;

   10. Serum phosphorus, calcium, magnesium and potassium ≥ LLN.

9. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.

10. Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control or practice abstinence during the study and for 4 months after the last dose of study drug(s).

Exclusion Criteria:

1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment;

2. Prior treatment with cabozantinib;

3. Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before the first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible;

4. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before the first dose of study treatment. Note: Subjects with prostate cancer currently receiving LHRH or GnRH agonists may be maintained on these agents;

5. The subject has received any other type of investigational agent within 28 days before the first dose of study treatment;

6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of the start of study treatment;

7. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment;

8. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, 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 randomization, and who have had no complications from a thromboembolic event or the anticoagulation regimen. ;

9. The subject has experienced any of the following:

   1. clinically-significant GI bleeding within 6 months before the first dose of study treatment;
   2. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose of study treatment;
   3. any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.

10. The subject has radiographic evidence of cavitating pulmonary lesion(s);

11. The subject has tumor invading or encasing any major blood vessels;

12. The subject has evidence of clinically significant bleeding from tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib;

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

    a. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening; ii. Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment; iii. Any history of congenital long QT syndrome; iv. Any of the following within 6 months before the first dose of study treatment:

    • unstable angina pectoris;

    • clinically-significant cardiac arrhythmias;

    • stroke (including transient ischemic attack (TIA), or other ischemic event);

    • myocardial infarction;

    • thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (eg, vena cava filter) are not eligible for this study).

      b. GI disorders particularly those associated with a high risk of perforation or fistula formation including: i. Active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization, Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization c. Other clinically significant disorders that would preclude safe study participation;

14. Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. Minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible;

15. QTcF > 500 msec within 1 month before the first dose of study treatment:

    a. Three ECGs must be performed for eligibility determination. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.

16. Pregnant or lactating females;

17. Inability to swallow intact tablets;

18. Previously identified allergy or hypersensitivity to components of the study treatment formulations;

19. Diagnosis of another malignancy within 2 years before the first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy;