Investigating Cabozantinib in Patients With Refractory Metastatic Colorectal Cancer

Inclusion Criteria

• 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.
• Measurable disease per RECIST 1.1 as determined by the investigator.
• 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.
• The subject is ≥ 18 years old on the day of consent.
• The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 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.
• Adequate archival frozen or fixed tissue available from primary or metastatic site for genotypic analysis (at least 15 unstained slides and/or tumor block).
• The subject has organ and marrow function and laboratory values as follows within 7 days before the first dose of cabozantinib:
• ANC ≥ 1500/mm3 without colony stimulating factor support;
• Platelets ≥ 100,000/mm3;
• Hemoglobin ≥ 9 g/dL;
• Bilirubin ≤ 1.5 x ULN. For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL;
• Serum albumin ≥ 2.8 g/dl;
• 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;
• ALT and AST ≤ 3.0 x ULN;
• Lipase 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;

• 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;
• 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.

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