Investigating Cabozantinib in Patients With Refractory Metastatic Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Oral Tablet: Cabozantinib
Intervention description: Patients will take 60mg cabozantinib, by mouth, once daily, every day for 12 weeks. This medication should be taken on an empty stomach. Patients should not eat 2 hours before or 1 hour after taking cabozantinib. Only water is permitted during this 3 hour time frame.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 44.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Cabozantinib; Progression Free Survival; Metastatic Colorectal Cancer; Tumor

Summary:

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

Eligibility criteria:

        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;