Safety Study of Regorafenib and SIR-Spheres® Microspheres Radioembolization in Patients With Refractory Metastatic Colorectal Cancer With Liver Metastases

Recent targeted therapies and treatment strategies have shown promise in colorectal cancer;
however, elimination of disease remains a challenge once spread to the liver.
Radioembolization using SIR-Spheres® microspheres (SIR-Spheres) to treat liver-only or
liver-dominant metastatic colorectal cancer (mCRC) has been successful in this refractory
setting. In this open-label study we will compare the safety of two treatment cohorts in
which radioembolization will be administered using the device SIR-Spheres microspheres (90Y
resin microspheres) in combination with regorafenib to patients with mCRC with liver
metastases. The two treatment cohorts will be evaluated for safety, overall response (OR),
progression-free survival (PFS), and overall survival (OS).

Inclusion Criteria:

1. Histologically confirmed metastatic adenocarcinoma of the colon or rectum.

2. Patients who have been previously treated with or are not candidates for fluorouracil,
oxaliplatin, irinotecan, and if Kras wild-type, anti EGFR therapy.

3. Considered an appropriate candidate for regorafenib therapy.

4. Measurable disease or evaluable disease as measured by Response Evaluation Criteria in
Solid Tumors (RECIST) version 1.1.

5. Measurable computed tomography (CT) scan evidence of liver metastases which are not
treatable by surgical resection or local ablation with curative intent at the time of
study entry.

6. ECOG Performance Status score of 0-1.

7. Adequate hematologic, renal and liver function.

8. Male patients with female partners of childbearing potential and women female patients
of childbearing potential are required to use two forms of acceptable contraception,
including one barrier method, during their participation in the study and for 30 days
following last dose.

9. Life expectancy ≥ 3 months.

10. Ability to understand the nature of this study and give written informed consent

Exclusion Criteria:

1. Most recent chemotherapy ≤14 days and ≥Grade 1 chemotherapy-related side effects, with
the exception of alopecia.

2. Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to
initiation of study treatment. For study drugs for which 5 half-lives is ≤21 days, a
minimum of 10 days between termination of the study drug and administration of study
treatment is required.

3. Wide field radiotherapy (including therapeutic radioisotopes such as strontium-89
administered ≤28 days or limited field radiation for palliation ≤7 days prior to
starting study drug or has not recovered from side effects of such therapy.

4. Previous radiation delivered to the upper abdomen.

5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical
procedures ≤7 days. No waiting required following port-a-cath placement.

6. Previously untreated brain metastases. Patients who have received radiation or surgery
for brain metastases are eligible if therapy was completed at least 2 weeks previously
and there is no evidence of central nervous system disease progression, mild
neurologic symptoms, and no requirement for chronic corticosteroid therapy.

7. Leptomeningeal metastases or spinal cord compression due to disease.

8. Pregnant or lactating.

9. Evidence of ascites, cirrhosis, portal hypertension, or thrombosis as determined by
clinical or radiologic assessment.

10. History of abdominal fistula or gastrointestinal perforation ≤6 months prior to
beginning study treatment.

11. Serious non-healing wound, active ulcer, or untreated bone fracture.

12. Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption, distribution, metabolism, or excretion of oral
therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2,
and malabsorption syndrome).

13. Any of the following cardiac diseases currently or within the last 6 months:

- Unstable angina pectoris

- Congestive heart failure (NYHA ≥ Grade 2)

- Conduction abnormality not controlled with pacemaker or medication

- Significant ventricular or supraventricular arrhythmias (patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities
are eligible)

- Valvular disease with significant compromise in cardiac function

14. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] >180 mmHg or
diastolic blood pressure (DBP) >100 mmHg) (patients with values above these levels
must have their blood pressure (BP) controlled with medication prior to starting
treatment).

15. Serious active infection at the time of treatment, or another serious underlying
medical condition that would impair the ability of the patient to receive protocol
treatment.

16. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C.

17. Presence of other active cancers, or history of treatment for invasive cancer ≤5
years. Patients with Stage I cancer who have received definitive local treatment and
are considered unlikely to recur are eligible. All patients with previously treated in
situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of
non-melanoma skin cancer.

18. Use of strong CYP34A inducers or inhibitors.

19. The herbal medications St. John's wort, kava, ephedra (ma huang), gingko biloba,
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng will not be allowed
during study treatment. Patients should stop using these herbal medications 7 days
prior to first dose of study drug.

20. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.

21. Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol.