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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the safety of regorafenib, an antiangiogenic drug, when combined with radioembolization using SIR-Spheres® microspheres in the treatment of colorectal cancer (CRC) that has spread to the liver.

Detailed Description
-----------------
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).

Official Title
-----------------
A Two Arm Safety Study of Regorafenib Before or After SIR-Spheres Microspheres (90Y) for the Treatment of Patients With Refractory Metastatic Colorectal Cancer With Liver Metastases

Conditions
-----------------
Colorectal Neoplasms

Intervention / Treatment
-----------------
* Device: SIR-Spheres
* Drug: Regorafenib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed metastatic adenocarcinoma of the colon or rectum. Patients who have been previously treated with or are not candidates for fluorouracil, oxaliplatin, irinotecan, and if Kras wild-type, anti EGFR therapy. Considered an appropriate candidate for regorafenib therapy. Measurable disease or evaluable disease as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 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. ECOG Performance Status score of 0-1. Adequate hematologic, renal and liver function. 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. Life expectancy ≥ 3 months. Ability to understand the nature of this study and give written informed consent Exclusion Criteria: Most recent chemotherapy ≤14 days and ≥Grade 1 chemotherapy-related side effects, with the exception of alopecia. 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. 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. Previous radiation delivered to the upper abdomen. Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement. 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. Leptomeningeal metastases or spinal cord compression due to disease. Pregnant or lactating. Evidence of ascites, cirrhosis, portal hypertension, or thrombosis as determined by clinical or radiologic assessment. History of abdominal fistula or gastrointestinal perforation ≤6 months prior to beginning study treatment. Serious non-healing wound, active ulcer, or untreated bone fracture. 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). 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 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). 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. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C. 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. Use of strong CYP34A inducers or inhibitors. 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. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol. Inability or unwillingness to comply with study and/or follow-up procedures outlined in the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Regorafenib/SIR-Spheres/Regorafenib<br>Regorafenib (one cycle) followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres. Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres will then be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. Treatment with regorafenib will be re-started 2-4 weeks after SIR-Spheres administration. | Device: SIR-Spheres<br>* Radioembolization will be administered once by injection through a trans-femoral catheter into the hepatic artery.<br>* Other names: 90Y-Microspheres;Drug: Regorafenib<br>* All patients will take regorafenib 160mg orally once daily on Days 1-21 of each 28-day cycle.<br>* Other names: Stivarga;|
| Experimental: Cohort 2: SIR-Spheres/Regorafenib<br>SIR-Spheres followed by regorafenib to start 2-4 weeks after SIR-Spheres. SIR-Spheres microspheres will be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. After SIR-Spheres microspheres have been administered, the treatment with regorafenib will be initiated 2-4 weeks after administration of SIR-Spheres. Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle. | Device: SIR-Spheres<br>* Radioembolization will be administered once by injection through a trans-femoral catheter into the hepatic artery.<br>* Other names: 90Y-Microspheres;Drug: Regorafenib<br>* All patients will take regorafenib 160mg orally once daily on Days 1-21 of each 28-day cycle.<br>* Other names: Stivarga;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Treatment-Related Adverse Events and Serious Adverse Events as a Measure of Safety | A treatment-related adverse event or serious adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events and serious adverse events will be assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) V4.03. | up to 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With an Objective Response (CR or PR) | Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST v 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease in of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. | At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months | 
| Median Progression-Free Survival | Defined as the time (in months) from date of randomization to the date of first observation of progression based on radiological assessment by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or date of death from any cause, in the absence of progressive disease (PD) or censored at the date of last adequate tumor assessment. Progressive Disease is defined by RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum while on study (this includes the baseline sum if that is the smallest on study), or the appearance of one or more new lesions. | At 6 and 12 weeks after SIR-Spheres, and every 8 weeks thereafter, up to 18 months. | 
| Median Overall Survival | Defined as the time (in months) from date of randomization to date of death from any cause, or censored at the date last known alive. | up to 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Regorafenib, 90Y, Radioembolization, SIR-Spheres Microspheres, Metastatic Colorectal Cancer, Liver Metastases, SIRT, Refractory