Regorafenib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor

Study Overview
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Brief Summary
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The purpose of this research study is to determine the safety and activity of regorafenib in participants with advanced gastrointestinal stromal tumor (GIST) if the standard approved therapies, imatinib and sunitinib, have failed to control the disease. Regorafenib is a drug that blocks abnormally active signaling enzymes called tyrosine kinases which are important to the growth of GIST. This tyrosine kinase inhibition is similar to the way that both imatinib and sunitinib work; however, regorafenib blocks certain additional signaling pathways that are not blocked by imatinib or sunitinib. Regorafenib has been not been tested in GIST participants before this research study.

Detailed Description
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In this research study, each planned cycle of the study lasts 4 weeks. In the first cycle, participants will come to the clinic on Days 1, 15 and 16. For cycles 2 through 4, they will come to the clinic on Days 1 and 15 of each cycle. For cycle 5 and beyond, they will come to the clinic on Day 1 of each cycle. Repeat tumor imaging will be performed at the end of every 2 cycles during study drug administration (e.g. end of cycles 2, 4, 6, etc.) During each cycle, participants will take regorafenib by mouth, once a day in the morning, for 3 weeks followed by one week during which you do not take regorafenib (the rest period). FDG-PET/CT (Positron Emission Tomography) scans are required as part of this study to monitor effects of the study drug on the participant's GIST. The first scan will take place before the first dose of study drug. If the first scan shows that the tracer sugar collection is increased in the participant's GIST, they will have up to 5 additional scans performed at different time points throughout their participation in this research study. Participants may continue to participate in this research study for as long as they do not have serious side effects or their disease does not get worse.

Official Title
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A Multi-center Phase II Study Evaluating the Efficacy and Safety of Regorafenib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST), Resistent or Intolerant to at Least Imatinib and Sunitinib

Conditions
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Gastrointestinal Stromal Tumor

Intervention / Treatment
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* Drug: regorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age at the time of study entry Histologically confirmed metastatic and/or unresectable GIST with prior failure of both conventional tyrosine kinase inhibitors, imatinib and sunitinib. Measurable disease per RECIST 1.1. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion. ECOG Performance Status 0 or 1 Adequate organ and marrow function as outlined in the protocol Fully recovered from the acute effects of prior cancer therapy before initiation of study drug Patients must be suitable for oral drug administration Willingness to use effective means of birth control throughout the duration of clinical study and for at least 3 months after completion of study drug Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of study drug administration Exclusion Criteria: Use of any unapproved tyrosine kinase inhibitors or investigational agents within 2 weeks or 6 half-lives of the agent, whichever is shorter, prior to receiving study drug Participants who have had radiotherapy within 4 weeks prior to study entry Major surgery, or significant traumatic injury within 4 weeks prior to study entry Presence of symptomatic or uncontrolled brain or central nervous system metastases Prior exposure to sorafenib Prior exposure to regorafenib Known or suspected allergy to the investigational agent or any agent given in association with this trial Individuals with a history of a different malignancy, other than cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, are ineligible, except if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy or other primary malignancy is neither currently clinically significant nor requiring active intervention Clinically significant cardiac arrhythmias and/or patients who require anti-arrhythmic therapy (excluding beta blockers or digoxin) History of clinically significant cardiac disease or congestive heart failure > NYHA class 2. Patients must not have unstable angina or new-onset angina within the last 3 months or myocardial infarction within the past 6 months Hypertension as defined by systolic blood pressure 140-159 mmHg or diastolic blood pressure 90-99 mmHg; recurrent or persistent or symptomatic increase by > 20 mmHg (diastolic) or to systolic blood pressure greater than 140 mmHg or diastolic blood pressure greater than 90 mmHg if previously within normal limits, despite optimal medical management Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication Ongoing infection of Grade 3 or higher Patients with evidence of, or history of, bleeding diathesis. Any major hemorrhage or bleeding event of Grade 3 or higher within 4 weeks of start of study medication Non-healing wound, ulcer or bone fracture Renal failure requiring hemo-or peritoneal dialysis Dehydration of Grade 2 or greater Persistent proteinuria Grade 3 or higher Known history of HIV infection or chronic hepatitis B or C Uncontrolled intercurrent illness Pregnant or lactating females

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regorafenib<br>Regorafenib adminstered orally, 160 mg per day on days 1 through 21 of a 28 day cycle | Drug: regorafenib<br>* Taken orally, once a day in the morning for 3 weeks followed by a one week rest period<br>* Other names: Stivarga;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit as Defined by the Composite of Complete Response, Partial Response and Stable Disease Lasting 16 Weeks or More Per RECIST 1.1 as a Measure of Disease Control | The composite of complete response, partial response, and stable disease lasting 16 weeks or more per RECIST 1.1 as a measure of disease control. This is for target lesions. Complete response is disappearance of all target lesions and partial response is >+30% decrease in the sum of the longest diameter of target lesions. Stable disease is neither shrinkage by greater than or equal to 30% of the sum of the longest diameter of target lesions or the increase of lesions by greater than or equal to 20% of the sum of the longest diameter of target lesions. Progressive disease is considered an increase of the sum of the longest diameter of target lesions by greater than or equal to 20%. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival is defined as the duration of time from start of study drug administration to time of objective disease progression or death due to any cause, whichever comes first. Progression is evaluated every 8 weeks using Response Criteria for Solid Tumors (RECIST) 1.1. Objective disease progression is defined as a 20% increase in the sum of the longest diameter of target lesion(s). | From date of enrollment until date of first documented progression or date of death from any cause, whichever came first | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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regorafenib, GIST