Phase 2 Study to Evaluate the Efficacy of Regorafenib in Specific GIST Mutation Subsets (KIT Exon 17, 18, or 14 Mutation and SDHB Deficient GIST) in the Post-imatinib Second-line Setting.

Eligibility Criteria

• * Age ≥18 years.
• * Histologic diagnosis of GIST with presence of KIT exon 17, 18, or 14 mutation, or SDHB deficiency on tumor biopsy and/ or liquid biopsy.
• * Participants must have unresectable or metastatic GIST and radiologic progression on imatinib treatment. Imatinib treatment must have been discontinued at least 5 days prior to the first dose of study drug. All imatinib treatment will be counted as 1 line of therapy.
• * ECOG performance status ≤2 (Karnofsky ≥60%) at screening.
• * Life expectancy of at least 12 weeks (3 months).
• * Subjects must be able to understand and be willing to sign the written informed consent form. A signed informed consent form must be appropriately obtained prior to the conduct of any trialspecific procedure.
• * Patients must have adequate organ and marrow function as definedbelow:
• * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least
• * Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the ICF until at least 2 months after the last dose of study drug.
• * Patients who had received treatment with TKI other than imatinib
• * Uncontrolled hypertension (systolic pressure \>140 mm Hg or diastolic pressure \> 90 mm Hg \[NCI-CTCAE v4.0\] on repeated measurement) despite optimal medical management.
• * Active or clinically significant cardiac disease including:
• * Congestive heart failure - New York Heart Association (NYHA) \> Class II.
• * Active coronary artery disease.
• * Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.
• * Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction within 6 months before randomization.
• * Evidence or history of bleeding diathesis or coagulopathy.
• * Any hemorrhage or bleeding event ≥ NCI CTCAE v 5.0 Grade 3 within 4 weeks prior to start of study medication.
• * Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of informed consent.
• * Patients with any previously untreated or concurrent cancer that is distinct in primary site or histology except cervical cancer in-situ, treated ductal carcinoma in situ of the breast, curatively treated nonmelanoma skin carcinoma, noninvasive aerodigestive neoplasms, or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before registration are allowed. All cancer treatments must be completed at least 3 years prior to registration.
• * Patients with pheochromocytoma.
• * Patients with evidence of chronic hepatitis B virus (HBV) infection (except HBV viral load is undetectable on suppressive therapy)
• * Patients with a history of hepatitis C virus (HCV) infection (Except the patients have been treated and cured or are currently on treatment with an undetectable HCV viral load)
• * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• * Ongoing infection \> Grade 2 NCI-CTCAE v5.0.
• * Symptomatic metastatic brain or meningeal tumors.
• * Presence of a non-healing wound, non-healing ulcer, or bone fracture.
• * Major surgical procedure or significant traumatic injury within 28 days before start of study medication (minor surgical procedures such as central venous catheter placement, tumour needle biopsy, and feeding tube placement are not considered major surgical procedures).
• * Renal failure requiring hemo-or peritoneal dialysis.
• * Dehydration Grade \>1 NCI-CTCAE v5.0.
• * Patients with seizure disorder requiring medication.
• * Persistent proteinuria Grade 3 NCI-CTCAE v5.0 (\> 3.5 g/24 hrs, measured by urine protein: creatinine ratio on a random urine sample).
• * Interstitial lung disease with ongoing signs and symptoms at the time of informed consent.
• * Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 5.0 Grade 2 dyspnea).
• * History of organ allograft (including corneal transplant).
• * Any malabsorption condition.
• * Women who are pregnant or breast-feeding.
• * Any condition which, in the investigator's opinion, makes the subject unsuitable for trial participation.
• * Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
• * Pregnant women, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test obtained within 7 days before treatment consistent with pregnancy, are excluded from this study because regorafenib has evidence of the potential for teratogenic or abortifacient effects in animal studies. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with regorafenib, breastfeeding should be discontinued if the mother is treated with regorafenib. Females of non-childbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do not require a serum β-hCG test.