Sunitinib and Regorafenib for the Treatment of Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors and KIT Gene Mutations

Inclusion Criteria

• Patients who are >= 18 years of age
• Patients who have histologically confirmed metastatic or unresectable GIST. Unresectable GIST must be confirmed to be unresectable by an experienced surgeon
• Patients may have had any prior lines of tyrosine kinase inhibitor (TKI) therapy
• Patients who received imatinib prior treatment regimens, including adjuvant therapy, with objective disease progression, inadequate clinical benefit, or intolerance. Additionally, disease progression or intolerance to other systemic therapies including investigational agents and radiotherapy is allowed. Patients who experienced intolerance to prior therapies must have objective disease progression prior to enrollment
• Patients who have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2
• Patient, or legal guardian if permitted by local regulatory authorities, who provides informed consent to participate in the study
• Presence of KIT exon 13 or 17 secondary mutation will be determined through a circulating tumor DNA (ctDNA) blood test or biopsy performed as per standard of care

Exclusion Criteria

• Patients who are known to be KIT wild type
• Patients who received any systemic anticancer therapy within 2 weeks before. Prior radiotherapy to major organs within 2 weeks of admission, or focal radiotherapy, such as to bones, limbs, or other areas not involving major organs, within 3 days
• Patients who have clinically significant, uncontrolled, cardiovascular disease, including congestive heart failure grades II, III or IV according to the New York Heart Association classification, myocardial infarction or unstable angina within the previous 6 months, or uncontrolled hypertension
• Patients who have experienced arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before randomization or venous thrombotic events such as deep vein thrombosis within the 3 months before screening
• Patients who have experienced any hemorrhage or bleeding event National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3 or higher within 4 weeks before screening
• Patients who have a known risk of intracranial bleeding, such as a brain aneurysm or history of intracranial bleeding within 1 year prior to screening
• Patients who have a non-healing wound, ulcer, or bone fracture
• Persistent proteinuria of NCI-CTCAE version 4.03 grade 3 or higher
• Alanine aminotransferase and aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if hepatic metastases are present
• Total bilirubin >1.5 × ULN; and in presence of Gilbert’s syndrome, total bilirubin > 3 × ULN or direct bilirubin > 1.5 × ULN
• Estimated (Cockcroft-Gault formula) or measured creatinine clearance < 40 mL/min
• Platelet count < 90 × 10^9/L
• Absolute neutrophil count (ANC) < 1.0 × 10^9/L
• Hemoglobin < 9 g/dL. Transfusion and erythropoietin may be used to reach at least 9 g/dL, but must have been administered at least 2 weeks before screening
• Patients who have received neutrophil growth factor support within 14 days of screening
• Patients who require therapy with a concomitant medication that is a strong inhibitor or strong inducer of CYP3A4
• Patients who have had a major surgical procedure (minor surgical procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures) within 14 days of screening. Patient has significant traumatic injury within 28 days before screening
• Patients who have a history of another primary malignancy that has been diagnosed or required therapy within 2 years before screening. (The following are exempt from the 2-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.)
• Patients who have a history of a seizure disorder requiring anti-seizure medication
• Patients who have metastases to the brain
• Patients who are unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions
• Patients who have a QT interval corrected using Fridericia's formula (QTcF) of > 450 msec
• Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of randomization and for at least 30 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of randomization and for at least 90 days after the last dose of study drug
• Women who are pregnant, as documented by a serum beta human chorionic gonadotropin (beta-hCG) pregnancy test consistent with pregnancy, obtained within 7 days before the treatment assignment. Females with beta-hCG values that are within the range for pregnancy but are not pregnant (false positives) may be enrolled with written consent of the investigator, after pregnancy has been ruled out. Females of non-childbearing potential (postmenopausal for more than 1 year; bilateral tubal ligation; bilateral oophorectomy; hysterectomy) do not require a serum beta-hCG test
• Women who are breastfeeding
• Patients who have prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results
• Patients with impaired decision-making capacity